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 ROLE OF CDD44 IN CANCERCD44 is a polymorphic family of immunologically related cell surface proteoglycans and glycoproteins which normaly take part in cell-cell and cell-matrix adhesion interactions, lymphocyte activation and homing, and cell migration. The cytokine osteopontin (Eta-1), which regulates similar cellular functions, was found to be a protein ligand of CD44. Osteopontin induces cellular chemotaxis but not homotypic aggregation, whereas the reverse is true for the interaction between CD44 and its carbohydrate ligand, hyaluronate. The different responses of cells after CD44 ligation by either osteopontin or hyaluronate may account for the independent effects of CD44 on cell migration and growth. It has been suggested that this mechanism may also be exploited by the tumor cells in their metastatic spread. CD44 is a transmembrane glycoprotein and exists in several isoforms with different extracellular regions. Various transcripts of CD44 are encoded by one gene locus on chromosome 11 which contains 20 exons. From these, at least 10 can be alternatively spliced in nascent RNA. CD44 isoforms are cell adhesion molecules and, in view of their affinity for hyaluronate and their structural homology with the cartilage link protein, belong to the sub-family of the hyaladherins. The standard form of CD44, CD44H, exhibits a high affinity for hyaluronate. This isoform plays a role in the uptake and degradation of this glycosaminoglycan and participates in cell locomotion in its presence. CD44H plays a role in the homing of lymphocytes into Peyer's patches, in organogenesis and in the degradation of hyaluronate in lung or lymphoid tissues. It is likely that CD44H enhances the tumorigenic properties of some lymphomas and melanomas. On the other hand, the variant form CD44E exhibits low affinity for hyaluronate and its role in cell-cell adhesion in epithelia is suspected. The variant form CD44V (or CD44M) confers metastatic properties to rat carcinoma cells and is expressed in human breast and colorectal cancers and in adenomatous polyps. As opposed to the standard form of CD44 (CD44s) which is abundant in many tissues, isoforms encoded by the variant exons (termed CD44v) are highly restricted in their distribution in non-malignant tissues. In the Feb 2 issue of Journal of Biological Chemistry, Taher et al, showed that the function of the CD44, at least in T cells, may be mediated by virture of tyrosine phosphorylation of ZAP-70 and other intracellular proteins. For example, CD44 is physically associated with p56 and its cross linking induces an increase in the intrinsic activity of p56. It was shown that non-metastatic rat tumor cells that expressed specific variant isoforms containing exon 6v became metastatic. Based on its prominent role in rendering the capability to the rat tumor cells to metastasize, it was suggested that CD44v isoforms were involved in human tumor progression. Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinomas, for non-Hodgkin's lymphoma, and recently for breast carcinoma. In breast cancer, CD44s, CD44-9v, and CD44-6v are apparently markers for cellular differentiation but not for tumor progression. In breast cancer and in non-Hodgkin's lymphomas, expression of exon v6 was correlated with poor prognosis. In colorectal carcinomas, however, expression of exon v5 was found to be an early tumour marker. This marker was detectable on small dysplastic polyps but not on normal colon epithelium. In contrast, expression of exon v6 occurred with increased frequency with tumour progression, and its expression on colorectal tumours indicated reduced survival probability. In another study, as compared with the normal colorectal mucosa, all colorectal adenocarcinomas overexpressed CD44 variants containing the intron 9 sequence. The overexpression of such abnormal CD44 variants was observed from an early stage in colorectal cancer and did not correlate with nodal or distant metastatic status. In intestinal metaplasia of the stomach, aberrant CD44 transcripts with characteristic 2 or 3 peaks containing intron 9 were observed. On the other hand, in oral and esophageal squamous cell carcinomas and corresponding normal squamous epithelia, overexpression of CD44 variants with variable exons and retained intron 9 sequence was frequently observed in both cancer tissue and the normal mucosa. Overexpression of transcripts containing exons 11 and 14 as well as of the intron 9 sequence was constantly observed in squamous epithelia of skin, oral mucosa, esophagus and uterine cervix. Expression of these variants was also found in urinary bladder, respiratory tract, pancreas and salivary glands. Therefore, it was concluded that the overexpression of abnormal CD44 transcripts, especially those which contain the intron 9 sequence, could be used as an indicator for the presence of adenocarcinomas in the digestive tract. Conversely, such expression may not be used in the diagnosis of malignancies originating from squamous epithelia. All renal carcinomas expressed a higher level of CD44 mRNA than paired normal kidneys. The expression of standard form of CD44 (CD44s) was reported in a large number of brain tumors. Although, none of these tumors expressed CD44v, this variant was expressed in majority of the brain metastases. Deregulation of alternative CD44 splicing was found to be a common feature of disordered thyroid follicular cell growth, both in neoplastic and non-neoplastic lesions. Normal melanocytes expressed high levels of CD44s but no CD44v, whereas all melanoma cell lines expressed CD44v at the surface. In addition, expression of v5 was strongly increased in the highly metastatic cell lines. In cervical cancers, among the CD44 splice variants, expression of exon v6 was found to be the most promising prognostic marker. A novel CD44(v6) isoform was found in metastatic lesions and it was suggested that it may represent the human homologue of the rat pancreatic adenocarcinoma metastasis-associated CD44 isoform. In contrast to these studies which showed a correlation between the expression of the CD44 variants with either tumor metastasis, or prognosis, no definite correlation has been observed between the expression of specific CD44 isoform and tumor progression or metastasis in lung cancers. REFERENCES: Georg F. Weber (1), Samy Ashkar (1), Melvin J. Glimcher, Harvey Cantor. : Receptor-Ligand Interaction Between CD44 and Osteopontin (Eta-1): 271, 509-512, 1996 Sites:
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