[Frontiers in Bioscience E2, 1073-1080, June 1, 2010]
Adrenomedullin and its expression in cancers and bone. A literature Review
Xing Dai1, Wei Ma1, Rajiv Kumar Jha1, Xijing He2
1
TABLE OF CONTENTS
1. ABSTRACT
Adrenomedullin (ADM) was first isolated from pheochromocytoma tissue as a novel vasodilative peptide in 1993. ADM binds to two receptors on plasma membrane which are comprised of Calcitonin Receptor-Like Receptor (CRLR), a member of serpentine receptor superfamily, and Receptor Activity Modifying Protein (RAMP) type 2 or 3. ADM is known to have hypotensive activity. Recently, ADM has been shown to be an almost ubiquitous peptide, synthesized in many mammalian tissues. ADM has potent in vivo angiogenic activity and tumor growth promoting effect in animal models. Many human tumors express ADM. However, only little information exists regarding the expression or the role of ADM in bone and its effect in bone metabolism. It is still not clear whether ADM is involved in pathogenesis and development of osteosarcoma, the most common form of bone tumor. The purpose of this review is to examine the most salient features of adrenomedullin biology, its expression in tumors and its potential implication in the treatment of bone tumors.
2. INTRODUCTION
ADM is a 52-amino-acid peptide, originally isolated from human phaeochromocytoma, by Kitamura et al in 1993 (1). However, the mRNA of ADM has been shown to be expressed not only in the adrenal gland but also in a variety of organs and tissues, including vascular endothelial and smooth muscle cells, cardiomyocytes, fibroblasts, neurons and glial cells (2). ADM was initially characterized by its ability to stimulate cAMP production in human platelets and exerts a potent and long-lasting vasodilative effect in the rat. Recently expression and secretion of ADM has been demonstrated in many tumors and biological fluids. ADM has been implicated in the modulation of numerous physiological processes (3). Over the past few years, a variety of effects have been shown. It is hypothesized that ADM protects organs from hypertension (4) or infection (5); in vivo evidence has suggested that nitric oxide (NO) mediates ADM's effects in the brain (6); and ADM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions, inhibition of endothelial apoptosis (7), and promotion of angiogenesis (8,9). In addition, ADM has protective effects against vascular injury, including oxidative stress (10).
Its structure is homologous to calcitonin gene-related peptide (CGRP), calcitonin and amylin, all of which belong to the same peptide family. The ADM molecule contains a 6-amino-acid ring formed with a disulfide bond between residues 16 and 21 (11). ADM is encoded by a gene contained in humans in chromosome 11 and consisting of 4 exons and 3 introns. The mature ADM peptide is derived from preproADM containing 185 amino acids, and its DNA sequence encoding has been identified in human as well as rat tissue (12). Preproadrenomedullin cleavage at the signal peptide between Thr21 and Ala22 yields a truncated propeptide with 164 peptides that contains ADM. The first paired basic amino acids Lys43-Arg44 is a representative site for proteolytic cleavage and is preceded by a Arg41-Gly42 residue for the possible C-terminal amidation, giving the product named proadrenomedullin N-terminal 20 peptide (PAMP) (13,14). As a new hypotensive peptide, PAMP was isolated from human plasma, urine, kidney and brain. The transcription of its mRNA is reportedly affected by tumor necrosis factor-α (TNF-α), interleukin-1, interferon-γ, endothelin-1, angiotensin II, vasoactive intestinal peptide, and dexamethasone (15,16). Nevertheless, a new study found that PAMP mRNA is increased in ventricular muscle in patients with pulmonary hypertension (17).
2.1. ADM receptor
ADM and CGRP belong to a family of structurally related peptides, which also includes calcitonin (CT) and amylin. ADM and CGRP have common 6-amino-acid ring structures formed by disulfide bridges near the N-terminus, and amidated C-termini, both of which are required for biological activity. The ring structures are not essential for receptor binding. Of course they are both potent vasodilators. ADM acts as a circulating or paracrine hormone and exerts its effects via the G-protein coupled calcitonin-like receptor (CL), a member of the serpentine receptor superfamily complexed with a receptor accessory modifying protein known as RAMP2 (ADM1 receptor) or RAMP3 (ADM2 receptor) (18). RAMP1, 2 and 3 thus far identified are single transmembrane domain proteins with intracellular C-termini of up to 10 amino acids and extracellular N-termini of approximately 120 amino acids (19, 20). Non-covalent CL receptor/RAMP1 heterodimers at the cell surface are CGRP receptors. Co-expression of CL receptors with RAMP2 or 3 results in ADM1 or ADM2 receptor subtypes, respectively. CGRP and ADM1 or ADM2 receptor subtypes are distinguished by their selectivity for ADM and CGRP agonists and for hADM(22-52), rADM(20-50) and CGRP(8-37) antagonists (Figure 1). Although the sequence identity between both RAMPs is only 30%, ADM1 and ADM2 receptors are pharmacologically indistinguishable and are usually co-expressed within the same tissue (21). CL receptor/RAMP1 CGRP receptors and ADM1 and ADM2 receptors are predominantly linked to cAMP production. Cells treated with ADM showed elevated cAMP in a time (5-45min)-dependent and dose (10-6-10-14 M)-dependent manner (22, 23). Pre-treatment with the ADM receptor antagonist AM22-52 partially suppressed the ADM-induced increase in cAMP levels. We have investigated the effect of ADM on immortalized human microvascular endothelial cells, since endothelial cells are a major source as well as a target of ADM actions in vivo. ADM stimulates nitric oxide synthase (NOS) in ventricular cardiomyocytes (24) and endothelial cells (25). ADM may also stimulate mitogen-activated protein kinases (MAPKs) in vascular smooth muscle cells (VSMCs) (26) and inhibit MAPK activity in mesangial cells (27). Finally, ADM activates ATP-sensitive K+-channels in vascular smooth muscle cells independently of the other signaling pathways mentioned above (28).
