Dual Role of METCAM/MUC18 Expression in the Progression of Cancer Cells

The altered expression of cell adhesion molecules (CAMs) correlates with the malignant progression of many epithelial tumors. MUC18/CD146/A32/MelCAM/S-endo 1, a CAM in the immunoglobulin gene superfamily, is an integral membrane glycoprotein. MUC18 is not a mucin, resulting from its misleading nomenclature by the original discoverer. We re-named it as METCAM (metastasis-regulating CAM), based on its very interesting bio- logical roles in tumor formation and metastasis of many epithelial tumors. Initial findings show that METCAM/MUC18 expression has a positive effect (as a tumor and metastasis promoter) on the progression of breast cancer, most melanoma cell lines, nasopharyngeal carcinoma (NPC) type II, and prostate cancer. Later research results show that METCAM/ MUC18 expression has a negative effect (as a tumor suppressor and metastasis suppressor) on the progression of ovarian cancer, one mouse melanoma cell line, and nasopharyngeal carcinoma type I, and perhaps hemangioma. Since the above dual function of METCAM/ MUC18 occurs only in different cell lines from the same cancer type or in those from dif - ferent cancer types, we suggest that the different effect of METCAM/MUC18 on tumor formation and metastasis of different cancer cell line may be due to different intrinsic prop - erties (co-factors) in each cancer cell line that modify the biological functions of METCAM/ MUC18 in the intrinsic properties of tumor cells and their interactions with the tumor microenvironment. This chapter will review the published work and present some possible mechanisms for the METCAM/MUC18-mediated cancer progression for future studies. Western blot analysis and immunohistochemistry to detect the expression of huMETCAM/MUC18 antigens in prostate cancer cell lines and human prostate cancer tissues. We confirmed these results by using the RT-PCR analysis to show the presence of huMETCAM/MUC18 mRNA [70, 72]. We found that huMETCAM/MUC18 was neither expressed in most (90%) of the normal epithelial cells in the prostatic ducts/acini nor in any (100%) of these cells in BPH, but it was detectable in the majority (greater than 80%) of the neoplastic prostate epithelial cells (high-grade PIN), high-grade prostate adenocarcinomas, and metastatic lesions. HuMETCAM/MUC18 was expressed in two metastatic human prostate cancer cell lines, DU145 and PC-3, and one bladder cancer cell line, Tsu-Pr1, but not in one non-metastatic prostate cancer cell line, LNCaP [70, 72]. Thus, we conclude that huMETCAM/ MUC18 is not expressed in normal and benign hyperplastic human prostate tissues, but its expression increases during prostate cancer initiation (high-grade PIN), progression to carcinoma, and in metastatic cell lines and metastatic lesions. Taken together, over-expression of METCAM/MUC18 correlates with the initiation of malignant progression of human prostate cancer [70, 72], suggesting that huMETCAM/MUC18 may be a useful marker for monitoring the metastatic potential of prostate cancer cells [70, 72]. Furthermore, the extent of in vitro motility and invasiveness is directly proportional to the extent of huMETCAM/MUC18 expression in four human cancer cell lines [70 ]. Our anti-huMETCAM/MUC18 antibody was able to signifi cantly block the in vitro motility and invasiveness of various human prostate cancer cell lines [70]. Therefore, we propose the hypothesis that huMETCAM/MUC18 may directly mediate the increased epithelial-to-mesenchymal transition and initiate the progression of prostate cancers.