[Frontiers in Bioscience 16, 674-697, January 1, 2011]
Matricryptins derived from collagens and proteoglycans
Sylvie Ricard-Blum, Lionel Ballut
Institut de Biologie et Chimie des Proteines, UMR 5086 CNRS - University Lyon 1, France
TABLE OF CONTENTS
1. ABSTRACT
Controlled proteolysis of extracellular matrix components releases bioactive fragments or unmasks cryptic sites that play key roles in controlling various physio-pathological processes including angiogenesis, tissue remodeling, wound healing, inflammation, tumor growth, and metastasis. We review here the structure and mechanisms of release of i) the proteolytic fragments (matricryptins) cleaved from collagens, proteoglycans and glycosaminoglycans, and ii) the matricryptic sites existing in these molecules. The cell surface receptors and the signaling pathways they trigger to exert their biological activities is discussed with the major physio-pathological processes they control. Their involvement in autoimmune and inherited diseases is reported. Most matricryptins issued from collagens, proteoglycans and glycosaminoglycans exhibit anti-angiogenic and anti-tumor properties and their use as potential drugs and as potential disease markers is discussed. Perspectives for identifying the common structural features, if any, of the matricryptins and their use in combination with chemotherapy and radiotherapy in the treatment of cancer are presented.
2. INTRODUCTION
Controlled proteolysis of extracellular matrix components releases bioactive fragments or unmasks cryptic sites that play key roles in controlling various physio-pathological processes including angiogenesis, wound healing, inflammation, tumor growth and metastasis (1-4). Several matricryptins released from collagens (endostatin, arresten, canstatin, tumstatin, restin, vastatin) and from a proteoglycan (endorepellin) correspond to the C-terminal domain of those molecules (5). Most of them exert their biological activities through signaling pathways mediated by integrins. We will focus in this review on matricryptins or matrikines existing in tissues, in biological fluids or released by cultured cells. We will not discuss synthetic peptides displaying biological activities that are not produced in vivo.
We will first define the terms matricryptins and matricryptic, and we will summarize the mechanisms leading to the release of matricryptins and to the exposure of cryptic sites. Then we will describe the major matricryptins derived from collagens, proteoglycans and glycosaminoglycans and the major patho-physiological processes they regulate, namely angiogenesis, tumor growth and metastasis, tissue remodeling wound healing, and inflammation. We will briefly introduce the autoimmune diseases they are involved in. In the last part of this review, we will discuss the matricryptins as potential drugs, matricryptic sites as therapeutic targets and matricryptins as potential markers of diseases.
3. What are matricryptins and matricryptic sites?
3.1. Definition
The term matricryptin was proposed by Davis et al. (1) for enzymatic fragments of the extracellular matrix containing exposed matricryptic sites. This term refers specifically and is limited to biologically active extracellular matrix fragments that contain a cryptic domain that is not normally exposed in the intact molecule. Matricryptins are derived from molecular domains that are cryptic and enzymatic breakdown is required to expose the new biologically relevant activity. This is the major difference between matricryptins and matrikines that have been defined as peptides liberated by partial proteolysis of extracellular matrix macromolecules, which are able to regulate cell activities (6, 7). Matricryptic sites have been defined by Davis et al. (1) to be biologically active sites that are not exposed in the mature, secreted form of extracellular matrix molecules. They become exposed after structural or conformational alterations of the parent molecules. The appearance of matricryptic sites may provide important new signals to regulate biological processes such as cell migration, proliferation, differentiation, morphogenesis, survival, extracellular matrix assembly, and physio-pathological proccess such as angiogenesis, tumor growth and tissue repair.
3.2. Mechanisms of exposure
Mechanisms regulating the exposure of matricryptic sites within the extracellular matrix molecules include enzymatic breakdown, protein multimerization, adsorption, cell-mediated mechanical forces, and denaturation (1). Reactive oxygen species also expose cryptic epitopes as reported for epitopes associated with the autoimmune Goodpasture syndrome (8). In contrast, sugars may mask cryptic sites as reported for galactose that modulate the interaction of the triple-helical models of the a1(IV) 1263-1277 sequence with melanoma cell CD44 (9). Due to space limitation, this review will focus mostly on matricryptins generated from collagens and proteoglycans by limited proteolysis. Matricryptins derived from fibronectin and laminins will be discussed in other chapters of this volume.
Several matricryptins released by proteolytic cleavage are C-terminal domains of collagens and of a proteoglycan (perlecan) found in the vascular basement membrane zone. They play a role in maintaining basement membrane integrity as shown for endostatin that is co-localized with perlecan in basement membranes (10). Endostatin overexpression specifically in the lens and skin leads to cataract and ultrastructural alterations in basement membrane (11). Endostatin is also a component of elastic fibers in vessel walls (12).
Various matrix metalloproteinases (MMPs) are involved in the release of matricryptins. Tumstatin is cleaved from the a3 chain of collagen IV by MMP-9 (13). Fragments containing endostatin are cleaved from the NC1 domain of collagen XVIII by MMP-7 (14) and MMP-14 also referred to as MT1-MMP but not by MMP-2 or MMP-9 (15). Cathepsins B, L and V (16, 17) and pancreatic elastase (18) are also able to generate endostatin-containing fragments. MMP-2, able to degrade a number of extracellular matrix molecules, appears to act as a main 'decryptase' with MT1-MMP for collagen IV and laminin-332 (19). Hyaluronidase and heparinase that degrade glycosaminoglycans also release matricryptins. A matricryptin can exist under several forms depending on the presence of several cleavage sites in the parent molecule and on the enzyme cleaving the parent molecule. A matricryptin can also be further processed as it has been reported for the C-terminal matricryptin of perlecan, endorepellin, which is cleaved by Bone Morphogenetic Protein-1/Tolloid to generate the terminal laminin-like globular LG3 domain that possesses most of the biological activity on endothelial cells (20). MT-MMP1 cleaves syndecan-1 and this shedding stimulates cell migration (21).
The shedding of membrane proteins is a proteolytic process leading to the release of the extracellular domain of the proteins in the extracellular milieu. The shed ectodomain of membrane collagens XIII, XVII, XXIII, and XXV (22) and of syndecans 1-4 (21, 23) that are released from the membrane by enzymes belonging to the ADAM (a disintegrin and metalloproteinase), the MMP or the furin families might be considered as matricryptins because they exist under a membrane form and a soluble form corresponding to the shed ectodomain that exhibits biological activities regulating cell behavior upon shedding (22-25). They will not be discussed here due to space limitation. In the same way, synthetic peptides, resulting from cyanogen bromide cleavage and peptides not identified in tissue or biological fluids were not included in this review for the same reason.
Most matricryptins have been found in tissue or biological fluids. However more than 120 endogenous peptide inhibitors of endothelial cell proliferation and migration have been identified using a systematic computational methodology based on bioinformatics (26). They include peptides derived from the a4 chain (tetrastatins), the a5 chain (pentastatins) and a6 chain (hexastatins) of collagen IV. The computational bioinformatic analysis was based on the hypothesis that there is an underlying sequence-based correlation between the activity of the known endogenous protein fragments and the predicted peptides (26).
4. Matricryptins from collagens
Cryptic sites are present in the triple helical domains of collagens. In addition, several collagens located in vascular basement membrane (IV, XVIII) or in basement membrane zones (XV, XIX) are cleaved by proteases that release matricryptins with anti-angiogenic and anti-tumor properties (25, 27-29). The most extensively studied matricryptin is endostatin that has been identified in 1997 in Judah Folkman's laboratory (30).
4.1. Matricryptins and cryptic sites of collagen I
Several cryptic sites have been identified in collagen I (Table 1). Partially denatured collagen exposes RGD-motifs that trigger binding of a5b1 and av-integrins, which initiate cellular processes that stimulate osteoblast adhesion, spreading, motility and differentiation (31). 14 cryptic fibronectin binding sites of similar affinity have been identified in bovine collagen I treated with cyanogen bromide (32). Five were located on each of the a1(1) chains and four on the a2(I) chain. However, it should be noted that these cryptic sites were exposed by chemical cleavage and that they might not be exposed in vivo. Peptides of collagen I stimulate respiratory burst, granule exocytosis and cytokine secretion by human leukocytes (polymorphonuclear neutrophils or monocytes) for the detersion of inflammatory sites and then for the chemoattraction of various cell types needed for wound healing (33-35).
4.2. Chondrocalcin, the C-propeptide of collagen II
Chondrocalcin is identical to the C-propeptide of procollagen II, and plays a role in events leading to cartilage calcification (36, 37). It accumulates in calcifying cartilage and fetal bone. It may contribute to the anchorage of matrix vesicles to the extracellular matrix of calcifying cartilage through its binding to anchorin CII, a major component of matrix vesicles (38). Chondrocalcin has been found in serum and in synovial fluid, and is used as a marker of biosynthesis of collagen II in arthritic diseases (e.g. 39). Mutations in the C-Propeptide of procollagen II cause Stickler syndrome (40) and spondyloperipheral dysplasia (41). Specific mutations in the C-propeptide domain are associated with spondyloperipheral dysplasia and platyspondylic lethal skeletal dysplasia Torrance type that constitute a subfamily within the type II collagenopathies, distinct from other type 2 collagenopathies associated with mutations in the triple-helical domain of collagen II (42). Decreased collagen fibrillogenesis and accumulation of unfolded collagen chains inside the chondrocytes could contribute to the specific phenotype of mutations occurring in the C-propeptide (42).
4.3. Matricryptins and cryptic sites of collagen IV
The triple-helical domain of type IV collagen contains cryptic sites (Table 1). A series of monoclonal antibodies that bind to cryptic epitopes of collagen IV and that are differentially exposed during matrix remodeling and are key mediators of angiogenesis have been developed. Two cryptic angiogenesis regulatory epitopes have been identifed by monoclonal antibodies HUI77 and HUIV26. They have been detected within the basement membrane of angiogenic blood vessels and can be exposed by thermal denaturation or proteolytic cleavage. Ionizing radiation modulates the exposure of the HUIV26 cryptic epitope during angiogenesis and this might contribute to the mechanisms of angiogenesis inhibition by radiation (43). Proteolytic cleavage of collagen IV by MMP-9 results in the exposure of a cryptic site hidden within its triple helical structure (44). Exposure of this site is required for angiogenesis and tumor growth in vivo, and is associated with a loss of a1b1 integrin binding and the gain of avb3 binding (45). HU177 cryptic epitope could be exposed following tumor- and vascular smooth muscle cell-mediated proteolysis, ischemic injury and within the extracellular matrix of developing murine papillary membranes during angiogenesis. This second cryptic collagen epitope is present in both collagens IV and I and may be comprised of a peptide that includes the amino acid residues LPGFPG (46). It is selectively exposed within tumor blood vessel extracellular matrix, whereas little was associated with quiescent vessels (46).
Collagen IV is the source of several matricryptins or matrikines located in the C-terminal domains of a(IV) collagen chains (e.g. arresten, canstatin, tumstatin, and the NC1 domain of collagen IV) (see 28, 47-49 for reviews) (Table 2). Tetrastatins, pentastatins, and hexastatins are also part of the NC1 domain of the a4, a5 and a6 chains of collagen IV (26) (Table 2). Tumstatin is generated by MMP-9 (13) and TIMP-1 (Tissue Inhibitor of Metalloproteinases-1) inhibits the production of tumstatin (50). Cathepsin S, a cysteine protease, regulates the levels of canstatin and arresten, but not of tumstatin, by degrading these matricryptins (51). The release of arresten and canstatin is mediated by MT2-MMP in developing tissues (52). Arresten and canstatin have been identified in developing tissues (52). Canstatin has been identified in other tissue extracts and in serum (51, 53), and tumstatin in renal carcinoma (54). An ELISA has been developed to measure tumstatin level in serum samples and tissue extracts (55).
4.4. Vastatin, a matricryptin of collagen VIII
A single study reports that vastatin (Table 2), the NC1 domain of the a1 chain of collagen VIII, inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis (56).
4.5 Restin, a matricryptin of collagen XV
Collagen XV contains a C-terminal fragment released by proteolytic cleavage (57). This 22-kDa fragment is called restin (or endostatin-XV, Table 2) and is highly homologous (61% sequence identity) to the C-terminal domain of collagen XVIII referred to as endostatin (cf. the next paragraph). Both matricryptins are issued from collagens belonging to the same collagen subfamily, the multiplexins (multiple triple helix domains and interruptions) and their overall fold is very similar with two a helices, 16 b strands and two conserved disulfide bridges (58). However restin does not contain a zinc-binding site in contrast to endostatin (58). Restin-containing fragments of different sizes have been detected in tissues by Western blotting (58).
4.6. Matricryptins of collagen XVIII
Endostatin (Table 2) has been identified in 1997 in Judah Folkman's laboratory (30) and has been extensively reviewed (59-64). Endostatin raised high expectations for antiangiogenic therapy of experimental cancer because drug resistance does not develop in the first studies (65). It contains zinc-binding site and although conflicting results have been reported on the role of zinc in anti-angiogenic and anti-tumoral properties of endostatin (reviewed in 62), zinc increases the binding of endostatin to heparan sulfate by approximately 40% as well as its antiproliferative effect on endothelial cells stimulated by fibroblast growth factor-2 (FGF-2) (66). However, endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding (67). Zinc-dependent dimers have been observed in crystals of human endostatin (68). Zn(II)-binding largely stabilizes the structure of endostatin at physiological pH and engineering an extra zinc-binding peptide to the N-terminus of human endostatin makes this molecule more stable and cooperative in the presence of Zn(II) (69).The N-terminal fragment of endostatin also binds copper(II) with very high affinity (70). Endostatin is centered on a seven-stranded b-sheet. One side of the b-sheet contains the a1 a-helix and the other side is covered by short b sheets, loops, and a second helix, a2 (68, 71, 72). Endostatin is one of the three subdomains of the NC1 domain of collagen XVIII that is composed of a trimerization domain and a hinge region in addition to endostatin. Several proteolytic cleavage sites exist in the hinge region of the NC1 domain and they lead to the release of endostatin-containing fragments differing in molecular size (24-30 kDa) and in N-terminal sequences. These fragments are generated by MMP-3, -7, -9, -13 and -20. Several components containing endostatin (22-38 kDa) have also been detected in murine tissues (73, 74) and tumors. Endostatin is found in tumor stromal components, including vessel walls, basement membranes, extracellular spaces, and tumor cells (75). Endostatin and several fragments containing endostatin (24-38 kDa) are secreted by tumor cells (73, 76). Two C-terminal fragments of collagen XVIII containing the endostatin sequence, neostatin-7 (28 kDa) and neostatin-14 (23 kDa) generated by MMP-7 and MMP-14 cleavage respectively have been described (14, 15). It should be noted that a fragment issued from the digestion of fibulin-1 by cathepsin D, and inhibiting endothelial cell proliferation, has been also named neostatin (77).