3. ADM AND CELL
ADM was originally purified from a human adrenal tumor (29). Cuttitta et al extended their initial observation of ADM and L1 receptors in pulmonary tumors (30, 31) to study the general expression of ADM in human tumor cell lines (32). This opened up the possibility of ADM being an autocrine/paracrine growth factor in tumors and possibly normal cells. ADM has different effects on proliferation depending on cell type. ADM stimulates proliferation of fibroblasts, keratinocytes, endothelial cells, osteoblasts, and many tumor-derived cells. ADM has been expressed in almost all tumor cells studied to date, suggesting that it may be an important tumor growth factor. In addition, owing to its angiogenic properties, ADM may promote tumor angiogenesis (33). Experimental studies indicate that neutralization of ADM by specific antibodies inhibits, whereas ADM overexpression augments tumor growth (34). ADM has been shown to be involved in carcinogenesis and tumor progression by promoting tumor proliferation and angiogenesis and by inhibiting of apoptosis. It is thought that inflammatory cytokines and hypoxia-induced expression of ADM by tumor cells drive these processes. ADM increased DNA synthesis in a dose-dependent manner by a mechanism involving specific ADM receptors and increased cAMP/PKA (35). Moody et al (36) reported that ADM exerted mitogenic effects on these cells that correlated with increases in cAMP and c-fos expression. In contrast, in some cell types such as vascular smooth muscle cells, mesangial cells, glial cells and glial cell tumors, an inhibitory effect of ADM on growth intracellular cAMP was observed in most studies. Such as with rat VSMCs, ADM was shown to inhibit serum-stimulated 3H-thymidine uptake, which could be blocked by CGRP8-37 (37). These effects indicate an inhibition of growth by ADM as might be expected with increased intracellular cAMP, but some of these results are contradictory to those above. Nevertheless, ADM has also been proposed as an important factor in embryogenesis and differentiation (38-40).
4. ADM AND TUMORS
ADM has been implicated in the modulation of various physiological functions, ranging from vasorelaxation to acting as a cell growth regulator (41, 42). In 1998, ADM was shown using a chick chorioallantoic membrane assay (43) to be potently angiogenic, and it has subsequently been directed to be pro-tumorigenic by a number of groups employing both xenograft studies (44,45) and blocking antibodies (46). We believe that ADM and cancer are related; therefore we reviewed the expression of ADM in different human tumors.
4.1. Prostate cancer
Prostate cancer (CaP) is currently the second leading cause of cancer death in men (47). Because androgens stimulate tumor growth, hormone deprivation represents at present the main treatment of advanced CaP. A recent study (48) shows that whereas human prostate cancer cell lines PC-3 and DU145 cells produce and secrete ADM, ADM acts as a growth factor for DU145 cells, which suggests the existence of an autocrine loop mechanism that could potentially drive neoplastic growth. To investigate this growth factor effect, Rocchi et al used MTT assay techniques to examine the effects of ADM on the growth of prostate cell lines. DU145, PC-3, and LNCaP cells cultured in vitro were exposed to 2�10-7 M of ADM, and the effect on proliferation was followed by the MTT assay. ADM stimulated the proliferation of DU145 by 20% and 25% after 4 and 8 days of treatment, respectively. Both PC-3 and LNCaP cells showed no proliferative responses. ADM synthesis and secretion were also observed in the prostate cell line DU145 (49). A preliminary screening of amidated peptides present in cell lines has demonstrated that the ADM mRNA is by far the predominant message encoding for 2 α-amidated peptides, namely pro-ADM NH2-terminal 20 peptide (PAMP) and ADM. The data showed a marked increase in ADM mRNA levels during xenograph growth for both the PC-3 and DU145 cell lines. The observed elevated response in ADM transcript expression, a common feature of solid tumors, could be a result of reduced oxygen tension (1% O2) or exposure to hypoxia mimetics such as desferrioxamine mesylate (DFX) or CoCl2 through a hypoxia-inducible factor-1 dependent mechanism (50).
