METCAM/MUC18 Promotes Tumor Progression and Metastasis in Most Human Cancers

In addition to oncogenes and tumor suppressor genes, cell adhesion molecules (CAMs) also significantly contribute to tumor progression and metastasis. For the past two decades, we have demonstrated that METCAM/MUC18, a cell adhesion molecule in the immunoglobulin-like gene superfamily, orchestrates complex interactions of tumor cells with various stromal cells in the tumor microenvironment, resulting in augmentation or reduction of the metastatic potential of carcinoma cells. Here we show that METCAM/MUC18 plays a positive role in the tumor progression and metastasis in most human cancers, such as breast cancer, human melanoma and most mouse melanoma, nasopharyngeal carcinoma type III, prostate cancer LNCaP and DU145 cell lines, and perhaps angiosarcoma, gastric cancer, glioma, hepatocellular carcinoma, non-small cell lung adenocarcinoma, small cell lung cancer (SCLC), osteosarcoma, and human and mouse pancreatic cancer. Possible mechanisms in the METCAM/MUC18-mediated tumor progression and metastasis are proposed. Anti-METCAM/MUC18 antibodies and siRNAs may be used as therapeutic agents to treat these cancers

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 biological 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 different 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 properties (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

Dual Roles of METCAM in the Progression of Different Cancers

METCAM, an integral membrane cell adhesion molecule (CAM) in the Ig-like gene superfamily, is capable of performing typical functions of CAMs, such as mediating cell-cell and cell-extracellular interactions, crosstalk with intracellular signaling pathways, and modulating social behaviors of cells. METCAM is expressed in about nine normal cells/tissues. Aberrant expression of METCAM has been associated with the progression of several epithelial tumors. Further in vitro and in vivo studies show that METCAM plays a dual role in the progression of different tumors. It can promote the malignant progression of several tumors. On the other hand, it can suppress the malignant progression of other tumors. We suggest that the role of METCAM in the progression of different cancer types may be modulated by different intrinsic factors present in different cancer cells and also in different stromal microenvironment. Many possible mechanisms mediated by this CAM during early tumor development and metastasis are suggested

METCAM/MUC18: A Novel Tumor Suppressor for Some Cancers

METCAM/MUC18, a component of cellular membrane, is a cell adhesion molecule (CAM) in the Ig-like gene super-family. It is capable of carrying out general functions of CAMs, such as performing intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, interacting with various signaling pathways, and regulating social behaviors of cells. METCAM/MUC18 plays the tumor suppressor function in some cancers, such as colorectal cancer, nasopharyngeal carcinoma type I, one mouse melanoma subline K1735-9, ovarian cancer, pancreatic cancer, prostate cancer PC-3 cell line, and perhaps hemangioma. Possible mechanism in the METCAM/MUC18-mediated tumor suppression is proposed. By taking advantage of the tumor suppressor function of METCAM/MUC18, recombinant METCAM/MUC18 proteins and other derived products may be used as therapeutic agents to treat these cancers

Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Conflicting research has identified METCAM/MUC18, an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family, as both a tumor promoter and a tumor suppressor in the development of breast cancer. To resolve this, we have re-investigated the role of this CAM in the progression of human breast cancer cells.</p> <p>Methods</p> <p>Three breast cancer cell lines were used for the tests: one luminal-like breast cancer cell line, MCF7, which did not express any METCAM/MUC18, and two basal-like breast cancer cell lines, MDA-MB-231 and MDA-MB-468, which expressed moderate levels of the protein.</p> <p>MCF7 cells were transfected with the human METCAM/MUC18 cDNA to obtain G418-resistant clones which expressed the protein and were used for testing effects of human METCAM/MUC18 expression on <it>in vitro </it>motility and invasiveness, and <it>in vitro </it>and <it>in vivo </it>tumorigenesis. Both MDA-MB-231 and MDA-MB-468 cells already expressed METCAM/MUC18. They were directly used for <it>in vitro </it>tests in the presence and absence of an anti-METCAM/MUC18 antibody.</p> <p>Results</p> <p>In MCF7 cells, enforced METCAM/MUC18 expression increased <it>in vitro </it>motility, invasiveness, anchorage-independent colony formation (<it>in vitro </it>tumorigenesis), and <it>in vivo </it>tumorigenesis. In both MDA-MB-231 and MDA-MB-468 cells, the anti-METCAM/MUC18 antibody inhibited both motility and invasiveness. Though both MDA-MB-231 and MDA-MB-468 cells established a disorganized growth in 3D basement membrane culture assay, the introduction of the anti-METCAM/MUC18 antibody completely destroyed their growth in the 3D culture.</p> <p>Conclusion</p> <p>These findings support the notion that human METCAM/MUC18 expression promotes the progression of human breast cancer cells by increasing their motility, invasiveness and tumorigenesis.</p

METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells

METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma

METCAM Is a Potential Biomarker for Predicting the Malignant Propensity of and as a Therapeutic Target for Prostate Cancer

Prostate cancer is the second leading cause of cancer-related death worldwide. This is because it is still unknown why indolent prostate cancer becomes an aggressive one, though many risk factors for this type of cancer have been suggested. Currently, many diagnostic markers have been suggested for predicting malignant prostatic carcinoma cancer; however, only a few, such as PSA (prostate-specific antigen), Prostate Health Index (PHI), and PCA3, have been approved by the FDA. However, each biomarker has its merits as well as shortcomings. The serum PSA test is incapable of differentiating prostate cancer from BPH and also has an about 25% false-positive prediction rate for the malignant status of cancer. The PHI test has the potential to replace the PSA test for the discrimination of BPH from prostate cancer and for the prediction of high-grade cancer avoiding unnecessary biopsies; however, the free form of PSA is unstable and expensive. PCA3 is not associated with locally advanced disease and is limited in terms of its prediction of aggressive cancer. Currently, several urine biomarkers have shown high potential in terms of being used to replace circulating biomarkers, which require a more invasive method of sample collection, such as via serum. Currently, the combined multiple tumor biomarkers may turn out to be a major trend in the diagnosis and assessment of the treatment effectiveness of prostate cancer. Thus, there is still a need to search for more novel biomarkers to develop a perfect cocktail, which consists of multiple biomarkers, in order to predict malignant prostate cancer and follow the efficacy of the treatment. We have discovered that METCAM, a cell adhesion molecule in the Ig-like superfamily, has great potential regarding its use as a biomarker for differentiating prostate cancer from BPH, predicting the malignant propensity of prostate cancer at the early premalignant stage, and differentiating indolent prostate cancers from aggressive cancers. Since METCAM has also been shown to be able to initiate the spread of prostate cancer cell lines to multiple organs, we suggest that it may be used as a therapeutic target for the clinical treatment of patients with malignant prostate cancer