Mechanical factors are able to stimulate fibroblasts to release increased concentrations of endostatin (78). Tamoxifen exposure of highly hormone responsive ovarian cancer cells decreases proliferation, and increases MMP-9 activity leading to increased levels of endostatin both in cell culture in vitro and in solid tumors of nude mice (79). Hypoxia induces increase in endostatin in murine aorta and lung (74). Endostatin expression is up regulated in ischemic kidneys under the form of a 28-kDa fragment (80) and in the neuroblastoma cell line SK-N-SH (81). In contrast, hypoxia down-regulates endostatin production by human microvascular endothelial cells and pericytes (82). Endothelial endostatin release is also induced by general cell stress and modulated by the nitric oxide/cGMP pathway (83) and p53 expression greatly enhances the processing of full-length collagen XVIII to endostatin (84). p53 induction leads to an increase in endostatin levels in the Soas-2 human osteosarcoma cell line (85). Hypocrellin photochemotherapy induces endostatin release in glioma cells, and reduced it in macrophages and endothelial cells (81). Endostatin is present in serum, urine (73), in leg ulcer fluid, where most of it is bound to glypican-1 (86), in broncho-alveolar fluid (87), and in ocular fluid (88). Endogenous endostatin and related peptides are also widely distributed in murine tumors (75) and peri-infarct neurons express endostatin during the early stage of cerebral ischemia (89).
Collagen XVIII exists as three amino terminal end variants with specific amino terminal polypeptide modules. The variant 3 contains a 110-residue sequence with 10 cysteine residues, homologous with frizzled proteins belonging to the family of G-protein-coupled membrane receptors (90). This variant is proteolytically processed into a cell surface 50 kDa glycoprotein precursor containing the N-terminal frizzled module (Table 2). In human liver cancers, collagen XVIII is processed to frizzled cysteine-rich domain-containing polypeptides (91).
4.7. Matricryptin of collagen XIX
The NC1 domain of collagen XIX (Table 2) has anti-tumor and anti-angiogenic activities. It strongly inhibits the invasive capacities of tumor cells and the expression of MT-1 MMP and VEGF (92).
5 Matricryptins from proteoglycans and glycosaminoglycans
5.1. Endorepellin
Endorepellin, named from its repulsive activity against endothelial cells, is derived from the C-terminus (domain V) of perlecan (Table 2). It is comprised of three laminin-like globular (LG1-LG3) modules interspaced by four epidermal growth factor EGF-like repeats (93, see 94, 95 for reviews), and has a higher molecular weight than the other matricryptins (85 kDa versus ~ 20-30 kDa). Most of the anti-apoptotic and fibrogenic activity of endorepellin is mediated by the C-terminal LG3 module. Enzymes of the bone morphogenetic protein-1/Tolloid family of metalloproteinases cleave LG3 from recombinant endorepellin and from endogenous perlecan in cultured mouse and human cells (20). Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis (96). Apoptotic endothelial cells release LG3 that induces resistance to apoptosis in fibroblasts (97).
5.2. Hyaluronan fragments
Hyaluronan (HA) is a ubiquitous glycosaminoglycan that can have a molecular mass of several millions Dalton (98). Enzymatic degradation of hyaluronan by hyaluronidases 1 and 2 during tissue remodeling gives rise to fragments and oligosaccharides of various size (from 4 up to 1000 saccharides) that trigger cellular responses (proliferation, migration, cytokine synthesis) in a size-dependent manner (reviewed in 99, 100). Reactive oxygen species accumulated at sites of tissue injury may provide a mechanism for generating hyaluronan fragments in vivo (100). These fragments synergize with reactive oxygen species to activate the innate immune system and further promote reactive oxygen species, generation of hyaluronan fragments, inflammation, tissue injury, and ultimately fibrosis (101). In addition, hyaluronan fragments play a role in angiogenesis, chondrogenesis, wound healing, cancer and infection (99). 12-mers of hyaluronan inhibit the sequestration of Plasmodium falciparum-infected red blood cells in the placenta. We will focus in this review on the effects of hyaluronan fragments on angiogenesis, tumor growth and wound healing.
5.3. Heparan sulfate oligosaccharides
Tumor cell surface heparan sulfate contain cryptic bioactive sequences that either promote or inhibit tumor growth and metastasis in vivo. Heparinase I, which cleaves at the highly sulfated regions of heparan sulfate, releases heparan sulfate fragments that promote tumor growth in vivo. In contrast, heparinase III, that cleaves at the undersulfated regions of heparan sulfate chain, releases heparan sulfate fragments that inhibit primary tumor growth by ~ 70% (102). Heparin octasaccharides inhibit angiogenesis in vivo (103) but since they are synthetic oligosaccharides, they will not be discussed in this review.
6. Matricryptin receptors and signaling
Cell recognition of matricryptic sites appears to be an important component of a broad cell and tissue sensory system to detect and respond to environmental cues generated following varied types of tissue injury (104). Most matricryptins bind to integrins and some of them also bound to heparan sulfate chains (Table 3, Figure 1). Since it has been shown that several integrins regulating angiogenesis (a5b1, avb3 and avb5) bind to heparan sulfate (105), the cross-talk between integrins and cell surface proteoglycans requires further investigation to determine its impact on the mechanisms used by matricryptins to exert their anti-angiogenic and anti-tumor activities. Furthermore as detailed below, different cell types may bind to matricryptins via different cell surface receptors (106).
6.1. Matricryptins of collagen IV
Heparan sulfate proteoglycans might act as receptors or co-receptors for arresten (107) but most of the studies have focused on signaling mediated by integrins. The anti-angiogenic activity of arresten is mediated through the a1b1 integrin by its inhibition of FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in endothelial cells that lead to inhibition of hypoxia inducible factor (HIF-1 a) and VEGF expression (108). The pro-apoptotic effect of arresten on endothelial cells is also mediated by the a1b1 integrin and is due to a decrease in the amount of anti-apoptotic molecules of the Bcl-family, Bcl-2 and Bcl-xL (109). TSV-40-immortalized human glomerular epithelial cells bind to both tumstatin and arresten, with preferential binding to tumstatin, through the a3b1 and a2b1 integrin receptors, whereas HPV-16-immortalized human proximal tubular epithelial cells and primary human mesangial cells bind almost exclusively to arresten via the a3b1/avb3 and a1b1/a2b1 receptors, respectively (106).
Canstatin inhibits the phosphorylation of Akt, focal adhesion kinase (FAK), mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and ribosomal S6 kinase (110). It induces Fas-dependent apoptosis in endothelial cells (110). Canstatin exerts its pro-apoptotic activity on endothelial and tumor cells via procaspase-9 cleavage mediated through cross-talk between avb3 and avb5 integrins. Canstatin triggers two distinct apoptotic pathways in endothelial cells through the av-integrin-FAK/phosphatidylinositol 3-kinase (PI3K)/caspase-9 pathway and the Fas/Fas ligand/caspase-8/caspase-9 cascade leading to cleavage of procaspase-3 (111). Arresten and canstatin provide transcriptional feedback to increase MT-MMP, collagen IV, and proproliferative gene expression via b1-integrin signaling, influencing collagen IV proteolysis and synthesis during branching morphogenesis (52).
The signaling mechanisms induced by tumstatin and their implication in the control of tumor growth have been recently reviewed (48, 49). The peptide encompassing residues 185-203 of tumstatin has first been demonstrated to inhibit tumor cell proliferation via a CD47/integrin-associated protein, and avb3 integrin driven mechanism (112). The 185-206 peptide of tumstatin stimulates FAK and phosphatidylinositol 3-kinase (PI3K) phosphorylation in melanoma cells (113). Tumstatin inhibits the migration of tumor cells and the activation of membrane-bound MMP-2 by decreasing the expressions of MT1-MMP and the b3 integrin subunit (114). In endothelial cells, the anti-angiogenic activity of tumstatin is mediated through avb3 integrin. Tumstatin inhibits activation of FAK and PI3K, protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR), and prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4Ebinding protein 1 (115, 116). Tumstatin inhibits NF-kB-mediated signaling leading to inhibition of COX-2 expression, which in turn results in downregulation of hypoxia-induced VEGF/FGF-2 expression. This anti-angiogenic effect is mediated by a3b1 integrin (117), that transdominantly inhibits integrin avb3 activation (118). Tumstatin is also able to bind to a6b1 integrin on endothelial cells (119). The C-terminal part of tumstatin, encompassing to the 183 - 232 sequence, inhibits in vivo melanoma progression by triggering an intracellular transduction pathway, which involves a cyclic AMP-dependent mechanism. A decrease in cyclin D1 expression is associated with an increase of the intratumor cyclic AMP (cAMP) level (120).
6.2. Matricryptins of collagen XVIII
Endostatin does not bind to syndecans at the surface of endothelial cells, but to glypicans 1 and 4 via their glycosaminoglycan chains (121). Since the same residues are crucial for endostatin interaction with heparan sulfate and avb3 or a5b1 integrins, it seems unlikely that endostatin binds simultaneously to both integrins and glypicans at the cell surface (105). However, we have shown that heparan sulfate is able to bind integrins, and this suggests the possible existence of ternary complexes comprising endostatin, heparan sulfate and integrin at the endothelial cell surface (105).
Endostatin binds to a5b1 and avb3 integrins at the surface of endothelial cells (122). Endostatin also associates with caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells (123). The binding of endostatin to a5b1 integrin inhibits the focal adhesion kinase/c-Raf/MEK1/2/p38/ERK1 mitogen-activated protein kinase pathway (116). Endostatin interferes with another pathway by inhibiting vascular endothelial growth factor (VEGF)-mediated signaling via direct interaction with KDR/Flk-1. Endostatin blocks VEGF-induced tyrosine phosphorylation of KDR/Flk-1 and activation of ERK, p38 MAPK, and p125(FAK) in human umbilical vein endothelial cells (124). VEGF(121)-stimulated ERK activation is blocked by endostatin. ERK1/2 phosphorylation is regulated by endostatin via the protein phosphatase 2A (125).
Endostatin, the C-terminal fragment of collagen XVIII, is a potential inhibitor of Wnt signaling (126). The N-terminal domain of collagen XVIII binds to Wnt3a in vitro and suppressed Wnt3a-induced stabilization of b-catenin. Expression of the frizzled domain inhibits Wnt/b-catenin signaling in colorectal and liver cancer cell lines, downregulating major cell cycle checkpoint gatekeepers cyclin D1 and c-myc and reducing tumor cell growth (91).
Endostatin is internalized by endothelial cells (127, 128) and by AIDS-related Kaposi's sarcoma cells where it initiates activation of the transcription activating factors nuclear factor-kB and activating protein 1. Endostatin co-localizes to tropomyosin microfilaments and inhibits cytokine-mediated Kaposi cell migration and invasion (129). Endostatin treatment of endothelial cells induces tyrosine phosphorylation of Shb, an adaptor protein implicated in angiostatin-induced apoptosis, and formation of multiprotein complexes (127). Endostatin binds via its heparin-binding domain to the cell surface nucleolin, which mediates the antiangiogenic and antitumor functions of endostatin (128,130). Nucleolin mediates endostatin internalization in endothelial cells and endostatin inhibits FGF-2 stimulated phosphorylation of nucleolin (128).
6.3. Endorepellin
Endorepellin disrupts a2b1 integrin function that plays a key role in experimental and developmental angiogenesis (131). The binding of endorepellin to a2b1 integrin on endothelial cells triggers a signaling cascade that leads to the disassembly of the actin cytoskeleton and focal adhesions (132). Endorepellin increases intracellular cAMP level, accompanied by concurrent activation of protein kinase A, sustained activation of FAK and transient activation of p38 MAPK and the small chaperone heat shock protein 27 (5,94). The Src homology-2 protein phosphatase-1 (SHP-1) is a mediator of endorepellin angiostatic activity (133). The C-terminal fragment of endorepellin, LG3, interacts with the a2b1 integrin receptor of fibroblasts and triggers integrin-dependent signaling events leading to the inhibition of apoptosis of fibroblasts through PI3K-dependent pathways leading to down-regulation of the pro-apoptotic protein Bim-EL and up-regulation of the anti-apoptotic protein Bcl-xL (,97, 134). Endorepellin is internalized by tumor-derived endothelial cells causing a redistribution of a2b1 integrin that colocalizes with endorepellin to punctate deposits in the perivascular region (135).
6.4. Hyaluronan fragments
Several signal transduction pathways are initiated by various sizes of HA fragments binding to cell surface HA receptors such as CD44 and Receptor for HA-Mediated Motility (RHAMM, CD168) (99). They include Raf-1 kinase, MAP kinase, and extracellular signaling kinases such as ERK-1 activated by hyaluronan oligosaccharides, regulation of Erb2 phosphorylation and signaling in cancer cells and activation of an NF-kB/I-kB alpha auto-regulatory inducing transcription of MMP-9 and MMP-12 (99). Hyaluronan fragments (10-15 disaccharides) induce tyrosine phosphorylation of p125(FAK), paxillin, and p42/44 ERK in endothelial cells (100).
Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signaling pathways involving Cdc2 (Cdk1) for CD44 and gamma-adducin for both receptors (136). The stimulation of angiogenesis by hyaluronan oligosaccharides is initiated by RHAMM mediated signal pathway, but not by CD44, in wound healing (137). Signaling from hyaluronan degradation products also involves other signaling pathways through Toll-like receptors, TLR-2 and TLR-4 (see 100 for review), that are critical components in the innate immune response. The regulatory effect exerted by hyaluronan, whatever its molecular size, on NF-kB activation may depend upon the interaction between HA and Toll-like receptor-4 (TLR-4) (138). Hyaluronan fragments stimulate endothelial recognition of injury through TLR-4 (139) and low molecular weight hyaluronic acid obtained by biosynthesis (< 200 kDa) increases the self-defense of skin epithelium by induction of b-defensin 2 via TLR-2 and TLR-4 (140).
7. Physio-pathological processes controlled by matricryptins
Matricryptins and cryptic sites issued from the same molecule might have different biological roles. Cleavage of several a chains of collagen IV releases C-terminal fragments exhibiting anti-angiogenic properties, whereas the cryptic site demasked within collagen IV triple helix by proteolytic cleavage due to MMP-9 is pro-angiogenic (44, 45). Major physio-pathological processes regulated by matricryptins include angiogenesis and tumor growth. Matricryptin cleavage may be regulated by the same mechanism as reported for endostatin and tumstatin. The increased extracellular release of both matricryptins results from p53-dependent up-regulation of a(II) prolyl hydroxylase, p53 playing a role in the regulation of angiogenesis (84). The anti-angiogenic activity of endostatin and tumstatin mediate in part their tumor suppression activity (141). Anti-angiogenic matricryptins do not always act in synergy. Indeed, endorepellin binds to endostatin but it counteracts its anti-angiogenic effects (93).
7.1. Angiogenesis
Angiogenesis occurs in physiological (wound healing, menstrual cycle, embryogenesis) and pathological (rheumatoid arthritis, psoriasis, macular degeneration, diabetic retinopathy, and tumorigenesis). Several cryptic proteolytic fragments of extracellular matrix molecules exhibit anti-angiogenic properties including endostatin, arresten, canstatin, tumstatin, and vastatin (3, 27). Tumor growth being angiogenesis-dependent (142), numerous studies have investigated the clinical potential of antiangiogenic cryptic fragments of extracellular proteins as anti-tumor drugs (143, 144). Matrikines issued from collagen IV (arresten, canstatin, tumstatin, the NC1 domain of the a6 chain, 48, 145), VIII (vastatin), XV (restin), and XVIII (endostatin, see 62 for review), are endogenous inhibitors of angiogenesis. They inhibit the proliferation and migration of endothelial cells and several of them induce endothelial cell apoptosis. They are thus of potential therapeutic interest in all the pathological situations involving angiogenesis.