4.2. Breast cancer
The study by MK Oehler et al (51) shows that most breast cancer patient samples had moderate to strong staining intensity; only some tumors were negative for ADM. Furthermore, patients with axillary lymph node metastasis were found to have significantly higher ADM peptide expression than patients with no lymphatic metastasis. The probability of metastasis is correlated with the vascular density of primary tumors. ADM-overexpressing tumors are characterized by increased vascularity.
Enrique Zudaire et al (52) presented that ADM is an important regulator of mast cell (MC) function and plays a critical role as an autocrine/paracrine tumor cell survival factor in breast cancer promotion. ADM induced histamine or β-hexosaminidase release from rat and human MCs through a receptor-independent pathway, and human MCs responded to hypoxic insult with elevated ADM mRNA/protein expression. Furthermore, increased angiogenesis might enhance the opportunity of tumor cells to gain access to the lymphatic system and to metastasize. In addition, the angiogenic potential of ADM-overexpressing cells might increase the probability of tumor cells trapped in the lymphatic capillaries to induce neovascularization and to give rise to macroscopic tumor growth.
When analyzing plasma ADM levels and clinicopathological features of breast cancer patients, a significant positive correlation between tumor size and plasma ADM levels was observed. These results suggest that the source of circulating plasma ADM in those patients were indeed the breast malignancies. Active tumor growth, hypoxia and the associated ADM overexpression might be responsible for the increased production and release of the peptide. In addition to such properties, ADM might have an adaptive function for tumors by increasing the intratumoral blood flow as the result of its well-known vasodilative properties .
Nevertheless, ADM expression in breast cancer did not correlate with menopausal status, tumor extent, distant metastasis status, histological tumor type, grading, or expression of estrogen receptor (ER) or progesterone receptor (PR). However, a significant association between histological grading and ADM was found during analysis of ovarian malignancies (53). Until now, much research showed a wide range of ADM concentrations in healthy women (54). Whether this observation is tumor type-specific or whether the study could not detect this association because of the limited numbers of cases is unclear.
4.3. Other cancers
To sum up, ADM is a hypoxically-induced peptide under control of the hypoxia-inducible transcription factor-1 (HIF-1), as are several other angiogenic factors such as vascular endothelial growth factor (VEGF). Thus, circulating levels of ADM have been shown to be elevated in various disease states, including solid tumors such as gastrointestinal malignancies. Since the ADM peptide is rapidly secreted once produced in cells, it is conceivable that ADM peptide in the blood stream of tumor patients reflects ADM secretion from the malignancies.
Nevertheless, no data are available concerning ADM peptide expression in bone malignancies or of circulating ADM peptide in bone tumor patients.
5. ADM AND BONE
Expression of ADM and its receptor were not only detected in the cardiovascular system and fluid homeostasis but were also seen in osteoblasts during the later stages of rodent embryogenesis and in maturing chrondrocytes of fetal mice (55,56). Further research (57) demonstrated that ADM acts on osteoblasts to increase cell growth comparable to those of known osteoblast growth factors such as transforming growth factor- beta (TGF-β). Secondly, ADM increased protein synthesis in vitro and the area of mineralized and unmineralized bone in vivo. ADM is correlated with many different tumor types and often has high expression in tumor cells and patients` plasma. Unfortunately, we do not yet know its effect on bone tumor cells or in arthritis. This has important clinical implications; therefore, if we clarify the expression and effect mechanism of ADM and its receptor in bone, we will be able to use ADM as a novel way to cure some diseases that do not currently have effective therapeutic methods.
5.1. ADM and arthritis
ADM acts as an endogenous immunomodulatory factor with predominant anti-inflammatory effects. ADM and their receptors are detected in several immune cells, including macrophages/monocytes and T cells, and their expressions increase under inflammatory conditions (58-60).
It was reported that elevated ADM levels were found in plasma, joint fluid, and the synovial tissue in arthritis (61-62). In addition the present study evaluates the therapeutic effects of ADM by an experimental model of rheumatoid arthritis with antigen-induced arthritis (63). Using ovalbumin injected into the joint spaces of pre-immunized rabbits as the experimental group, they injected ADM into the contralateral knee joint spaces as the control, then compared the degree of joint swelling and histological change. The result revealed that ADM reduced edematous changes and infiltration of inflammatory cells in the synovial tissues and ADM significantly reduced TNF-α mRNA expression in a dose-dependent manner.
ADM ameliorated the inflammatory response and may be useful as a treatment for rheumatoid arthritis. A possible mechanism is reducing the expression of Th1-driven autoimmune and inflammatory responses. Moreover, ADM decreased generation and/or activation of efficient CD4+-CD25+ regulatory T cells in arthritis with the capacity to suppress autoreactive response and restore immune tolerance (64). As a consequence, ADM reduced the frequency of arthritis, ameliorated its symptoms, and prevented joint damage.
5.2. ADM and bone metabolism
Bone growth and maintenance are highly regulated processes. Throughout life, bone constantly undergoes remodeling, maintaining of balance between bone formation by osteoblasts and bone resorption by osteoclasts. This balance depends on the coordinated activities of many systemic hormones and locally acting factors in the bone microenvironment. Recently research found that ADM is expressed at high levels in osteoblasts and chondrocytes of mouse and rat embryos (65) and is also expressed in primary neonatal rat osteoblasts (66) and in human chondrocytes cultured from articular cartilage explants.
ADM is from the calcitonin family, which is a group of peptide hormones, concluding calcitonin, CGRP, amylin and ADM-2 (intermedin). They share structural similarities and produce rapid lowering of serum calcium levels. ADM stimulate the proliferation of primary rat osteoblasts at periphysiological concentrations of 10−11 M and 10−12 M, respectively (67). ADM significantly increased osteoid area and mineralized bone area.
Osteoporosis is a common systemic skeletal disorder characterized by reduced bone mass, increased bone turnover and micro-architectural deterioration of bone tissue that leads to bone fragility and increased risk of fracture (68). Osteoporosis is closely related with the bone resorption, which is dependent on numerous processes, the key role of which is played by osteoclasts. Osteoclasts are sometimes activated by mechanisms dependent upon prior osteoblastic stimulation. Osteoblasts possess surface receptors for parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), ADM and CGRP. In vitro experiments show that ADM is a potent mitogen of fetal rat osteoblasts (69). This effect is dependent on the presence of the IGF-1 receptor and is blocked by AMY antagonists.
5.3. ADM and osteosarcoma
Osteosarcoma is a kind of malignant tumor originating from mesenchymal tissue whose incidence is in the second place of primary bone tumors, characterized by generation of spindle stromal cells of bone-like tissue (70, 71). Since the standard treatment before 1970 was osteotomy, the majority of patients died of lung cancer metastasis within 2 years, and the annual survival rate was only 10-20% (72). In recent years, with the extensive application of neoadjuvant chemotherapy and limb salvage surgery, the annual survival rate and quality of life of patients with osteosarcoma have been greatly improved (73, 74), but the general prognosis of osteosarcoma has not significantly improved, and a change in surgical or chemical treatment is unlikely to change disease-related poor prognosis in the near future (75). The marker of osteosarcoma has to be discovered to determine its biological characteristics and prognosis, and the effective molecular target has to be positioned for clinical treatment at the same time.
The main reason for increased expression of ADM in osteosarcoma is thought to be hypoxia (76-77). The occurrence and development of a tumor relies on angiogenesis, formation of capillary vessels that provide the tumor with a structure into which nutrients enter and wastes exit, in other words, generation and secretion of angiectasia and angiogenesis-related substances may be the mode required for tumor survival (78). A solid tumor with a high degree of malignancy exceeds its blood vessels` load because of its active growth, so the central part of the tumor is under hypoxia. Hypoxia may become the induced factor to increase ADM by activating hypoxia-inducible factor (HIF-1), since ADM has the ability to expand blood vessels to alleviate the tumor hypoxia (79). Ouafik (80) prove that externally supportive access to ADM can stimulate the growth of in vitro malignant glioma cells, and use of ADM specific polyclonal antibodies can block the combination of ADM and its cell receptors, causing a 33% reduction in growth of in vitro malignant glioma U87 cell stain (P <0.001). Anti-ADM antibodies are injected into the tumor with mice allogeneic vaccination resulted in a 70% weight reduction of subcutaneous U87 xenograft (P <0.001) after 21-day treatment.
6. CONCLUSION
ADM has been shown to mediate multifunctional cell responses including regulation of cardiovascular tone, bronchodilation, natriuretic action, antimicrobial activity, inhibition of hormone release, growth regulation, apoptosis survival, and induction of angiogenesis. Additionally, it was found that many human tumor cell lines express high levels of ADM mRNA and that ADM is released into the culture medium. Anti-tumor angiogenesis is an effective method to treat malignant tumors. As a result of an in-depth study on ADM and the occurrence and development of tumor vessels, ADM is expected to become a new target for anti-angiogenesis therapy. All of these findings support that ADM can be used as an effective autocrine /paracrine growth factor and that the growth of the in vivo tumor can be inhibited by blocking the activity of ADM generated by tumor cells. ADM will be a useful predictive and prognostic marker in human cancer.
7. ACKNOWLEDGEMENT
Special thanks to Wei Jiang for supporting in writing the paper.