Tumstatin is an endothelial cell-specific inhibitor of protein synthesis (115) and its anti-angiogenic activity is localized in the 54 -132 sequence. Angiogenesis is a feature of remodeling in asthma and the tumstatin level is markedly decreased in the airways of patients with asthma. It inhibits airway hyperresponsiveness and angiogenesis and is of potential use as a therapeutic agent in asthma (146) and in diseases that are characterized by angiogenesis and tissue remodeling.
Restin inhibits the migration of endothelial cells in vitro but has no effect on the proliferation of these cells (57). Restin and the NC1(XV) domain inhibit angiogenesis in the chick chorioallantoic membrane assay. Both reduced stimulation by VEGF levels close to background (58).
Mice lacking collagen XVIII and its proteolytically derived product endostatin show delayed regression of blood vessels in the vitreous along the surface of the retina after birth (147). Endostatin has a biphasic effect on the inhibition of endothelial cell migration and proliferation in vitro and on the inhibition of tumor growth in vivo (148). Neostatin-7, a fragment of collagen XVIII containing endostatin, regulates FGF-2-induced corneal lymphangiogenesis (149). Angiogenesis is perpetuated in arthritis and endostatin abrogates arthritis and suppresses pannus formation and joint destruction in rodent models (150).
Endorepellin inhibits angiogenesis by altering the endothelial cytoskeleton, which is essential for the ability of cells to migrate and form capillary-like structures, in a Ca2+-dependent, heparan sulfate-independent fashion (5). It can act in a paracrine function on sprouting endothelial cells, either locally or distantly (95). A proteomic analysis of endorepellin-treated human endothelial cells show that b-actin, calreticulin, and chaperonin/Hsp60 (heat shock protein 60) are down-regulated and vimentin and the b subunit of prolyl 4-hydroxylase (protein disulfide isomerase) are up-regulated in response to endorepellin treatment (151). These proteins represent potential target areas involved with endorepellin action. Perlecan is essential for the integrity of somitic muscle and developmental angiogenesis in zebrafish and endorepellin mediates most of these biological activities (152). Endorepellin is present in the upper proliferating zone of fetal growth plate suggesting that it might counteract blood vessel formation in cartilage (153).
The trimer carboxyl propeptide of collagen I produced by mature osteoblasts is chemotactic for endothelial cells (154), and induces directional migration and metalloproteinases in breast cancer cells (155) and VEGF-A and CXCR4 (C-X-C chemokine receptor type 4) expression in breast carcinoma cells (156). It promotes rapid vascularization of the tumors while does not affect mitotic and apoptotic indexes and overall tumor growth. It has an early promoting effect in the acquisition by the tumors of prometastatic phenotype (157).
The regulation of angiogenesis by hyaluronan depends on its molecular size. High molecular weight hyaluronan inhibits angiogenesis, whereas hyaluronan oligosaccharides (3-25 disaccharides) promote angiogenesis by stimulating endothelial cell proliferation, migration and tube formation (reviewed in 99). The study of several hyaluronan of defined size showed that hyaluronan hexasaccharide, octasaccharide and decasaccharide, but not tetrasaccharide, are proangiogenic (158). Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses (159). Oligosaccharides of 3-10 disaccharide units (1350-4500 Da) increase the synthesis of collagens I and VIII by endothelial cells (160).
7.2. Tumor growth and metastasis
Proteolytic exposure of matricryptic sites or matricryptin release regulates tumor cell growth and invasive properties (161). Matrikines issued from collagen IV (arresten, canstatin, tumstatin, the NC1 domain of the a6 collagen IV chain, 28, 47, 48, 145) inhibit tumor growth. In vivo mice showing decreased circulating levels of tumstatin due to deficience in MMP-9 showed also accelerated tumor growth (13). Mice deficient in endostatin show increased tumor growth when implanted with cancer cells that do not produce collagen XVIII (144).
Melanoma progression is controlled by matrikines from basement membrane proteins that regulate the proteolytic cascades leading to cancer cell dissemination and metastasis. Tumstatin inhibits melanoma cell proliferation, migration and invasion by decreasing MMP production and activation (reviewed in 28, 47, 120). The NC1 domain of the a6(IV) chain suppresses the growth of subcutaneously transplanted Lewis lung carcinoma and of spontaneous pancreatic insulinomas that develop in the Rip1Tag2 mice (145). Canstatin inhibits M21 melanoma tumor growth within full thickness human skin and exhibits a dose-dependent inhibition of tumor growth in nude mice. Canstatin also retards the growth of pancreatic cancer (162). Furthermore it enhances cellular senescence in tumor cells in vivo and in vitro (163). A peptide encompassing amino acids 69 to 98 of tumstatin has direct growth-suppression activity dependent on Akt/mTOR activation in tumor cells. Indeed, direct growth suppression of glioma multiforme cells by this peptide occurs only if the cells express the avb3 integrin and have a functional PTEN/low levels of Akt (164). Pentastatin-1, issued from the a5 chain of collagen IV, inhibits tumor growth in vivo in a breast xenograft model (165), and in a small cell lung cancer xenograft model (166). The cryptic epitope HU177 regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo (167).
Systemic administration of restin suppressed the growth of tumors in a xenograft renal carcinoma model (57). Endostatin inhibits the proliferation of several tumor cell lines including HT 29 and C51 cell lines from human and murine colon adenocarcinoma (66). It inhibits migration and invasion of head and neck squamous cell carcinoma cells. Endostatin activates the transcription factors NF-kB and AP-1 and down-regulated the gene expression of several pro-migratory molecules (168). Endostatin inhibits human tongue carcinoma cell invasion and intravasation. This anti-tumor effect might be explained, at least in part, by the inhibition by endostatin of activation and activities of tumor-associated pro-MMPs, such as pro-MMP-2, -9, and -13 (169) and MT1-MMP (170). Other matricryptins inhibit matrix metalloproteases. Arresten inhibits matrix metalloproteinase-2 activation and FGF-2-induced proliferation in murine retinal endothelial cells (171), whereas the NC1 domain of collagen XIX inhibits MT1-MMP expression and activity (92).
Endorepellin specifically targets the tumor vasculature, inhibits tumor angiogenesis, enhances tumor hypoxia, and leads to a statistically significant decrease in tumor metabolism and mitotic index in two human tumor models in mice (135). In contrast to other angiogenesis inhibitors, endorepellin does not increase the apoptotic index of human tumor cells in vivo (135).
6.9-kDa hyaluronan fragments (36 mers) promote tumor cell motility in a CD44-dependent manner (100). Hyaluronan fragments modulate growth and cell survival and sensitize multidrug resistance breast cancer cells to cytotoxic drugs by decreasing p-Akt as well as Pgp activity in a CD44-dependent way (172). They inhibit cell viability and induce apoptosis of human and murine osteoblastic osteosarcoma cell lines. In vivo, intratumoral injection of hyaluronan octasaccharides results in significant suppression of the formation of distant lung metastasis (173).
7.3. Tissue remodeling and wound healing
Tissue remodeling and repair includes angiogenesis and several studies have focused on the role of anti-angiogenic matricryptins on these processes. Implications of matricryptins and matricryptic sites for cutaneous cancers and skin repair and for the control of tissue injury in the cardiovascular system have been reviewed (104).
Endostatin does not affect murine cutaneous wound healing, and does not induce a significant decrease in breaking strength of cutaneous wounds in mice (174). Endostatin treatment reduces the number of functional blood vessels and the matrix density in the granulation tissue, but does not significantly affect the overall wound healing process in mice (175). However, in another study, endostatin-treated mice showed a significant delay in wound healing. Granulation tissue formation and wound vascularity were significantly decreased, but reepithelialization was not effected (176). Overexpression of endostatin leads to delayed wound healing in mice, whereas the lack of collagen XVIII accelerates cutaneous wound healing (177). Endostatin participates in cardiovascular remodeling by suppressing aberrant left ventricular remodeling and heart failure after myocardial infarction. Endostatin may thus have a cardioprotective effect (178). Tumstatin prevents glomerular hypertrophy in the early stage of diabetic nephropathy (179).
The topical application of a pool of hyaluronan oligosaccharides ranging from 2 to 10 disaccharides promote excisional wound healing through enhanced angiogenesis in vivo. This treatment promotes collagen deposition and fibroblast proliferation and may be useful in acute wound repair (180). Skin atrophy, often associated with delayed wound healing, is reversed by hyaluronan fragments through a CD44-dependent mechanism. This effect is dependent upon the size of the fragments. Fragments with molecular weight ranging from 50 up to 400 kDa, but not smaller or higher fragments, induce keratinocyte proliferation (181).
7.4. Inflammation
Matricryptins play a role as mediators of inflammation by exhibiting chemotactic activity for inflammatory cells, enhancing phagocytic functions, and inducing immune responses and changes in gene expression of inflammatory cells (see 182 for review). Fragments of collagen I and IV exhibit chemotactic activity for inflammatory cells (182). The acetylated Pro-Gly-Pro tripeptide, derived from proteolytic cleavage of collagen I in vivo, is a potent neutrophil chemoattractant and utilizes CXC chemokine receptors CXCR1 and CXCR2 (183). The N-terminal 7S domain of collagen IV chains has neutrophil chemotactic activity, whereas a tumstatin peptide suppresses neutrophil activation (184). The 185-203 sequence of tumstatin protects basement membrane against damage by polymorphonuclear neutrophils (185).
At sites of inflammation, hyaluronan is degraded into fragments that induce chemokines and cytokines, thereby augmenting the inflammatory response. The effect of hyaluronan on the inflammatory response is related to its molecular size. High-molecular-weight hyaluronan has anti-inflammatory activity while smaller hyaluronan fragments have proinflammatory activity (138). Low molecular weight hyaluronan (<500 kDa) induces inflammatory responses in inflammatory macrophages. Hyaluronan fragments, but not native high-molecular-weight hyaluronan, can stimulate the production of inflammatory mediators by many cell types (see 100 for review). Fragments of hyaluronan increase the expression of MMP-12, plasminogen activator inhibitor and stimulate the production of several cytokines, including macrophage inflammatory protein-1a, macrophage inflammatory protein-1b, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-8, and interleukin-12 by macrophages (182). Hyaluronan fragments induce MMP-9 and MMP-13 expression in tumor cells, MMP-9 transcription being mediated via NF-kB (186). They also induce macrophage metalloelastase (187) and nitric oxide synthase (188) in macrophages. HA fragments can influence dendritic cell maturation (100).
7.5. Autoimmune and inherited diseases
Some proteolytic fragments generated from collagens trigger autoimmune diseases. An autoantigen generated from proteolytic cleavage of collagen I is associated with autoimmune uveitis (189).
Goodpasture syndrome is an autoimmune disease of the kidneys and lungs mediated by antibodies and T-cells directed to cryptic epitopes hidden within basement membrane hexamers rich in a3(NC1) domain (tumstatin) of collagen IV (8). Residues 17-31 and 127-141 of tumstatin are two conformational epitopes of anti-glomerular basement membranes antibodies leading to Goodpasture syndrome. These autoantibodies bind to a3(IV) collagen in glomerular basement membrane, and cause progressive glomerulonephritis and pulmonary hemorrhage (190). Goodpasture autoantibody epitopes are cryptic because they are structurally sequestered by adjacent non-collagenous domains of a4 and a5 chains of collagen IV. The epitope sequestered inside the hexamer becomes exposed and binds with the Goodpasture antibody upon dissociation of the hexamer formed by two trimeric NC1 domains in the collagen IV network found in tissues into its subunits (191, 192). Mucosal tolerance can be induced in an animal model of Goodpasture's disease by nasal administration of an immunodominant peptide from the N-terminus of tumstatin (pCol 24-38,193). This opens new perspectives for treating patients with Goodpasture's disease.
The C-terminal part of the a3, a4 and a5 chains of collagen IV contain polymorphisms and mutations that have been found in patients with Alport syndrome (194-197). All known variants in the COL4A5 gene and their clinical significance are recorded in a database (http://www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php).
Endostatin contains a D104N polymorphism (D1437N in the sequence of the a1 chain of collagen XVIII). Individuals homozygous for the D104N polymorphism in the COL18A1 gene have a high risk of occurrence of sporadic breast cancer (198). This polymorphism may influence the age of onset of acute myeloid leukemia (199). It was initially thought to predispose for the development of prostatic adenocarcinoma (200). However, more recent studies show that the D104N polymorphism does not appear to be associated with increased risk to develop androgen independent prostate cancer (201), with breast cancer susceptibility or severity (202), or with lung cancer susceptibility (203). This variant has been found in patients with Knobloch syndrome, an autosomal recessive disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment, and congenital encephalocele. This polymorphism may represent a pathogenic mutation (204).
8 MATRICRYPTINS, CRYPTIC SITES AND THERAPEUTICS
8.1. Matricryptins as potential drugs
Endostatin has raised very high expectations as antiangiogenic therapy of cancer because it induces tumor dormancy in experimental model of cancer and does not induce significant drug resistance (65). Endostatin inhibits 65 different tumor types and modifies 12% of the human genome to downregulate pathological angiogenesis without side-effect (62). Its potential use in cancer therapy has been extensively reviewed (62, 63, 205, 206). Due to the poor clinical responses observed in phase I and II trials, recombinant endostatin (EndostatinTM, EntreMed Inc) was terminated at phase II trials (63). Trial design, administration regimen and patient selection might not have been optimally designed to assess the effect of endostatin that might cause only tumor stabilization (143). A derivative of recombinant endostatin has been designed with an additional metal chelating sequence (MGGSHHHHH, or Zn(II)-binding peptide) at the N-terminus that enhances endostatin solubility and stability (207). This derivative called Endostar has been approved for the treatment of non-small-cell lung cancer in 2005 by the State Food and Drug Administration in China. It exerts its antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells (208), and suppresses invasion through downregulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells (209). Endostar induces apoptotic effects in HUVECs through activation of caspase-3 and decrease of Bcl-2 (210).
Several other derivatives of endostatin have been prepared to extend its half-life (see 64 for review). Modification of endostatin by low molecular weight heparin increases its half-life (64). PEGylation enhances the stability of recombinant endostatin and improves its antitumor activity as shown with N-terminal mono-PEGylated endostatin (211). Endostar has also been PEGylated (212). Another modification linking the Fc region of an IgG molecule to endostatin significantly increases endostatin half-life. Furthermore, the amount of antitumor dose of Fc-endostatin was ~ 100 times less than endostatin (213). Therapeutic efficacy of Fc-endostatin (213) and of endostatin (148) exhibits a biphasic dose-response curve. A 27-amino-acid peptide corresponding to the N-terminal zinc binding domain of endostatin and exhibiting the anti-angiogenic and anti-tumor properties of endostatin might be of drug candidate too (214).
Experimental approaches and clinical trials focusing on delivery of endostatin have been reviewed (215). Anti-angiogenic gene therapy of cancer has been reviewed (216, 217). A phase I clinical trial of an adenovirus-mediated endostatin gene named E10A has already been carried out in patients with solid tumors showing mild antitumor effects (218). Conditionally-replicating adenovirus is currently being developed as anti-tumor therapeutics in solid tumors including pancreatic cancer, and a new virus carrying the gene sequence coding for canstatin has been successfully designed for selective replication in tumor cells. Its replication leads to decreased microvessel density and increased cancer cell apoptosis in vitro and in vivo (219). Biodegradable poly(lactide-co-glycolide) microspheres have been used to deliver Endostar in vitro and in vivo (220). CHO cells expressing endostatin encapsulated into a polytetrafluoroethylene semi-permeable membrane (Theracyte system) deliver endostatin continuously at a high level (221). This should improve the efficacy and potency of the antitumor therapy.