8. REFERENCES
1. Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H, and Eto T. 1993. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun 194: 720-725.
doi:10.1006/bbrc.1993.1881
2. Kato H, Shichiri M, Marumo F, and Hirata Y. 1997. Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. Endocrinology 138:2615-2620.
doi:10.1210/en.138.6.2615
3. Coppock HA, Owji AA, Austin C, Upton PD, Jackson ML, Gardiner JG, Ghatei MA, Bloom SR, and Smith DM. 1999. Rat-2 fibroblasts express specific adrenomedullin receptors, but not calcitonin-gene-related peptide receptors, which mediate increased intracellular cAMP and inhibit mitogen-activated protein kinase activity. Biochem J 338:15-22.
doi:10.1042/0264-6021:3380015
4. Yamasaki M, Kawai J, Nakaoka T, Ogita T, Tojo A, and Fujita T. 2003. Adrenomedullin overexpression to inhibit cuff-induced arterial intimal formation. Hypertension 41:302-307.
doi:10.1161/01.HYP.0000050645.11117.9E
5. Miksa M, Wu R, Cui X, and Dong W. 2007. Vasoactive hormone adrenomedullin and its binding protein: anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-γ. J Immunol 179:6263-6272.
6. Xu Y and Krukoff TL. 2004b. Decrease in arterial pressure induced by adrenomedullin in the hypothalamic paraventricular nucleus is mediated by nitric oxide and GABA. Regul Pept 119:21-30.
doi:10.1016/j.regpep.2003.12.018
7. Kato H, Shichiri M, Marumo F, and Hirata Y. 1997. Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. Endocrinology 138:2615-2620.
doi:10.1210/en.138.6.2615
8. Abe M, Sata M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Minamino N, Kangawa K, Matsuo H, Hirata Y, and Nagai R. 2003. Adrenomedullin augments collateral development in response to acute ischemia. Biochem Biophys Res Commun 306:10-15.
doi:10.1016/S0006-291X(03)00903-3
9. Kim W, Moon SO, Sung MJ, Kim SH, Lee S, So JN, and Park SK. 2003. Angiogenic role of adrenomedullin through activation of Akt, mitogenactivated protein kinase, and focal adhesion kinase in endothelial cells. FASEB J 13:1937-1939.
10. Kawai J, Ando K, Tojo A, Shimosawa T, Takahashi K, Onozato ML, Yamasaki M, Ogita T, Nakaoka T, and Fujita T. 2004. Endogenous adrenomedullin protects against vascular response to injury in mice. Circulation 109:1147-1153.
doi:10.1161/01.CIR.0000117231.40057.6D
11. Beltowski J and Jamroz A. 2004. Adrenomedullin-what do we know 10 years since its discovery? Pol J Pharmacol 56:5-27.
12. Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H, and Eto T. 1993. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun 194:720-725.
doi:10.1006/bbrc.1993.1881
13. Ishiyama Y, Kitamura K, Ichiki Y, Nakamura S, Kida O, Kangawa K, and Eto T. 1993. Hemodynamic effects of a novel hypotensive peptide, human adrenomedullin, in rats. Eur J Pharm 241:271-273.
doi:10.1016/0014-2999(93)90214-3
14. Kamura K, Kangawa K, Ishiyama Y, Washimine H, Ichiki Y, Kawamoto M, Minamino N, Matsuo H, and Eto T. 1994. Identification and hypotensive activity of proadrenomedullin N-terminal 20 peptide (PAMP). FEBS Letters 351:35-37.
doi:10.1016/0014-5793(94)00810-8
15. Minamino N, Shoji H, Sugo S, Kangawa K, and Matsuo H. 1995 Adrenocortical steroids, thyroid hormones and retinoic acid augment the production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 211:686-693.
doi:10.1006/bbrc.1995.1866
16. Imai T, Hirata Y, Iwashina M, and Marumo F. 1995 Hormonal regulation of rat adrenomedullin gene in vasculature. Endocrinology 136:1544-1548.
doi:10.1210/en.136.4.1544
17. Shimokubo T, Sakata J, Kitamura K, Kangawa K, Matsuo H, and Eto T. 1995. Augmented adrenomedullin concentrations in right ventricle and plasma of experimental pulmonary hypertension. Life Sci 57:1771-1779.
doi:10.1016/0024-3205(95)02155-C
18. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, and Foord SM. 1998. RAMPs regulate the transport and ligand binding specificity of the calcitonin-receptor-like receptor. Nature 393:333-339.
doi:10.1038/30666
19. Sexton PM, Albiston A, Morfis M, and Tilakaratne N. 2001. Receptor activity modifying proteins. Cell Signal 13:73-83.
doi:10.1016/S0898-6568(00)00143-1
20. Muff R, Born W, and Fischer JA. 2001. Adrenomedullin and related peptides: receptors and accessory proteins. Peptides 22:1765-1772.
doi:10.1016/S0196-9781(01)00515-0
21. Kuwasako K, Kitamura K, Onitsuka H, Uemura T, Nagoshi Y, Kato J, and Tanenao E. 2002. Rat RAMP domains involved in adrenomedullin binding specificity. FEBS Letters 519:113-116.
doi:10.1016/S0014-5793(02)02721-7
22. Hinson JP, Kapas S, Smith DM. 2000. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21:138-167.
doi:10.1210/er.21.2.138
23. Ross GR and Yallampalli C. 2006. Endothelium-independent relaxation by adrenomedullin in pregnant rat mesenteric artery: role of cAMP-dependent protein kinase A and calcium-activated potassium channels. J Pharmacol Exp Ther 317:1269-1275.
doi:10.1124/jpet.106.101790
24. Ikenouchi H, Kangawa K, Matsuo H, and Hirata Y. 1997. Negative inotropic effect of adrenomedullin in isolated adult rabbit cardiac ventricular myocytes. Circulation 95:2318-2324.
PMid:9142011
25. Hayakawa H, Hirata Y, Kakoki M, Suzuki Y, Nishimatsu H, Nagata D, Suzuki E, et al. 1999. Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat. Hypertension 33:689-693.
PMid:10024329
26. Iwasaki H, Eguchi S, Shichiri M, Marumo F, and Hirata Y. 1998. Adrenomedullin as a novel growth-promoting factor for cultured vascular smooth muscle cells: role of tyrosine kinase-mediated mitogen-activated protein kinase activation. Endocrinology 139:3432-3441.
doi:10.1210/en.139.8.3432
27. Chini EN, Chini CC, Bolliger C, Jougasaki M, Grande JP, Burnett JC Jr, and Dousa TP. 1997. Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway. Kidney Int 52:917-925.
doi:10.1038/ki.1997.413
28. Sakai K, Saito K, and Ishizuka N. 1998. Adrenomedullin synergistically interacts with endogenous vasodilators in rats: a possible role of K (ATP) channels. Eur J Pharmacol 359:151-159.
doi:10.1016/S0014-2999(98)00641-4
29. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, and Eto T. 1993. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192:553-560.
doi:10.1006/bbrc.1993.1451
30. Martinez A, Miller MJ, Unsworth EJ, Siegfried JM, and Cuttitta F. 1995. Expression of adrenomedullin in normal human lung and in pulmonary tumors. Endocrinology 136:4099-4105.
doi:10.1210/en.136.9.4099
31. Martinez A, Miller MJ, Catt KJ, and Cuttitta F. 1997. Adrenomedullin receptor expression in human lung and in pulmonary tumors. J Histochem Cytochem 45:159-164.
PMid:9016306
32. Miller MJ, Martinez A, Unsworth EJ, Thiele CJ, Moody TW, Elsasser T, and Cuttitta F. 1996. Adrenomedullin expression in human tumor cell lines. Its potential role as an autocrine growth factor. J Biol Chem 271:23345-23351
doi:10.1074/jbc.271.38.23345
33. Nakayama M, Takahashi K, Hara E, Murakami O, Totsune K, Sone M, Satoh F, and Shibahara S. 1998. Production and secretion of two vasoactive peptides, endothelin-1 and adrenomedullin, by a colorectal adenocarcinoma cell line, DLD-1. J Cardiovasc Pharmacol 31(Suppl 1):S534-S536
doi:10.1097/00005344-199800001-00154
34. Barker S, Kapas S, Corder R, and Clark AJ. 1996. Adrenomedullin acts via stimulation of cyclic AMP and not via calcium signalling in vascular cells in culture. J Hum Hypertens 10:421-423.
PMid:8872811
35. Withers DJ, Coppock HA, Seufferlein T, Smith DM, Bloom SR, and Rozengurt E. 1996. Adrenomedullin stimulates DNA synthesis and cell proliferation via elevation ofcAMPin Swiss 3T3 cells. FEBS Lett 378:83-87.
doi:10.1016/0014-5793(95)01427-6
36. Moody TW, Miller MJ, Martinez A, Unsworth E, and Cuttitta F. 1997. Adrenomedullin binds with high affinity, elevates cyclic AMP, and stimulates c-fos mRNA in C6 glioma cells. Peptides 18:1111-1115.
doi:10.1016/S0196-9781(97)00179-4
37. Kano H, Kohno M, Yasunari K, Yokokawa K, Horio T, Ikeda M, Minami M, Hanehira T, Takeda T, and Yoshikawa J. 1996. Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells. J Hypertens 14:209-213.
doi:10.1097/00004872-199602000-00009
38. Montuenga LM, Martinez A, Miller MJ, Unsworth EJ, and Cuttitta F. 1997. Expression of adrenomedullin and its receptor during embryogenesis suggests autocrine or paracrine modes of action. Endocrinology 138:440-451.