Arresten, canstatin, and tumstatin have not been investigated intensively in clinic so far. Preclinical trials show that canstatin gene electrotransfer combined with radiotherapy has a better efficacy over irradiation alone, as a result of strong vessel disorganization and dramatic increase of tumor cells apoptosis in two xenografted human carcinomas from mammary and prostate origin in nude mice (222). Treatment using the canstatin- or TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand)-expressing vector significantly suppresses tumor growth in human xenograft tumor models, but their combination lead to a greater antitumor activity than either treatment alone (223). The combination of TRAIL and canstatin appears thus to be a promising approach for the gene therapy of breast tumors.
A preliminary study carried out in mice bearing S180 tumors shows that the gene delivery of tum-5, the fragment encoding amino acids 45-132 of tumstatin, may be an effective strategy for cancer therapy (224). The addition of a NGR motif, a marker of angiogenic endothelial cells, to the 45-132 sequence of tumstatin increases its anti-angiogenic and anti-tumor properties (225). However, the epitope recognised by the pathogenic auto-antibodies for Goodpasture's syndrome is localized in tumstatin sequence and its potential effect has to be carefully evaluated when considering the use of tumstatin as a drug (143).
Anti-angiogenic inhibitors may improve the efficacy of anti-tumoral treatment by normalizing tumor vasculature and microenvironment. Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in a murine model of Lewis lung carcinoma (226).
8.2. Cryptic sites as therapeutic targets
Selective targeting of angiogenic cryptic collagen IV epitopes may represent an effective antiangiogenic treatment strategy. Indeed primary melanoma induces detectable changes in systemic levels of HU177 cryptic epitope shedding. A subset of patients with nodular melanoma may be more responsive to treatment with D93 (TRC093), a humanized monoclonal antibody directed to the HU177 site that is currently undergoing a phase I clinical trial in patients with advanced cancers (167).
8.3 .Matricryptins as potential markers of disease
Several matricryptins have been detected in serum and a number of studies have investigated their possible use as diagnostic, pronostic, or follow-up markers. Serum endostatin level has been investigated in patients with various cancers and in patients with coronary heart disease (227). Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma (228). Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury and its plasma level correlated with the severity of injury (87). The expression of endostatin is increased in patients with osteosarcoma and may be used as a pronostic marker of the disease progression and of responsiveness to therapy (229). The C-terminal domain of endorepellin (LG3) has been detected in various tissues and biological fluids (urine, blood, amniotic fluid) and might be a marker of vascular injury (see 95 for review). Circulating LG3 levels are reduced in patients with breast cancer suggesting that they might be a useful biomarker for cancer progression and invasion (230).
Circulating levels of cryptic collagen IV epitope HU177 can be detected in the sera of melanoma patients. A significant correlation was observed between HU177 serum concentration and nodular melanoma histologic subtype (167). Furthermore increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis (231).
9. PerspectiveS
The extracellular matrix is not the single reservoir of cryptic sites or cryptic fragments. Intracellular, blood or exogenous proteins (e.g. from milk) also give rise by limited proteolytic cleavage to biologically active fragments termed crypteins and collectively designed as the cryptome (232). Besides the extracellular matrix, the sources of cryptic peptides are frequently proteins involved in endocrine signaling and the complement cascade.
Most matricryptins bind to different receptors to exert their biological activities and several matricryptins are able to bind to the same integrin receptors. Canstatin, tumstatin, the NC1 domain of the a6(IV) chain and endostatin all bind to the avb3 integrin. In order to understand the complex interplay between all these matricryptins regulating angiogenesis and tumor growth, a global, integrative, approach is needed. The first draft of the interaction network of endostatin has been established (233), and the building of the interaction network of the other matricryptins will allow us to identify cross-talks between signaling pathways and molecular mechanisms underlying the anti-angiogenic and anti-tumor activities of those matricryptins. The study of the effect of matricryptins on a single cell type (i.e. endothelial cells) has provided valuable insights into signaling pathways underlying their anti-angiogenic activities. However, different matricryptins target the same integrin receptor and are released by the same cells. One challenge is thus to integrate these data in a single network to understand how all the anti-angiogenic matricryptins and cryptic sites work together to regulate angiogenesis in vivo. Davis (104) proposes that two classes of pattern recognition receptors, scavenger receptors and toll-like receptors are critical receptors for matricryptic sites and matricryptins that could be functionally relevant during tissue injury response as shown for hyaluronan fragments. Despite the fact that a number of matricryptins exhibit the same biological activities and share some receptors, no structural features associated with cryptic sites or matricryptins have been identified so far. Endostatin and tumstatin share 14% amino acid homology for example (3). A common feature of antiangiogenic matricryptins might be a cross-b structure, stacked b-sheets composed of non-twisted b strands, which is present in amyloidogenic polypeptides (234). Cross-b sheets are present in endostatin (235), and amyloid endostatin induces endothelial cell detachment by stimulation of the plasminogen activation system (236). However, the presence of this structure in other antiangiogenic matricryptins derived from collagens and proteoglycans remains to be investigated. Another challenge would be to be able to predict the release of matricryptins and/or the existence of cryptic sites in extracellular proteins. The investigation of intrinsic disorder might be a useful approach for this purpose.
Regarding the use of matricryptins as anti-tumor drugs, it seems that tumors might escape from matricryptins, including endostatin and tumstatin, by up-regulating multiple proangiogenic factors (237). Anti-angiogenic matricryptins might thus be used in combination with other anti-angiogenic agents or with conventional anticancer therapies such as chemotherapy and radiotherapy as reported for canstatin (222, 238) and endostatin (239).
10. Acknowledgments
We apologize to the many colleagues whose work could not be cited because of space limitations. Dr. Jean-Claude Monboisse (UMR 6237 Matrice Extracellulaire et Dynamique Cellulaire, CNRS - Université de Reims Champagne Ardenne, France) is gratefully acknowledged for his critical reading of the manuscript and his excellent suggestions.
11. References
1 Davis GE, Bayless KJ, Davis MJ, Meininger GA. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am J Pathol 156, 1489-1498 (2000)
PMid:10793060 PMCid:1876929
2 Schenk S, Quaranta V. Tales from the cryptic sites of the extracellular matrix. Trends Cell Biol 13, 366-375 (2003)
doi:10.1016/S0962-8924(03)00129-6
3 Nyberg P, Xie L, Kalluri R. Endogenous inhibitors of angiogenesis. Cancer Res 65, 3967-3979 (2005)
doi:10.1158/0008-5472.CAN-04-2427
PMid:15899784
4 Tran KT, Lamb P, Deng JS. Matrikines and matricryptins: Implications for cutaneous cancers and skin repair. J Dermatol Sci 40, 11-20 (2005)
doi:10.1016/j.jdermsci.2005.05.001
PMid:15993569
5 Bix G, Iozzo RV. Matrix revolutions: "tails" of basement-membrane components with angiostatic functions. Trends Cell Biol 15, 52-60 (2005)
doi:10.1016/j.tcb.2004.11.008
PMid:15653078
6 Maquart FX, Simeon A, Pasco S, Monboisse JC. Regulation of cell activity by the extracellular matrix : the concept of matrikines. J Soc Biol 193, 423-428 (1999)
PMid:10689625
7 Maquart FX, Pasco S, Ramont L, Hornebeck W, Monboisse JC. An introduction to matrikines: extracellular matrix-derived peptides which regulate cell activity. Implication in tumor invasion. Crit Rev Oncol Hematol 49, 199-202 (2004)
doi:10.1016/j.critrevonc.2003.06.007
PMid:15036260
8 Kalluri R, Cantley LG, Kerjaschki D, Neilson EG. Reactive oxygen species expose cryptic epitopes associated with autoimmune goodpasture syndrome. J Biol Chem 275, 20027-20032 (2000)
doi:10.1074/jbc.M904549199
PMid:10748075
9 Lauer-Fields JL, Malkar NB, Richet G, Drauz K, Fields GB. Melanoma cell CD44 interaction with the alpha 1(IV)1263-1277 region from basement membrane collagen is modulated by ligand glycosylation. J Biol Chem 278, 14321-14330 (2003)
doi:10.1074/jbc.M212246200
PMid:12574156
10 Miosge N, Simniok T, Sprysch P, Herken R. The collagen type XVIII endostatin domain is co-localized with perlecan in basement membranes in vivo. J Histochem Cytochem 51, 285-296 (2003)
PMid:12588956
11 Elamaa H, Sormunen R, Rehn M, Soininen R, Pihlajaniemi T. Endostatin overexpression specifically in the lens and skin leads to cataract and ultrastructural alterations in basement membranes. Am J Pathol 166, 221-229 (2005)
PMid:15632014 PMCid:1602290
12 Miosge N, Sasaki T, Timpl R. Angiogenesis inhibitor endostatin is a distinct component of elastic fibers in vessel walls. FASEB J 13, 1743-1750 (1999)
PMid:10506577
13 Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, Yang C, Hynes RO, Werb Z, Sudhakar A, Kalluri R: Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphavbeta3 integrin. Cancer Cell 3, 589-601 (2003)
doi:10.1016/S1535-6108(03)00133-8
14 Lin HC, Chang JH, Jain S, Gabison EE, Kure T, Kato T, Fukai N, Azar DT: Matrilysin cleavage of corneal collagen type XVIII NC1 domain and generation of a 28-kDa fragment. Invest Ophthalmol Vis Sci 42, 2517-2524 (2001)
PMid:11581192
15 Chang JH, Javier JA, Chang GY, Oliveira HB, Azar DT. Functional characterization of neostatins, the MMP-derived, enzymatic cleavage products of type XVIII collagen. FEBS Lett 579, 3601-3606 (2005)
doi:10.1016/j.febslet.2005.05.043
PMid:15978592
16 Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J 19, 1187-1194 (2000)
doi:10.1093/emboj/19.6.1187
PMid:10716919 PMCid:305660
17 Ma DH, Yao JY, Kuo MT, See LC, Lin KY, Chen SC, Chen JK, Chao AS, Wang SF, Lin KK: Generation of endostatin by matrix metalloproteinase and cathepsin from human limbocorneal epithelial cells cultivated on amniotic membrane. Invest Ophthalmol Vis Sci 48, 644-651 (2007)
doi:10.1167/iovs.06-0884
18 Wen W, Moses MA, Wiederschain D, Arbiser JL, Folkman J. The generation of endostatin is mediated by elastase. Cancer Res 59, 6052-6056 (1999)
PMid:10626789
19 Hornebeck W, Emonard H, Monboisse JC, Bellon G. Matrix-directed regulation of pericellular proteolysis and tumor progression. Semin Cancer Biol 12, 231-241 (2002)
doi:10.1016/S1044-579X(02)00026-3
20 Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV. BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J Biol Chem 280, 7080-7087 (2005)
doi:10.1074/jbc.M409841200
PMid:15591058
21 Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, Sato H. Cleavage osyndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem 278, 40764-4070 (2003)
doi:10.1074/jbc.M306736200
PMid:12904296
22 Franzke CW, Tasanen K, Schumann H, Bruckner-Tuderman L. Collagenous transmembrane proteins: collagen XVII as a prototype. Matrix Biol 22, 299-309 (2003)
doi:10.1016/S0945-053X(03)00051-9
23 Alexopoulou AN, Multhaupt HA, Couchman JR. Syndecans in wound healing, inflammation and vascular biology. Int J Biochem Cell Biol 39, 505-528 (2007)
doi:10.1016/j.biocel.2006.10.014
24 Ricard-Blum S, Ruggiero F. The collagen superfamily: from the extracellular matrix to the cell membrane. Pathol Biol 53, 430-42 (2005)
doi:10.1016/j.patbio.2004.12.024
PMid:16085121
25 Ricard-Blum S, Ruggiero F, van der Rest M: The collagen superfamily. Topics Curr Chem 247, 35-84 (2005)
26 Karagiannis ED, Popel AS: A systematic methodology for proteome-wide identification of peptides inhibiting the proliferation and migration of endothelial cells. Proc Natl Acad Sci U S A 105, 13775-13780 (2008)
doi:10.1073/pnas.0803241105
PMid:18780781 PMCid:2544530
27 Marneros AG, Olsen BR: The role of collagen-derived proteolytic fragments in angiogenesis. Matrix Biol 20, 337-345 (2001)
doi:10.1016/S0945-053X(01)00151-2
28 Pasco S, Ramont L, Maquart FX, Monboisse JC. Control of melanoma progression by various matrikines from basement membrane macromolecules. Crit Rev Oncol Hematol 49, 221-233 (2004)
doi:10.1016/j.critrevonc.2003.09.006
PMid:15036262
29 Ricard-Blum S, Faye C. Collagens associated with basement membranes and their matricryptins. J Soc Biol 199, 321-328 (2005)
doi:10.1051/jbio:2005033
30 O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277-285 (1997)
PMid:20053443
31 Taubenberger AV, Woodruff MA, Bai H, Muller DJ, Hutmacher DW. The effect of unlocking RGD-motifs in collagen I on pre-osteoblast adhesion and differentiation. Biomaterials 31, 2827-2835 (2010)
doi:10.1016/j.biomaterials.2009.12.051
32 Ingham KC, Brew SA, Migliorini M. Type I collagen contains at least 14 cryptic fibronectin binding sites of similar affinity. Arch Biochem Biophys 407, 217-223 (2002)
doi:10.1016/S0003-9861(02)00454-X
PMid:2825644 PMCid:1148322
33 Monboisse JC, Bellon G, Dufer J, Randoux A, Borel JP. Collagen activates superoxide anion production by human polymorphonuclear neutrophils. Biochem J 246, 599-603 (1987)
PMid:7499207
34 Garnotel R, Monboisse J, Randoux A, Haye B, Borel JP. The binding of type I collagen to lymphocyte function-associated antigen 1 (LFA-1) integrin triggers the respiratory burst of human polymorphonuclear neutrophils. J Biol Chem 270, 27495-27503 (1995)
doi:10.1074/jbc.270.46.27495
PMid:12868264
35 Pasco S, Ramont L, Maquart FX, Monboisse JC. (Biological effects of collagen I and IV peptides) J Soc Biol 197, 31-39 (2003)
PMid:3800925 PMCid:1147077
36 Van der Rest M, Rosenberg LC, Olsen BR, Poole AR. Chondrocalcin is identical with the C-propeptide of type II procollagen. Biochem J 237, 923-5 (1986)
PMid:3494735
37 Hinek A, Reiner A, Poole AR. The calcification of cartilage matrix in chondrocyte culture: studies of the C-propeptide of type II collagen (chondrocalcin) J Cell Biol 104, 1435-1441 (1987)
doi:10.1083/jcb.104.5.1435
38 Kirsch T, Pfäffle M. Selective binding of anchorin CII (annexin V) to type II and X collagen and to chondrocalcin (C-propeptide of type II collagen) Implications for anchoring function between matrix vesicles and matrix proteins. FEBS Lett 310, 143-147 (1992)
doi:10.1016/0014-5793(92)81316-E
39 Cibere J, Zhang H, Garnero P, Poole AR, Lobanok T, Saxne T, Kraus VB, Way A, Thorne A, Wong H, Singer J, Kopec J, Guermazi A, Peterfy C, Nicolaou S, Munk PL, Esdaile JM. Association of biomarkers with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study. Arthritis Rheum 60, 1372-1380 (2009)
doi:10.1002/art.24473
PMid:7487609
40 Ahmad NN, Dimascio J, Knowlton RG, Tasman WS. Stickler syndrome. A mutation in the nonhelical 3' end of type II procollagen gene. Arch Ophthalmol 113, 1454-1457 (1995)
PMid:15316962
41 Zankl A, Zabel B, Hilbert K, Wildhardt G, Cuenot S, Xavier B, Ha-Vinh R, Bonafé L, Spranger J, Superti-Furga A. Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1. Am J Med Genet A 129A, 144-148 (2004)
doi:10.1002/ajmg.a.30222
PMid:15643621
42 Zankl A, Neumann L, Ignatius J, Nikkels P, Schrander-Stumpel C, Mortier G, Omran H, Wright M, Hilbert K, Bonafé L, Spranger J, Zabel B, Superti-Furga A. Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies. Am J Med Genet A 133A, 61-67 (2005)
doi:10.1002/ajmg.a.30531
43 Brooks PC, Roth JM, Lymberis SC, DeWyngaert K, Broek D, Formenti SC. Ionizing radiation modulates the exposure of the HUIV26 cryptic epitope within collagen type IV during angiogenesis. Int J Radiat Oncol Biol Phys 54, 1194-1201 (2002)
doi:10.1016/S0360-3016(02)03748-3
PMid:12368215 PMCid:1867273
44 Hangai M, Kitaya N, Xu J, Chan CK, Kim JJ, Werb Z, Ryan SJ, Brooks PC: Matrix metalloproteinase-9-dependent exposure of a cryptic migratory control site in collagen is required before retinal angiogenesis. Am J Pathol 161, 1429-1437 (2002)
PMid:11535623 PMCid:2196184
45 Xu J, Rodriguez D, Petitclerc E, Kim JJ, Hangai M, Moon YS, Davis GE, Brooks PC: Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol 154, 1069-79 (2001)
doi:10.1083/jcb.200103111
PMid:9008168
46 Cretu A, Roth JM, Caunt M, Akalu A, Policarpio D, Formenti S, Gagne P, Liebes L, Brooks PC. Disruption of endothelial cell interactions with the novel HU177 cryptic collagen epitope inhibits angiogenesis. Clin Cancer Res 13, 3068-3078 (2007)
doi:10.1158/1078-0432.CCR-06-2342
PMid:17505010
47 Pasco S, Brassart B, Ramont L, Maquart FX, Monboisse JC : Control of melanoma cell invasion by type IV collagen. Cancer Detect Prev 29, 260-266 (2005)
doi:10.1016/j.cdp.2004.09.003
PMid:15936594
48 Mundel TM, Kalluri R: Type IV collagen-derived angiogenesis inhibitors. Microvasc Res 74, 85-99 (2007)
doi:10.1016/j.mvr.2007.05.005
PMid:17602710
49 Sudhakar A, Boosani CS. Inhibition of tumor angiogenesis by tumstatin: insights into signaling mechanisms and implications in cancer regression Pharm Res 25, 2731-2739 (2008)
doi:10.1007/s11095-008-9634-z
PMid:18551250
50 Liu H, Chen B, Lilly B. Fibroblasts potentiate blood vessel formation partially through secreted factor TIMP-1. Angiogenesis 11, 223-234 (2008)
doi:10.1007/s10456-008-9102-8
PMid:18273688
51 Wang B, Sun J, Kitamoto S, Yang M, Grubb A, Chapman HA, Kalluri R, Shi GP. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J Biol Chem 281, 6020-6029 (2006)
doi:10.1074/jbc.M509134200
PMid:16365041
52 Rebustini IT, Myers C, Lassiter KS, Surmak A, Szabova L, Holmbeck K, Pedchenko V, Hudson BG, Hoffman MP. MT2-MMP-dependent release of collagen IV NC1 domains regulates submandibular gland branching morphogenesis. Dev Cell 17, 482-493 (2009)
doi:10.1016/j.devcel.2009.07.016
PMid:19853562
53 Petitclerc E, Boutaud A, Prestayko A, Xu J, Sado Y, Ninomiya Y, Sarras MP Jr, Hudson BG, Brooks PC. New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J Biol Chem 275, 8051-8061 (2000)
doi:10.1074/jbc.275.11.8051
PMid:10713126
54 Xu CX, Liu XX, Hou GS, Yan YF, Chen SM, Wang W, Jiang GS, Liu B, Xin JX. The expression of tumstatin is down-regulated in renal carcinoma. Mol Biol Rep 37, 2273-2277 (2010)
doi:10.1007/s11033-009-9718-9
PMid:19688274
55 Luo YQ, Li-JuanYao, Zhao L, Sun AY, Dong H, Du JP, Wu SZ, Hu W. Development of an ELISA for quantification of tumstatin in serum samples and tissue extracts of patients with lung carcinoma. Clin Chim Acta 411, 510-515 (2010)
doi:10.1016/j.cca.2010.01.001
PMid:20064495
56 Xu R, Yao ZY, Xin L, Zhang Q, Li TP, Gan RB. NC1 domain of human type VIII collagen (alpha1) inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis. Biochem Biophys Res Commun 289, 264-268 (2001)
doi:10.1006/bbrc.2001.5970
PMid:11708810
57 Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H, Knebelmann B, Sukhatme VP. Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Commun 255, 735-739 (1999)
doi:10.1006/bbrc.1999.0248
PMid:10049780
58 Sasaki T, Larsson H, Tisi D, Claesson-Welsh L, Hohenester E, Timpl R. Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity. J Mol Biol 301, 1179-1190 (2000)
doi:10.1006/jmbi.2000.3996
PMid:10966814
59 Zatterstrom UK, Felbor U, Fukai N, Olsen BR. Collagen XVIII/endostatin structure and functional role in angiogenesis. Cell Struct Funct 25, 97-101 (2000)
doi:10.1247/csf.25.97
60 Sasaki T, Hohenester E, Timpl R: Structure and function of collagen-derived endostatin inhibitors of angiogenesis. IUBMB Life 53, 77-84 (2002)
doi:10.1080/15216540211466
PMid:12049199
61 Marneros AG, Olsen BR: Physiological role of collagen XVIII and endostatin. FASEB J 19, 716-728 (2005)
doi:10.1096/fj.04-2134rev
PMid:15857886
62 Folkman J. Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action. Exp Cell Res 312, 594-607 (2006)
doi:10.1016/j.yexcr.2005.11.015
PMid:16376330
63 Fu Y, Tang H, Huang Y, Song N, Luo Y: Unraveling the mysteries of endostatin. IUBMB Life 61, 613-26 (2009)
doi:10.1002/iub.215
PMid:19472178
64 Zheng MJ. Endostatin derivative angiogenesis inhibitors. Chin Med J (Engl) 122, 1947-1951 (2009)
65 Boehm T, Folkman J, Browder T, O'Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404-407 (1997)
doi:10.1038/37126
PMid:9389480
66 Ricard-Blum S, Féraud O, Lortat-Jacob H, Rencurosi A, Fukai N, Dkhissi F, Vittet D, Imberty A, Olsen BR, van der Rest M. Characterization of endostatin binding to heparin and heparan sulfate by surface plasmon resonance and molecular modeling: role of divalent cations. J Biol Chem 279, 2927-2936 (2004)
doi:10.1074/jbc.M309868200
PMid:14585835
67 Yamaguchi N, Anand-Apte B, Lee M, Sasaki T, Fukai N, Shapiro R, Que I, Lowik C, Timpl R, Olsen BR. Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J 18, 4414-4423 (1999)
doi:10.1093/emboj/18.16.4414
PMid:10449407 PMCid:1171516
68 Ding YH, Javaherian K, Lo KM, Chopra R, Boehm T, Lanciotti J, Harris BA, Li Y, Shapiro R, Hohenester E, Timpl R, Folkman J, Wiley DC. Zinc-dependent dimers observed in crystals of human endostatin. Proc Natl Acad Sci U S A 95, 10443-10448 (1998)
doi:10.1073/pnas.95.18.10443
69 Han Q, Fu Y, Zhou H, He Y, Luo Y. Contributions of Zn(II)-binding to the structural stability of endostatin. FEBS Lett 581, 3027-3032 (2007)
doi:10.1016/j.febslet.2007.05.058
PMid:17544408
70 Kolozsi A, Jancsó A, Nagy NV, Gajda T. N-terminal fragment of the anti-angiogenic human endostatin binds copper(II) with very high affinity. J Inorg Biochem 103, 940-947 (2009)
doi:10.1016/j.jinorgbio.2009.04.006
PMid:19447499
71 Hohenester E, Sasaki T, Olsen BR, Timpl R. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO J 17, 1656-1664 (1998)
doi:10.1093/emboj/17.6.1656
PMid:9501087 PMCid:1170513
72 Hohenester E, Sasaki T, Mann K, Timpl R. Variable zinc coordination in endostatin. J Mol Biol 297, 1-6 (2000)
doi:10.1006/jmbi.2000.3553
PMid:10704302
73 Sasaki T, Fukai N, Mann K, Göhring W, Olsen BR, Timpl R. Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. EMBO J 17, 4249-4256 (1998)
doi:10.1093/emboj/17.15.4249
PMid:9687493 PMCid:1170758
74 Paddenberg R, Faulhammer P, Goldenberg A, Kummer W. Hypoxia-induced increase of endostatin in murine aorta and lung. Histochem Cell Biol 125, 497-508 (2006)
doi:10.1007/s00418-006-0158-5
PMid:16465514
75 Sun J, Ding I, Fenton B, Yi WS, Okunieff P. Immunohistochemical identification and localization of endogenous endostatin and its related peptides in murine tumors. Adv Exp Med Biol 599, 147-153 (2007)
doi:10.1007/978-0-387-71764-7_20
76 Heljasvaara R, Nyberg P, Luostarinen J, Parikka M, Heikkilä P, Rehn M, Sorsa T, Salo T, Pihlajaniemi T. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp Cell Res 307, 292-304 (2005)
doi:10.1016/j.yexcr.2005.03.021
PMid:15950618
77 Xie L, Palmsten K, MacDonald B, Kieran MW, Potenta S, Vong S, Kalluri R. Basement membrane derived fibulin-1 and fibulin-5 function as angiogenesis inhibitors and suppress tumor growth. Exp Biol Med 233, 155-162 (2008)
doi:10.3181/0706-RM-167
PMid:18222970
78 Pufe T, Petersen W, Kurz B, Tsokos M, Tillmann B, Mentlein R. Mechanical factors influence the expression of endostatin -an inhibitor of angiogenesis- in tendons. Orthop Res. 21, 610-616 (2003)
doi:10.1016/S0736-0266(02)00262-0
79 Bendrik C, Karlsson L, Dabrosin C. Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer. Cancer Lett 292, 32-40 (2010)
doi:10.1016/j.canlet.2009.11.002
PMid:19944523
80 Bellini MH, Coutinho EL, Filgueiras TC, Maciel TT, Schor N. Endostatin expression in the murine model of ischaemia/reperfusion-induced acute renal failure. Nephrology 12, 459-465 (2007)
doi:10.1111/j.1440-1797.2007.00850.x
PMid:17803469
81 Deininger MH, Weinschenk T, Morgalla MH, Meyermann R, Schluesener HJ. Release of regulators of angiogenesis following hypocrellin-A and -B photodynamic therapy of human brain tumor cells. Biochem Biophys Res Commun 298, 520-530 (2002)
doi:10.1016/S0006-291X(02)02512-3
82 Wu P, Yonekura H, Li H, Nozaki I, Tomono Y, Naito I, Ninomiya Y, Yamamoto H. Hypoxia down-regulates endostatin production by human microvascular endothelial cells and pericytes. Biochem Biophys Res Commun 288, 1149-1154 (2001)
doi:10.1006/bbrc.2001.5903
PMid:11700031
83 Deininger MH, Wybranietz WA, Graepler FT, Lauer UM, Meyermann R, Schluesener HJ. Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway. FASEB J 17, 1267-1276 (2003)
doi:10.1096/fj.02-1118com
PMid:12832291
84 Teodoro JG, Parker AE, Zhu X, Green MR. p53-mediated inhibition of angiogenesis throughup-regulation of a collagen prolyl hydroxylase. Science 313, 968-971 (2006)
doi:10.1126/science.1126391
PMid:16917063
85 Miled C, Pontoglio M, Garbay S, Yaniv M, Weitzman JB. A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network. Cancer Res 65, 5096-5104 (2005)
doi:10.1158/0008-5472.CAN-04-4232
PMid:15958553
86 Smith E, Hoffman R. Multiple fragments related to angiostatin and endostatin in fluid from venous leg ulcers. Wound Repair Regen 13, 148-157 (2005)
doi:10.1111/j.1067-1927.2005.130205.x
PMid:15828939
87 Perkins GD, Nathani N, Richter AG, Park D, Shyamsundar M, Heljasvaara R, Pihlajaniemi T, Manji M, Tunnicliffe W, McAuley D, Gao F, Thickett DR. Type XVIII collagen degradation products in acute lung injury. Crit Care 13, R52 (2009)
doi:10.1186/cc7779
PMid:19358707 PMCid:2689499
88 Määttä M, Heljasvaara R, Pihlajaniemi T, Uusitalo M. Collagen XVIII/endostatin shows a ubiquitous distribution in human ocular tissues and endostatin-containing fragments accumulate in ocular fluid samples. Graefes Arch Clin Exp Ophthalmol 245, 74-81 (2007)
89 Hou Q, Ling L, Wang F, Xing S, Pei Z, Zeng J. Endostatin expression in neurons during the early stage of cerebral ischemia is associated with neuronal apoptotic cell death in adult hypertensive rat model of stroke. Brain Res 1311, 182-188 (2010)