doi:10.1210/en.138.1.440
39. Montuenga LM, Mariano JM, Prentice MA, Cuttitta F, and Jakowlew SB. 1998. Coordinate expression of transforming growth factor-beta 1 and adrenomedullin in rodent embryogenesis. Endocrinology 139:3946-3957.
doi:10.1210/en.139.9.3946
40. Yotsumoto S, Shimada T, Cui CY, Nakashima H, Fujiwara H, and Ko MSH. 1998. Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse. Dev Biol 203:264-275.
doi:10.1006/dbio.1998.9073
41. Hinson JP, Kapas S, Smith DM. 2000. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21:138-167.
doi:10.1210/er.21.2.138
42. Nikitenko LL, Smith DM, Hague S, Wilson CR, Bicknell R, Rees MCP. 2002. Adrenomedullin and the microvasculature. Trends Pharm Sci 23:101-103.
doi:10.1016/S0165-6147(00)01983-0
43. Zhao Y, Hague S, Manek S, Zhang L, Bicknell R, and Rees MCP. 1998. PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium. Oncogene 16:409-415.
doi:10.1038/sj.onc.1201768
44. Martinez A, Vos M, Guedez L, Kaur G, Chen Z, Garayoa M, Pio R, Moody T, Stetler-Stevenson WG, Kleinman HK, and Cuttitta F. 2002. The effects of adrenomedullin overexpression in breast tumor cells. J Natl Cancer Inst 94:1226-1237.
PMid:12189226
45. Oehler MK, Hague S, Rees MC, and Bicknell R. 2002. Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis. Oncogene 21:2815-2821.
doi:10.1038/sj.onc.1205374
PMid:11973640
46. Ouafik L, Sauze S, Boudouresque F, Chinot O, Delfino C, Fina F, Vuaroqueaux V, Dussert C, Palmari J, Dufour H, Grisoli F, Casellas P, Brunner N, and Martin PM. 2002. Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumour xenograft growth in vivo. Am J Pathol 160:1279-1292.
47. Parker SL, Tong T, Bolden S, and Wingo PA. 1996. Cancer statistics. CA Cancer J Clin 46:5-27.
doi:10.3322/canjclin.46.1.5
48. Rocchi P, Boudouresque F, Zamora AJ, Muracciole X, Lechevallier E, Martin P-M, and Ouafik L. 2001. Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines. Cancer Res 61:1196-1206.
PMid:11221851
49. Miller MJ, Martinez A, Unsworth EJ, Thiele CJ, Moody TW, Elsasser T, and Cuttitta F. 1996. Adrenomedullin expression in human tumor cell lines: its potential role as an autocrine growth factor. J Biol Chem 271:23345-23351.
doi:10.1074/jbc.271.38.23345
50. Garayoa M, Martinez A, Lee S, Pio R, An WG, Neckers L, Trepel J, Montuenga LM, Ryan H, Johnson R, Gassmann M, and Cuttitta F. 2000. Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol Endocrinol 14:848-862.
doi:10.1210/me.14.6.848
51. Oehler MK, Fischer DC, Orlowska-Volk M, Herrle F, et al. Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer. Br J Cancer 89:1927-1933.
doi:10.1038/sj.bjc.6601397
52. Zudaire E, Martinez A, Garayoa M, and Pio R. 2006. Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis. Am J Pathol 168:280-291.
doi:10.2353/ajpath.2006.050291
53. Hata K, Takebayashi Y, Akiba S, Fujiwaki R, Iida K, Nakayama K, Nakayama S, Fukumoto M, and Miyazaki K. 2000. Expression of the adrenomedullin gene in epithelial ovarian cancer. Mol Hum Reprod 6:867-872.
doi:10.1093/molehr/6.10.867
54. Hinson JP, Kapas S, and Smith DM. 2000. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21:138-167.
doi:10.1210/er.21.2.138
55. Montuenga LM, Martinez A, Miller MJ, Unsworth EJ, and Cuttitta F. 1997. Expression of adrenomedullin and its receptor during embryogenesis suggests autocrine or paracrine modes of action. Endocrinology 138:440-451.
doi:10.1210/en.138.1.440
PMid:8977434
56. Montuenga LM, Mariano JM, Prentice MA, Cuttitta F, and Jakowlew SB. 1998. Coordinate expression of transforming growth factor-beta and adrenomedullin in rodent embryogenesis. Endocrinology 139:3946-3957.
doi:10.1210/en.139.9.3946
57. Cornish J, Callon KE, Coy DH, Jiang NY, Xiao LQ, Cooper GJS, and Reid IR. 1997. Adrenomedullin is a potent stimulator of osteoblastic activity in vitro and in vivo. Am J Physiol 36:E1113-E1120.
58. Elsasser TH and Kahl S. 2002. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Tech 57:120-129.
doi:10.1002/jemt.10058
59. Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, Matsuo H, Fujimura Y, Yoshioka A, Masui K, Doi N, Murao Y, and Miyamoto S. 1999. Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med 160:132-136.