doi:10.1016/j.brainres.2009.11.033
PMid:19941836
90 Rehn M, Pihlajaniemi T. Identification of three N-terminal ends of type XVIII collagen chains and tissue-specific differences in the expression of the corresponding transcripts. The longest form contains a novel motif homologous to rat and Drosophila frizzled proteins. J Biol Chem 270, 4705-4711 (1995)
PMid:7876242
91 Quélard D, Lavergne E, Hendaoui I, Elamaa H, Tiirola U, Heljasvaara R, Pihlajaniemi T, Clément B, Musso O. A cryptic frizzled module in cell surface collagen 18 inhibits Wnt/beta-catenin signaling. PLoS One 3:e1878 (2008)
92 Ramont L, Brassart-Pasco S, Thevenard J, Deshorgue A, Venteo L, Laronze JY, Pluot M, Monboisse JC, Maquart FX. The NC1 domain of type XIX collagen inhibits in vivo melanoma growth. Mol Cancer Ther 6, 506-514 (2007)
doi:10.1158/1535-7163.MCT-06-0207
PMid:17308049
93 Mongiat M, Sweeney SM, San Antonio JD, Fu J, Iozzo RV. Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J Biol Chem 278, 4238-4249 (2003)
doi:10.1074/jbc.M210445200
PMid:12435733
94 Whitelock JM, Melrose J, Iozzo RV. Diverse cell signaling events modulated by perlecan. Biochemistry 47, 11174-11783 (2008)
doi:10.1021/bi8013938
PMid:18826258 PMCid:2605657
95 Iozzo RV, Zoeller JJ, Nyström A. Basement membrane proteoglycans: modulators ParExcellence of cancer growth and angiogenesis. Mol Cells 27, 503-513 (2009)
doi:10.1007/s10059-009-0069-0
PMid:19466598
96 Cailhier JF, Sirois I, Laplante P, Lepage S, Raymond MA, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV, Hébert MJ. Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis. J Biol Chem 283, 27220-27229 (2008)
doi:10.1074/jbc.M801164200
PMid:18658137
97 Laplante P, Raymond MA, Gagnon G, Vigneault N, Sasseville AM, Langelier Y, Bernard M, Raymond Y, Hébert MJ. Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J Immunol 174, 5740-5749 (2005)
PMid:15843576
98 Almond A. Hyaluronan. Cell Mol Life Sci 64, 1591-1596 (2007)
doi:10.1007/s00018-007-7032-z
PMid:17502996
99 Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol 85, 699-715 (2006)
doi:10.1016/j.ejcb.2006.05.009
PMid:16822580
100 Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 23, 435-461 (2007)
doi:10.1146/annurev.cellbio.23.090506.123337
PMid:17506690
101 Eberlein M, Scheibner KA, Black KE, Collins SL, Chan-Li Y, Powell JD, Horton MR. Anti-oxidant inhibition of hyaluronan fragment-induced inflammatory gene expression. J Inflamm 5, 20 (2008)
doi:10.1186/1476-9255-5-20
PMid:18986521 PMCid:2627834
102 Liu D, Shriver Z, Venkataraman G, El Shabrawi Y, Sasisekharan R. Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis. Proc Natl Acad Sci U S A 99, 568-573 (2002)
doi:10.1073/pnas.012578299
PMid:11805315 PMCid:117346
103 Hasan J, Shnyder SD, Clamp AR, McGown AT, Bicknell R, Presta M, Bibby M, Double J, Craig S, Leeming D, Stevenson K, Gallagher JT, Jayson GC. Heparin octasaccharides inhibit angiogenesis in vivo. Clin Cancer Res 11, 8172-8179 (2005)
doi:10.1158/1078-0432.CCR-05-0452
PMid:16299249
104 Davis GE. Matricryptic sites control tissue injury responses in the cardiovascular system: relationships to pattern recognition receptor regulated events. J Mol Cell Cardiol 48, 454-460 (2010)
doi:10.1016/j.yjmcc.2009.09.002
PMid:19751741
105 Faye C, Moreau C, Chautard E, Jetne R, Fukai N, Ruggiero F, Humphries MJ, Olsen BR, Ricard-Blum S. Molecular interplay between endostatin, integrins, and heparan sulfate. J Biol Chem 284, 22029-22040 (2009)
doi:10.1074/jbc.M109.002840
PMid:19502598
106 Aggeli AS, Kitsiou PV, Tzinia AK, Boutaud A, Hudson BG, Tsilibary EC: Selective binding of integrins from different renal cell types to the NC1 domain of alpha3 and alpha1 chains of type IV collagen. J Nephrol 22, 130-136 (2009)
PMid:19229828
107 Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R. Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 60, 2520-2526 (2000)
PMid:10811134
108 Sudhakar A, Nyberg P, Keshamouni VG, Mannam AP, Li J, Sugimoto H, Cosgrove D, Kalluri R. Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin. J Clin Invest 115, 2801-2810 (2005)
doi:10.1172/JCI24813
PMid:16151532 PMCid:1199529
109 Nyberg P, Xie L, Sugimoto H, Colorado P, Sund M, Holthaus K, Sudhakar A, Salo T, Kalluri R. Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin dependent collagen-derived tumor suppressor. Exp Cell Res 314, 3292-3305 (2008)
doi:10.1016/j.yexcr.2008.08.011
PMid:18775695 PMCid:2613512
110 Panka DJ, Mier JW. Canstatin inhibits Akt activation and induces Fas-dependent apoptosis in endothelial cells. J Biol Chem 278, 37632-37636 (2003)
doi:10.1074/jbc.M307339200
PMid:12876280
111 Magnon C, Galaup A, Mullan B, Rouffiac V, Bouquet C, Bidart JM, Griscelli F, Opolon P, Perricaudet M. Canstatin acts on endothelial and tumor cells via mitochondrial damage initiated through interaction with alphavbeta3 and alphavbeta5 integrins. Cancer Res 65, 4353-4361 (2005)
doi:10.1158/0008-5472.CAN-04-3536
PMid:15899827
112 Shahan TA, Ziaie Z, Pasco S, Fawzi A, Bellon G, Monboisse JC, Kefalides NA. Identification of CD47/integrin-associated protein and alpha(v)beta3 as two receptors for the alpha3(IV) chain of type IV collagen on tumor cells. Cancer Res 59, 4584-4590 (1999)
PMid:10493512
113 Pasco S, Monboisse JC, Kieffer N. The alpha 3(IV)185-206 peptide from noncollagenous domain 1 of type IV collagen interacts with a novel binding site on the beta 3 subunit of integrin alpha Vbeta 3 and stimulates focal adhesion kinase and phosphatidylinositol 3-kinase phosphorylation. J Biol Chem 275, 32999-33007 (2000)
doi:10.1074/jbc.M005235200
PMid:10934203
114 Pasco S, Han J, Gillery P, Bellon G, Maquart FX, Borel JP, Kefalides NA, Monboisse JC. A specific sequence of the noncollagenous domain of the alpha3(IV) chain of type IV collagen inhibits expression and activation of matrix metalloproteinases by tumor cells. Cancer Res 60, 467-473 (2000)
PMid:10667602
115 Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science 295, 140-143 (2002)
doi:10.1126/science.1065298
PMid:11778052
116 Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci U S A. 100, 4766-4771 (2003)
doi:10.1073/pnas.0730882100
PMid:12682293 PMCid:153630
117 Boosani CS, Mannam AP, Cosgrove D, Silva R, Hodivala-Dilke KM, Keshamouni VG, Sudhakar A. Regulation of COX-2 mediated signaling by alpha3 type IV noncollagenous domain in tumor angiogenesis. Blood 110, 1168-1177 (2007)
doi:10.1182/blood-2007-01-066282
PMid:17426256 PMCid:1939900
118 Borza CM, Pozzi A, Borza DB, Pedchenko V, Hellmark T, Hudson BG, Zent R. Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3. J Biol Chem 281, 20932-20939 (2006)
doi:10.1074/jbc.M601147200
PMid:16731529
119 Maeshima Y, Colorado PC, Kalluri R. Two RGD-independent alpha vbeta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J Biol Chem 275, 23745-23750 (2000)
doi:10.1074/jbc.C000186200
PMid:10837460
120 Pasco S, Ramont L, Venteo L, Pluot M, Maquart FX, Monboisse JC. In vivo overexpression of tumstatin domains by tumor cells inhibits their invasive properties in a mouse melanoma model. Exp Cell Res 301, 251-265 (2004)
doi:10.1016/j.yexcr.2004.07.036
PMid:15530861
121 Karumanchi SA, Jha V, Ramchandran R, Karihaloo A, Tsiokas L, Chan B, Dhanabal M, Hanai JI, Venkataraman G, Shriver Z, Keiser N, Kalluri R, Zeng H, Mukhopadhyay D, Chen RL, Lander AD, Hagihara K, Yamaguchi Y, Sasisekharan R, Cantley L, Sukhatme VP. Cell surface glypicans are low-affinity endostatin receptors. Mol Cell 7, 811-822 (2001)
doi:10.1016/S1097-2765(01)00225-8
122 Rehn M, Veikkola T, Kukk-Valdre E, Nakamura H, Ilmonen M, Lombardo C, Pihlajaniemi T, Alitalo K, Vuori K. Interaction of endostatin with integrins implicated in angiogenesis. Proc Natl Acad Sci U S A 98, 1024-1029 (2001)
doi:10.1073/pnas.031564998
PMid:11158588
123 Wickström SA, Alitalo K, Keski-Oja J. Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res 62, 5580-5589 (2002)
124 Kim YM, Hwang S, Kim YM, Pyun BJ, Kim TY, Lee ST, Gho YS, Kwon YG. Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J Biol Chem 277, 27872-27879 (2002)
doi:10.1074/jbc.M202771200
PMid:12029087
125 Schmidt A, Wenzel D, Thorey I, Sasaki T, Hescheler J, Timpl R, Addicks K, Werner S, Fleischmann BK, Bloch W. Endostatin influences endothelial morphology via the activated ERK1/2-kinase endothelial morphology and signal transduction. Microvasc Res 71, 152-162 (2006)
doi:10.1016/j.mvr.2006.01.001
PMid:16650878
126 Hanai J, Gloy J, Karumanchi SA, Kale S, Tang J, Hu G, Chan B, Ramchandran R, Jha V, Sukhatme VP, Sokol S. Endostatin is a potential inhibitor of Wnt signaling. J Cell Biol 158, 529-539 (2002)
doi:10.1083/jcb.200203064
PMid:12147676 PMCid:2173844
127 Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engström A, Timpl R, Welsh M, Claesson-Welsh L. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95, 3403-3411 (2000)
PMid:10828022
128 Shi H, Huang Y, Zhou H, Song X, Yuan S, Fu Y, Luo Y. Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin. Blood 110, 2899-2906 (2007)
doi:10.1182/blood-2007-01-064428
PMid:17615292
129 Mallery SR, Morse MA, Wilson RF, Pei P, Ness GM, Bradburn JE, Renner RJ, Schuller DE, Robertson FM. AIDS-related Kaposi's sarcoma cells rapidly internalize endostatin, which co-localizes to tropomysin microfilaments and inhibits cytokine-mediated migration and invasion. J Cell Biochem 89, 133-143 (2003)
doi:10.1002/jcb.10489
PMid:12682914
130 Fu Y, Chen Y, Luo X, Liang Y, Shi H, Gao L, Zhan S, Zhou D, Luo Y. The heparin binding motif of endostatin mediates its interaction with receptor nucleolin. Biochemistry 48, 11655-11663 (2009)
doi:10.1021/bi901265z
PMid:19877579
131 San Antonio JD, Zoeller JJ, Habursky K, Turner K, Pimtong W, Burrows M, Choi S, Basra S, Bennett JS, DeGrado WF, Iozzo RV. A key role for the integrin alpha2beta1 in experimental and developmental angiogenesis. Am J Pathol 175, 1338-1347 (2009)
doi:10.2353/ajpath.2009.090234
PMid:19700757
132 Bix G, Fu J, Gonzalez EM, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Höök M, Reed CC, Iozzo RV. Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin. J Cell Biol 166, 97-109 (2004)
doi:10.1083/jcb.200401150
PMid:15240572 PMCid:2172143
133 Nyström A, Shaik ZP, Gullberg D, Krieg T, Eckes B, Zent R, Pozzi A, Iozzo RV. Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity. Blood 114, 4897-4906 (2009)
doi:10.1182/blood-2009-02-207134
PMid:19789387
134 Laplante P, Raymond MA, Labelle A, Abe J, Iozzo RV, Hébert MJ. Perlecan proteolysis induces an alpha2beta1 integrin- and Src family kinase-dependent anti-apoptotic pathway in fibroblasts in the absence of focal adhesion kinase activation. J Biol Chem 281, 30383-30392 (2006)
doi:10.1074/jbc.M606412200
PMid:16882656
135 Bix G, Castello R, Burrows M, Zoeller JJ, Weech M, Iozzo RA, Cardi C, Thakur ML, Barker CA, Camphausen K, Iozzo RV. Endorepellin in vivo: targeting the tumor vasculature and retarding cancer growth and metabolism. J Natl Cancer Inst 98, 1634-1646 (2006)
doi:10.1093/jnci/djj441
PMid:17105986
136 Matou-Nasri S, Gaffney J, Kumar S, Slevin M. Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and gamma-adducin. Int J Oncol 35, 761-773 (2009)
PMid:19724912
137 Gao F, Yang CX, Mo W, Liu YW, He YQ. Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Clin Invest Med 31, E106-16 (2008)
138 Campo GM, Avenoso A, Campo S, D'Ascola A, Nastasi G, Calatroni A. Molecular size hyaluronan differently modulates toll-like receptor-4 in LPS-induced inflammation in mouse chondrocytes. Biochimie 92, 204-215 (2010)
doi:10.1016/j.biochi.2009.10.006
PMid:19879319
139 Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, Gallo RL. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem 279, 17079-17084 (2004)
doi:10.1074/jbc.M310859200
PMid:14764599
140 Gariboldi S, Palazzo M, Zanobbio L, Selleri S, Sommariva M, Sfondrini L, Cavicchini S, Balsari A, Rumio C. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J Immunol 181, 2103-2110 (2008)
PMid:18641349
141 Folkman J. Tumor suppression by p53 is mediated in part by the antiangiogenic activity of endostatin and tumstatin. Sci STKE 2006, pe35 (2006)
doi:10.1126/stke.3542006pe35
PMid:17003465
142 Folkman J. Tumor angiogenesis: therapeutic implications. New Engl J Med 285, 1182-1186 (1971)
PMid:4938153
143 Clamp AR, Jayson GC. The clinical potential of antiangiogenic fragments of extracellular matrix proteins. Br J Cancer 93, 967-972 (2005)
doi:10.1038/sj.bjc.6602820
PMid:16234821 PMCid:2361682
144 Sund M, Zeisberg M, Kalluri R. Endogenous stimulators and inhibitors of angiogenesis in gastrointestinal cancers: basic science to clinical application. Gastroenterology 129, 2076-2091 (2005)
doi:10.1053/j.gastro.2005.06.023
PMid:16344073
145 Mundel TM, Yliniemi AM, Maeshima Y, Sugimoto H, Kieran M, Kalluri R: Type IV collagen alpha6 chain-derived noncollagenous domain 1 (alpha6(IV)NC1) inhibits angiogenesis and tumor growth. Int J Cancer 122, 1738-1744 (2008)
doi:10.1002/ijc.23269
PMid:18074349
146 Burgess JK, Boustany S, Moir LM, Weckmann M, Lau JY, Grafton K, Baraket M, Hansbro PM, Hansbro NG, Foster PS, Black JL, Oliver BG. Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness. Am J Respir Crit Care Med 181, 106-115 (2010)
doi:10.1164/rccm.200904-0631OC
PMid:19875687
147 Fukai N, Eklund L, Marneros AG, Oh SP, Keene DR, Tamarkin L, Niemelä M, Ilves M, Li E, Pihlajaniemi T, Olsen BR. Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J 21, 1535-1544 (2002)
doi:10.1093/emboj/21.7.1535
PMid:11927538 PMCid:125362
148 Celik I, Sürücü O, Dietz C, Heymach JV, Force J, Höschele I, Becker CM, Folkman J, Kisker O. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve. Cancer Res 65, 11044-11050 (2005)
doi:10.1158/0008-5472.CAN-05-2617
PMid:16322254
149 Kojima T, Azar DT, Chang JH. Neostatin-7 regulates bFGF-induced corneal lymphangiogenesis. FEBS Lett 582, 2515-2520 (2008)
doi:10.1016/j.febslet.2008.06.014
PMid:18570894 PMCid:2579793
150 Szekanecz Z, Besenyei T, Paragh G, Koch AE. New insights in synovial angiogenesis. Joint Bone Spine 77, 13-19 (2010)
doi:10.1016/j.jbspin.2009.05.011
PMid:20022538
151 Zoeller JJ, Iozzo RV. Proteomic profiling of endorepellin angiostatic activity on human endothelial cells. Proteome Sci 6, 7 (2008)
doi:10.1186/1477-5956-6-7
PMid:18269764 PMCid:2275231
152 Zoeller JJ, McQuillan A, Whitelock J, Ho SY, Iozzo RV. A central function for perlecan in skeletal muscle and cardiovascular development. J Cell Biol 181, 381-394 (2008)
doi:10.1083/jcb.200708022
PMid:18426981 PMCid:2315682
153 West L, Govindraj P, Koob TJ, Hassell JR. Changes in perlecan during chondrocyte differentiation in the fetal bovine rib growth plate. J Orthop Res 24, 1317-1326 (2006)
doi:10.1002/jor.20160
PMid:16705694
154 Palmieri D, Camardella L, Ulivi V, Guasco G, Manduca P. Trimer carboxyl propeptide of collagen I produced by mature osteoblasts is chemotactic for endothelial cells. J Biol Chem 275, 32658-32663 (2000)
doi:10.1074/jbc.M002698200
PMid:10924500
155 Palmieri D, Poggi S, Ulivi V, Casartelli G, Manduca P. Pro-collagen I COOH-terminal trimer induces directional migration and metalloproteinases in breast cancer cells. J Biol Chem 278, 3639-47 (2003)
doi:10.1074/jbc.M207483200
PMid:12441353
156 Palmieri D, Astigiano S, Barbieri O, Ferrari N, Marchisio S, Ulivi V, Volta C, Manduca P. Procollagen I COOH-terminal fragment induces VEGF-A and CXCR4 expression in breast carcinoma cells. Exp Cell Res 314, 2289-2298 (2008)
doi:10.1016/j.yexcr.2008.04.016
PMid:18570923
157 Visigalli D, Palmieri D, Strangio A, Astigiano S, Barbieri O, Casartelli G, Zicca A, Manduca P. The carboxyl terminal trimer of procollagen I induces pro-metastatic changes and vascularization in breast cancer cells xenografts. BMC Cancer 9, 59 (2009)
doi:10.1186/1471-2407-9-59
PMid:19226458 PMCid:2652491
158 Cui X, Xu H, Zhou S, Zhao T, Liu A, Guo X, Tang W, Wang F. Evaluation of angiogenic activities of hyaluronan oligosaccharides of defined minimum size. Life Sci 85, 573-577 (2009)
doi:10.1016/j.lfs.2009.08.010
PMid:19720068
159 Slevin M, Kumar S, Gaffney J. Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. J Biol Chem 277, 41046-41059 (2002)
doi:10.1074/jbc.M109443200
PMid:12194965
160 Rooney P, Wang M, Kumar P, Kumar S. Angiogenic oligosaccharides of hyaluronan enhance the production of collagens by endothelial cells. J Cell Sci 105, 213-218 (1993)
PMid:7689574
161 Hornebeck W, Maquart FX. Proteolyzed matrix as a template for the regulation of tumor progression. Biomed Pharmacother 57, 223-30 (2003)
doi:10.1016/S0753-3322(03)00049-0
162 He XP, Li ZS, Zhu RM, Tu ZX, Gao J, Pan X, Gong YF, Jin J, Man XH, Wu HY, Xu AF. Effects of recombinant human canstatin protein in the treatment of pancreatic cancer. World J Gastroenterol 12, 6652-6657 (2006)
PMid:17075979
163 Roth JM, Akalu A, Zelmanovich A, Policarpio D, Ng B, MacDonald S, Formenti S, Liebes L, Brooks PC. Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo. Am J Pathol 166, 901-911 (2005)
PMid:15743801 PMCid:1602358
164 Kawaguchi T, Yamashita Y, Kanamori M, Endersby R, Bankiewicz KS, Baker SJ, Bergers G, Pieper RO. The PTEN/Akt pathway dictates the direct alphaVbeta3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo. Cancer Res 66, 11331-11340 (2006)
doi:10.1158/0008-5472.CAN-06-1540
PMid:17145879
165 Koskimaki JE, Karagiannis ED, Rosca EV, Vesuna F, Winnard PT Jr, Raman V, Bhujwalla ZM, Popel AS. Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts. Neoplasia 11, 1285-1291 (2009)
PMid:20019836 PMCid:2794509
166 Koskimaki JE, Karagiannis ED, Tang BC, Hammers H, Watkins DN, Pili R, Popel AS. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model. BMC Cancer 10, 29 (2010)
doi:10.1186/1471-2407-10-29
PMid:20122172 PMCid:2824711
167 Ng B, Zakrzewski J, Warycha M, Christos PJ, Bajorin DF, Shapiro RL, Berman RS, Pavlick AC, Polsky D, Mazumdar M, Montgomery A, Liebes L, Brooks PC, Osman I. Shedding of distinct cryptic collagen epitope (HU177) in sera of melanoma patients. Clin Cancer Res 14, 6253-6258 (2008)
doi:10.1158/1078-0432.CCR-07-4992
PMid:18829505
168 Wilson RF, Morse MA, Pei P, Renner RJ, Schuller DE, Robertson FM, Mallery SR. Endostatin inhibits migration and invasion of head and neck squamous cell carcinoma cells. Anticancer Res 23, 1289-1295 (2003)
PMid:12820385
169 Nyberg P, Heikkilä P, Sorsa T, Luostarinen J, Heljasvaara R, Stenman UH, Pihlajaniemi T, Salo T. Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13. J Biol Chem 278, 22404-22411 (2003)
doi:10.1074/jbc.M210325200
PMid:12690120
170 Kim YM, Jang JW, Lee OH, Yeon J, Choi EY, Kim KW, Lee ST, Kwon YG. Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res 60, 5410-5413 (2000)
PMid:11034081
171 Boosani CS, Nalabothula N, Sheibani N, Sudhakar A. Inhibitory Effects of arresten on bFGF-induced proliferation, migration, and matrix metalloproteinase-2 activation in mouse retinal endothelial cells. Curr Eye Res 35, 45-55 (2010)
doi:10.3109/02713680903374208
PMid:20021254 PMCid:2827929
172 Cordo Russo RI, García MG, Alaniz L, Blanco G, Alvarez E, Hajos SE. Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P-glycoprotein activity and PI3K/Akt pathway. Int J Cancer 122, 1012-1018 (2008)
doi:10.1002/ijc.23122
PMid:17985348
173 Hosono K, Nishida Y, Knudson W, Knudson CB, Naruse T, Suzuki Y, Ishiguro N. Hyaluronan oligosaccharides inhibit tumorigenicity of osteosarcoma cell lines MG-63 and LM-8 in vitro and in vivo via perturbation of hyaluronan-rich pericellular matrix of the cells. Am J Pathol 171, 274-286 (2007)
doi:10.2353/ajpath.2007.060828
PMid:17591972 PMCid:1941604
174 Berger AC, Feldman AL, Gnant MF, Kruger EA, Sim BK, Hewitt S, Figg WD, Alexander HR, Libutti SK. The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing. J Surg Res 91, 26-31 (2000)
doi:10.1006/jsre.2000.5890
PMid:10816345
175 Bloch W, Huggel K, Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing. FASEB J 14, 2373-2376 (2000)
PMid:11024009
176 Michaels J 5th, Dobryansky M, Galiano RD, Bhatt KA, Ashinoff R, Ceradini DJ, Gurtner GC. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration. Wound Repair Regen 13, 506-512 (2005)
doi:10.1111/j.1067-1927.2005.00071.x
PMid:16176459
177 Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing. Matrix Biol 27, 535-546 (2008)
doi:10.1016/j.matbio.2008.03.003
PMid:18455382
178 Isobe K, Kuba K, Maejima Y, Suzuki J, Kubota S, Isobe M. Inhibition of endostatin/collagen XVIII deteriorates left ventricular remodeling and heart failure in rat myocardial infarction model. Circ J 74, 109-119 (2010)
doi:10.1253/circj.CJ-09-0486
PMid:19966499
179 Yamamoto Y, Maeshima Y, Kitayama H, Kitamura S, Takazawa Y, Sugiyama H, Yamasaki Y, Makino H. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 53, 1831-1840 (2004)
doi:10.2337/diabetes.53.7.1831
PMid:15220208
180 Gao F, Liu Y, He Y, Yang C, Wang Y, Shi X, and Wei G: Hyaluronan oligosaccharides promote excisional wound healing through enhanced angiogenesis. Matrix Biol 29, 107-116 (2010)
doi:10.1016/j.matbio.2009.11.002
PMid:19913615
181 Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, Didierjean L, Stamenkovic I, Saurat JH. Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med 3, e493 (2006)
doi:10.1371/journal.pmed.0030493
PMid:17177600 PMCid:1702558
182 Adair-Kirk TL, Senior RM. Fragments of extracellular matrix as mediators of inflammation. Int J Biochem Cell Biol 40, 1101-1110 (2008)
doi:10.1016/j.biocel.2007.12.005
183 Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, Galin FS, Folkerts G, Nijkamp FP, Blalock JE. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med 12, 317-323 (2006)
doi:10.1038/nm1361
PMid:16474398
184 Monboisse JC, Garnotel R, Bellon G, Ohno N, Perreau C, Borel JP, Kefalides NA. The alpha 3 chain of type IV collagen prevents activation of human polymorphonuclear leukocytes. J Biol Chem 269, 25475-25482 (1994)
PMid:7929248
185 Ziaie Z, Fawzi A, Bellon G, Monboisse JC, Kefalides NA. A peptide of the alpha3 chain of type IV collagen protects basement membrane against damage by PMN. Biochem Biophys Res Commun 261, 247-250 (1999)
doi:10.1006/bbrc.1999.1029
PMid:10425173
186 Fieber C, Baumann P, Vallon R, Termeer C, Simon JC, Hofmann M, Angel P, Herrlich P, Sleeman JP. Hyaluronan-oligosaccharide-induced transcription of metalloproteases. J Cell Sci 117, 359-367 (2004)
doi:10.1242/jcs.00831
PMid:14657275
187 Horton MR, Shapiro S, Bao C, Lowenstein CJ, Noble PW. Induction and regulation of macrophage metalloelastase by hyaluronan fragments in mouse macrophages. J Immunol 162, 4171-4176 (1999)
PMid:10201943
188 McKee CM, Lowenstein CJ, Horton MR, Wu J, Bao C, Chin BY, Choi AM, Noble PW. Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappaB-dependent mechanism. J Biol Chem 272, 8013-8018 (1997)
doi:10.1074/jbc.272.12.8013
PMid:9065473
189 Jha P, Manickam B, Matta B, Bora PS, Bora NS: Proteolytic cleavage of type I collagen generates an autoantigen in autoimmune uveitis. J Biol Chem 284, 31401-3111 (2009)
doi:10.1074/jbc.M109.033381
PMid:19755419
190 Borza DB, Neilson EG, Hudson BG. Pathogenesis of Goodpasture syndrome: a molecular perspective. Semin Nephrol 23, 522-531 (2003)
doi:10.1053/S0270-9295(03)00131-1
191 Wieslander J, Langeveld J, Butkowski R, Jodlowski M, Noelken M, Hudson BG: Physical and immunochemical studies of the globular domain of type IV collagen. Cryptic properties of the Goodpasture antigen. J Biol Chem 260, 8564-8570 (1985)
PMid:2409091
192 David M, Borza DB, Leinonen A, Belmont JM, Hudson BG: Hydrophobic amino acid residues are critical for the immunodominant epitope of the Goodpasture autoantigen. A molecular basis for the cryptic nature of the epitope. J Biol Chem 276, 6370-6377 (2001)
doi:10.1074/jbc.M008956200
PMid:11098057
193 Reynolds J, Abbott DS, Karegli J, Evans DJ, Pusey CD. Mucosal tolerance induced by an immunodominant peptide from rat alpha3(IV)NC1 in established experimental autoimmune glomerulonephritis. Am J Pathol 174, 2202-2210 (2009)
doi:10.2353/ajpath.2009.081041
PMid:19406992 PMCid:2684185
194 Lemmink HH, Schröder CH, Brunner HG, Nelen MR, Zhou J, Tryggvason K, Haagsma-Schouten WA, Roodvoets AP, Rascher W, van Oost BA, Smeets HJM. Identification of four novel mutations in the COL4A5 gene of patients with Alport syndrome. Genomics 17, 485-489 (1993)
doi:10.1006/geno.1993.1351
PMid:8406498
195 Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12, 97-106 (2001)
PMid:11134255
196 Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frascá G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61, 1947-1956 (2002)
doi:10.1046/j.1523-1755.2002.00379.x
PMid:12028435
197 Nagel M, Nagorka S, Gross O. Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Hum Mutat 26, 60 (2005)
doi:10.1002/humu.9349
PMid:15954103
198 Lourenço GJ, Cardoso-Filho C, Gonçales NS, Shinzato JY, Zeferino LC, Nascimento H, Costa FF, Gurgel MS, Lima CS. A high risk of occurrence of sporadic breast cancer in individuals with the 104NN polymorphism of the COL18A1 gene. Breast Cancer Res Treat 100, 335-338 (2006)
doi:10.1007/s10549-006-9259-z
PMid:16807676
199 Nascimento H, Lourenço GJ, Ortega MM, Yamaguti GG, Costa FF, Lima CS. D104N polymorphism in endostatin, an angiogenesis inhibitor, in acute and chronic myeloid leukaemia. Leuk Res 31, 1158-1159 (2007)
doi:10.1016/j.leukres.2006.09.019
PMid:17067672
200 Iughetti P, Suzuki O, Godoi PH, Alves VA, Sertié AL, Zorick T, Soares F, Camargo A, Moreira ES, di Loreto C, Moreira-Filho CA, Simpson A, Oliva G, Passos-Bueno MR. A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma. Cancer Res 61, 7375-7378 (2001)
PMid:11606364
201 Macpherson GR, Singh AS, Bennett CL, Venzon DJ, Liewehr DJ, Franks ME, Dahut WL, Kantoff PW, Price DK, Figg WD. Genotyping and functional analysis of the D104N variant of human endostatin. Cancer Biol Ther 3, 1298-1303 (2004)
PMid:15662127
202 Balasubramanian SP, Cross SS, Globe J, Cox A, Brown NJ, Reed MW. Endostatin gene variation and protein levels in breast cancer susceptibility and severity. BMC Cancer 7, 107 (2007)
doi:10.1186/1471-2407-7-107
PMid:17587451 PMCid:1924861
203 Zambon L, Honma HN, Lourenço GJ, Saad IA, Mussi RK, Lima CS. A polymorphism in the angiogenesis inhibitor, endostatin, in lung cancer susceptibility. Lung Cancer 59, 276-278 (2008)
doi:10.1016/j.lungcan.2007.10.018
PMid:18054814