60. Kubo A, Minamino N, Isumi Y, Katafuchi T, Kangawa K, Dohi K, and Matsuo H. 1998. Production of adrenomedullin in macrophage cell line and peritoneal macrophage. J Biol Chem 273:16730-16738.
doi:10.1074/jbc.273.27.16730
61. Chosa E, Hamada H, Kitamura K, Eto T, and Tajima N. 2003. Increased plasma and joint tissue adrenomedullin concentrations in patients with rheumatoid arthritis compared to those with osteoarthritis. J Rheumatol 30:2553-2556.
62. Yudoh K, Matsuno H, and Kimura T. 1999. Plasma adrenomedullin in rheumatoid arthritis compared with other rheumatic diseases. Arthritis Rheum. 42:1297-1298.
doi:10.1002/1529-0131(199906)42:6<1297::AID-ANR30>3.0.CO;2-J
63. Consden R, Doble A, Glynn LE, and Nind AP. 1971. Production of a chronic arthritis with ovalbumin. Its retention in the rabbit knee joint. Ann Rheum Dis. 30:307-315.
doi:10.1136/ard.30.3.307
64. Gonzalez-Rey E, Chorny A, O'Valle F, and Delgado M. 2007. Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells. Am J Pathol 170:263-271.
doi:10.2353/ajpath.2007.060596
65. Montuenga LM, Martinez A, Miller MJ, Unsworth EJ, Cuttitta F. 1997. Expression of adrenomedullin and its receptor during embryogenesis suggests autocrine or paracrine modes of action. Endocrinology 138:440-451.
doi:10.1210/en.138.1.440
66. Naot D, Callon KE, Grey A, Cooper GJS, Reid IR, Cornish J. 2001. A potential role for adrenomedullin as a local regulator of bone growth. Endocrinology 142:1849-1857.
doi:10.1210/en.142.5.1849
67. Cornish J and Reid IR. 1999. Skeletal effects of amylin and related peptides. Endocrinologist 9:183-189.
doi:10.1097/00019616-199905000-00004
68. Dennison E, Cole Z, and Cooper C. 2005. Diagnosis and epidemiology of osteoporosis. Curr Opin Rheumatol 17:456-461.
doi:10.1097/01.bor.0000166384.80777.0d
69. Cornish J, Callon KE, Cooper GJ, and Reid IR. Amylin stimulates osteoblast proliferation and increases mineralized bone volume in adult mice. Biochem Biophys Res Commun 207:133-139.
doi:10.1006/bbrc.1995.1163
70. Parkin DM, Stiller CA, Draper GJ, et al. International incidence of childhood cancer, Vol. 2. Lyon: IARC (IARC Scientific Publications No 87); 1998.
71. Stiller CA, Bielack SS, Jundt G, et al. Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42:2124-2135.
doi:10.1016/j.ejca.2006.05.015
72. Caudill JS, Arndt CA. Diagnosis and management of bone malignancy in adolescence. Adolesc Med 2007; 18:62-78. Library Holdings A very good review article on osteosarcoma and ESFT.
73. Bacci G, Rocca M, Salone M, et al. High grade osteosarcoma of the extremities with lung metastases at presentation: Treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Onc 2008; 98:415-420.
doi:10.1002/jso.21140
74. Bacci G, Ferrari S, Forni C. The effect of intra-arterial versus intravenous cisplatinum in the neoadjuvant treatment of osteosarcoma of the limbs: the experience at the Rizzoli Institute. Chir Organi Mov 1996; 81:369-382.
PMid:9147928
75. Bacci G, Longhi A, Versari M, et al. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15 year experience in 789 patients treated in a single institution. Cancer 2006; 106:1154-1161.
doi:10.1002/cncr.21724
76. Vaupel P, Schlenger K, Knoop C, et al. 1991. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51:3316-3322.
PMid:2040005
77. Zhong H, De Marzo AM, Laughner E, et al. 1999. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830-5835.
PMid:10582706
78. Oehler MK, Norbury C, Hague S, et al. 2001. Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth. Oncogene 20:2937-2945.
doi:10.1038/sj.onc.1204422
79. Rocchi P, Boudouresque F, Zamora AJ, et al. 2001. Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines. Cancer Res 61:1196-1206.
PMid:11221851
80. Ouafik L, Sauze S, Boudouresque F, et al. 2002. Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumour xenograft growth in vivo. Am J Pathol 160:1279-1292.
PMid:11943713
Key Words: Adrenomedullin, Angiogenic, Calcitonin, receptor-like receptor, Cancer; Osteosarcoma, Review
Send correspondence to: Wei Ma, Department of Orthopedic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road,Xi'an 710061, China, Tel: 86-29 85323938, Fax: 86-29 85252580, E-mail:mawei60@126.com