204 Menzel O, Bekkeheien RC, Reymond A, Fukai N, Boye E, Kosztolanyi G, Aftimos S, Deutsch S, Scott HS, Olsen BR, Antonarakis SE, Guipponi M. Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin. Hum Mutat 23, 77-84 (2004)
doi:10.1002/humu.10284
PMid:14695535
205 Abdollahi A, Hlatky L, Huber PE. Endostatin: the logic of antiangiogenic therapy. Drug Resist Updat 8, 59-74 (2005)
doi:10.1016/j.drup.2005.03.001
PMid:15939343
206 Karamouzis MV, Moschos SJ: The use of endostatin in the treatment of solid tumors. Expert Opin Biol Ther 9, 641-648 (2009)
doi:10.1517/14712590902882118
PMid:19368526
207 Jiang LP, Zou C, Yuan X, Luo W, Wen Y, Chen YL. The N-terminal modification increases the stability of the recombinant human endostatin in vitro. Biotechnol Appl Biochem 54, 113-120 (2009)
doi:10.1042/BA20090063
PMid:19527221
208 Ling Y, Yang Y, Lu N, You QD, Wang S, Gao Y, Chen Y, Guo QL: Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells. Biochem Biophys Res Commun 361, 79-84 (2007)
doi:10.1016/j.bbrc.2007.06.155
PMid:17644065
209 Lu N, Ling Y, Gao Y, Chen Y, Mu R, Qi Q, Liu W, Zhang H, Gu H, Wang S, Yang Y, Guo Q. Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells. Exp Biol Med 233, 1013-20 (2008)
doi:10.3181/0801-RM-7
PMid:18480415
210 Ling Y, Lu N, Gao Y, Chen Y, Wang S, Yang Y, Guo Q. Endostar induces apoptotic effects in HUVECs through activation of caspase-3 and decrease of Bcl-2. Anticancer Res 29, 411-417 (2009)
PMid:19331180
211 Nie Y, Zhang X, Wang X, Chen J. Preparation and stability of N-terminal mono-PEGylated recombinant human endostatin. Bioconjug Chem 17, 995-999 (2006)
doi:10.1021/bc050355d
PMid:16848407
212 Tong Y, Zhong K, Tian H, Gao X, Xu X, Yin X, Yao W. Characterization of a monoPEG20000-Endostar. Int J Biol Macromol 46, 331-336 (2010)
doi:10.1016/j.ijbiomac.2010.01.017
PMid:20122957
213 Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, Gillies SD, Folkman J, Javaherian K. Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy. Clin Cancer Res 14, 1487-1493 (2008)
doi:10.1158/1078-0432.CCR-07-1530
PMid:18316573
214 Tjin Tham Sjin RM, Satchi-Fainaro R, Birsner AE, Ramanujam VM, Folkman J, Javaherian K. A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity. Cancer Res 65, 3656-3663 (2005)
doi:10.1158/0008-5472.CAN-04-1833
PMid:15867360
215 Xu F, Ma Q, Sha H. Optimizing drug delivery for enhancing therapeutic efficacy of recombinant human endostatin in cancer treatment. Crit Rev Ther Drug Carrier Syst 24, 445-492 (2007)
PMid:18197781
216 Indraccolo S. Undermining tumor angiogenesis by gene therapy: an emerging field. Curr Gene Ther 4, 297-308 (2004)
PMid:15384943
217 Persano L, Crescenzi M, Indraccolo S. Anti-angiogenic gene therapy of cancer: current status and future prospects. Mol Aspects Med 28, 87-114 (2007)
doi:10.1016/j.mam.2006.12.005
PMid:17306361
218 Lin X, Huang H, Li S, Li H, Li Y, Cao Y, Zhang D, Xia Y, Guo Y, Huang W, Jiang W. A phase I clinical trial of an adenovirus-mediated endostatin gene (E10A) in patients with solid tumors. Cancer Biol Ther 6, 648-653 (2007)
doi:10.4161/cbt.6.5.4004
219 He XP, Su CQ, Wang XH, Pan X, Tu ZX, Gong YF, Gao J, Liao Z, Jin J, Wu HY, Man XH, Li ZS. E1B-55kD-deleted oncolytic adenovirus armed with canstatin gene yields an enhanced anti-tumor efficacy on pancreatic cancer. Cancer Lett 285, 89-98 (2009)
doi:10.1016/j.canlet.2009.05.006
220 Wu J, Wu L, Xu X, Xu X, Yin X, Chen Y, Hu Y. Microspheres made by w/o/o emulsion method with reduced initial burst for long-term delivery of endostar, a novel recombinant human endostatin. J Pharm Sci 98, 2051-2058 (2009)
doi:10.1002/jps.21589
PMid:18823006
221 Malavasi N, Rodrigues D, Chammas R, Chura-Chambi R, Barbuto J, Balduino K, Nonogaki S, Morganti L. Continuous and high level in vivo delivery of endostatin from recombinant cells encapsulated in TheraCyte immunoisolation devices. Cell Transplant 19, 269-277 (2010)
doi:10.3727/096368909X480927
PMid:19951460
222 Magnon C, Opolon P, Connault E, Mir LM, Perricaudet M, Martel-Renoir D. Canstatin gene electrotransfer combined with radiotherapy: preclinical trials for cancer treatment. Gene Ther 15, 1436-1445 (2008)
doi:10.1038/gt.2008.100
PMid:18548116
223 Wang WB, Zhou YL, Heng DF, Miao CH, Cao YL. Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and canstatin gene suppression therapy on breast tumor xenograft growth in mice. Breast Cancer Res Treat 110, 283-295 (2008)
doi:10.1007/s10549-007-9731-4
PMid:17899369
224 You Y, Xue X, Li M, Qin X, Zhang C, Wang W, Giang C, Wu S, Liu Y, Zhu W, Ran Y, Inhibition effect of pcDNA-tum-5 on the growth of S180 tumor. Cytotechnology 56, 97-104 (2008)
doi:10.1007/s10616-007-9117-9
PMid:19002847 PMCid:2259260
225 Meng J, Ma N, Yan Z, Han W, Zhang Y. NGR enhanced the anti-angiogenic activity of tum-5. J Biochem 140, 299-304 (2006)
doi:10.1093/jb/mvj152
PMid:16845126
226 Huang G, Chen L. Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma. J Cancer Res Clin Oncol 136, 1201-1211 (2010)
doi:10.1007/s00432-010-0770-6
PMid:20130910
227 Mitsuma W, Kodama M, Hanawa H, Ito M, Ramadan MM, Hirono S, Obata H, Okada S, Sanada F, Yanagawa T, Kashimura T, Fuse K, Tanabe N, Aizawa Y. Serum endostatin in the coronary circulation of patients with coronary heart disease and its relation to coronary collateral formation. Am J Cardiol 99, 494-498 (2007)
doi:10.1016/j.amjcard.2006.09.095
PMid:17293192
228 Woo IS, Kim KA, Jeon HM, Hong SH, Rho SY, Koh SJ, Lee MA, Byun JH, Kang JH, Hong YS, Lee KS, Cho CS, Choi MG, Chung IS. Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma. Int J Cancer 119, 2901-2906 (2006)
doi:10.1002/ijc.22216
PMid:16998835
229 Kim HS, Lim SJ, Park YK. Anti-angiogenic factor endostatin in osteosarcoma. APMIS 117, 716-23 (2009)
doi:10.1111/j.1600-0463.2009.02524.x
PMid:19775339
230 Chang JW, Kang U-B, Kim DH, Yi JK, Lee JW, Noh D-Y, Lee C, Yu M-H. Identification of circulating endorepellin LG3 fragment: Potential use as a serological biomarker for breast cancer. Proteomics Clin Appl 2, 23-32 (2008)
doi:10.1002/prca.200780049
231 Hamilton HK, Rose AE, Christos PJ, Shapiro RL, Berman RS, Mazumdar M, Ma MW, Krich D, Liebes L, Brooks PC, Osman I. Increased shedding of HU177 correlates with worse prognosis in primary melanoma. J Transl Med 8, 19 (2010)
doi:10.1186/1479-5876-8-19
PMid:20178639 PMCid:2837640
232 Autelitano DJ, Rajic A, Smith AI, Berndt MC, Ilag LL, Vadas M. The cryptome: a subset of the proteome, comprising cryptic peptides with distinct bioactivities. Drug Discov Today 11, 306-314 (2006)
doi:10.1016/j.drudis.2006.02.003
PMid:16580972
233 Faye C, Chautard E, Olsen BR, Ricard-Blum S. The first draft of the endostatin interaction network. J Biol Chem 284, 22041-22047 (2009)
doi:10.1074/jbc.M109.002964
PMid:19542224
234 Gebbink MF, Voest EE, Reijerkerk A. Do antiangiogenic protein fragments have amyloid properties? Blood 104, 1601-1605 (2004)
doi:10.1182/blood-2004-02-0433
PMid:15166035
235 Kranenburg O, Kroon-Batenburg LM, Reijerkerk A, Wu YP, Voest EE, Gebbink MF. Recombinant endostatin forms amyloid fibrils that bind and are cytotoxic to murine neuroblastoma cells in vitro. FEBS Lett 539, 149-155 (2003)
doi:10.1016/S0014-5793(03)00218-7
236 Reijerkerk A, Mosnier LO, Kranenburg O, Bouma BN, Carmeliet P, Drixler T, Meijers JC, Voest EE, Gebbink MF. Amyloid endostatin induces endothelial cell detachment by stimulation of the plasminogen activation system. Mol Cancer Res 1, 561-568 (2003)
PMid:12805403
237 Fernando NT, Koch M, Rothrock C, Gollogly LK, D'Amore PA, Ryeom S, Yoon SS. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14, 1529-1539 (2008)
doi:10.1158/1078-0432.CCR-07-4126
PMid:18316578
238 Magnon C, Opolon P, Ricard M, Connault E, Ardouin P, Galaup A, Métivier D, Bidart JM, Germain S, Perricaudet M, Schlumberger M. Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1alpha-mediated tumor apoptotic switch. J Clin Invest 117, 1844-1855 (2007)
doi:10.1172/JCI30269
PMid:17557121 PMCid:1884687
239 Zhuang HQ, Yuan ZY. Process in the mechanisms of endostatin combined with radiotherapy. Cancer Lett 282, 9-13 (2009)
doi:10.1016/j.canlet.2008.12.008
PMid:19136200
240 Davis GE. Affinity of integrins for damaged extracellular matrix: alpha v beta 3 binds to denatured collagen type I through RGD sites. Biochem Biophys Res Commun 182, 1025-1031 (1992)
doi:10.1016/0006-291X(92)91834-D
241 Yamamoto M, Yamato M, Aoyagi M, Yamamoto K. Identification of integrins involved in cell adhesion to native and denatured type I collagens and the phenotypic transition of rabbit arterial smooth muscle cells. Exp Cell Res 219, 249-256 (1995)
doi:10.1006/excr.1995.1225
PMid:7628540
242 Xu J, Rodriguez D, Kim JJ, Brooks PC. Generation of monoclonal antibodies to cryptic collagen sites by using subtractive immunization. Hybridoma 19, 375-385 (2000)
doi:10.1089/02724570050198893
PMid:11128027
243 Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem 275, 1209-1215 (2000)
doi:10.1074/jbc.275.2.1209
PMid:10625665
244 Maeshima Y, Yerramalla UL, Dhanabal M, Holthaus KA, Barbashov S, Kharbanda S, Reimer C, Manfredi M, Dickerson WM, Kalluri R. Extracellular matrix-derived peptide binds to alpha(v)beta(3) integrin and inhibits angiogenesis. J Biol Chem 276, 31959-31968 (2001)
doi:10.1074/jbc.M103024200
PMid:11399763
245 Shahan T, Grant D, Tootell M, Ziaie Z, Ohno N, Mousa S, Mohamad S, Delisser H, Kefalides N. Oncothanin, a peptide from the alpha3 chain of type IV collagen, modifies endothelial cell function and inhibits angiogenesis. Connect Tissue Res 45, 151-163 (2004)
doi:10.1080/03008200490505923
PMid:15512769
246 Eikesdal HP, Sugimoto H, Birrane G, Maeshima Y, Cooke VG, Kieran M, Kalluri R. Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity. Proc Natl Acad Sci U S A 105, 15040-15045 (2008)
doi:10.1073/pnas.0807055105
PMid:18818312 PMCid:2567489
247 Karagiannis ED, Popel AS. Identification of novel short peptides derived from the alpha 4, alpha 5, and alpha 6 fibrils of type IV collagen with anti-angiogenic properties. Biochem Biophys Res Commun 354, 434-439 (2007)
doi:10.1016/j.bbrc.2006.12.231
PMid:17239819 PMCid:1899480
248 Chelberg MK, McCarthy JB, Skubitz AP, Furcht LT, Tsilibary EC. Characterization of a synthetic peptide from type IV collagen that promotes melanoma cell adhesion, spreading, and motility. J Cell Biol 111, 261-270 (1990)
doi:10.1083/jcb.111.1.261
PMid:2365734
249 Eble JA, Golbik R, Mann K, Kühn K. The alpha 1 beta 1 integrin recognition site of the basement membrane collagen molecule (alpha 1(IV))2 alpha 2(IV) EMBO J 12, 4795-802 (1993)
PMid:8223488 PMCid:413926
250 Vandenberg P, Kern A, Ries A, Luckenbill-Edds L, Mann K, Kühn K. Characterization of a type IV collagen major cell binding site with affinity to the alpha 1 beta 1 and the alpha 2 beta 1 integrins. J Cell Biol 113, 1475-1483 (1991)
doi:10.1083/jcb.113.6.1475
PMid:1646206
251 Miles AJ, Knutson JR, Skubitz AP, Furcht LT, McCarthy JB, Fields GB. A peptide model of basement membrane collagen alpha 1 (IV) 531-543 binds the alpha 3 beta 1 integrin. J Biol Chem 270, 29047-29050 (1995)
doi:10.1074/jbc.270.49.29047
PMid:7493922
252 Lauer JL, Gendron CM, Fields GB. Effect of ligand conformation on melanoma cell alpha3beta1 integrin-mediated signal transduction events: implications for a collagen structural modulation mechanism of tumor cell invasion. Biochemistry 37, 5279-5287 (1998)
doi:10.1021/bi972958l
PMid:9548759
253 Knutson JR, Iida J, Fields GB, McCarthy JB. CD44/chondroitin sulfate proteoglycan and alpha2 beta1 integrin mediate human melanoma cell migration on type IV collagen and invasion of basement membranes. Mol Biol Cell 7, 383-396 (1996)
PMid:8868467 PMCid:275891
254 Elamaa H, Snellman A, Rehn M, Autio-Harmainen H, Pihlajaniemi T. Characterization of the human type XVIII collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif. Matrix Biol 22, 427-442 (2003)
doi:10.1016/S0945-053X(03)00073-8
255 Pedchenko V, Zent R, Hudson BG. Alpha(v)beta3 and alpha(v)beta5 integrins bind both the proximal RGD site and non-RGD motifs within noncollagenous (NC1) domain of the alpha3 chain of type IV collagen: implication for the mechanism of endothelia cell adhesion. J Biol Chem 279, 2772-2780 (2004)
doi:10.1074/jbc.M311901200
PMid:14610079
Abbreviations: BCL-2: B cell CLL/lymphoma-2, cAMP: Cyclic adenosine monophosphate, cGMP: Cyclic guanosine monophosphate, COX: Cyclooxygenase, EGF: Epidermal growth factor, ERK1/2, Extracellular signal-regulated kinase , FAK: Focal adhesion kinase, FGF: Fibroblast growth factor, KDR: Kinase insert domain receptor, Flk-1: Fetal liver kinase 1, MEK: Map-Erk kinase, p38: MAPK p38 mitogen-activated protein kinase, MMP: Matrix metalloproteinase, MT-MMP Membrane-type matrix metalloproteinase, NC1: Non collagenous domain 1, PTEN: Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity: protein phosphatase, SV40: Simian virus 40, TLR: Toll-like receptor, VEGF: Vascular endothelial growth factor
Key Words Extracellular matrix, Matricryptic sites, Matricryptins, Collagens, Proteoglycans, Review
Send correspondence to : Sylvie Ricard-Blum, Institut de Biologie et Chimie des Proteines, UMR 5086 CNRS - Universite Lyon 1,7 passage du Vercors, 69367 Lyon Cedex 07, France, Tel: 330437652926, Fax: 330472722604, E-mail:s.ricard-blum@ibcp.fr