METCAM/MUC18 Expression and Cancer Metastasis

Abstract

The aberrant expression of cell adhesion molecules (CAMs) is correlated with the malignant progression of many tumors. MUC18/CD146/A32/MelCAM/S-endo, an integral membrane glycoprotein, is a CAM in the immunoglobulin gene superfamily. MUC18 has often been mistaken as a mucin because of the misleading nomenclature. Based on its biological functions and other known biochemical properties, we propose to re-name it as METCAM (metastasis CAM). METCAM/MUC18 expression has a very interesting effect on tumor formation and metastasis. The overexpression of METCAM/MUC18 has been correlated with the malignant progression of human melanoma and human prostate cancer. In melanoma, the ectopic over-expression of METCAM/MUC18 has no effect on tumorigenesis, but augments the metastasis of cancer cells. In prostate cancer, the ectopic over-expression of human METCAM/MUC18 has an even greater effect, increasing tumorigenesis and initiating the metastasis of cancer cells. However, an opposite effect of METCAM/MUC18 on tumorigenesis and metastasis of breast cancer, some mouse melanoma cell lines, and perhaps haemangioma and nasopharygeal carcinoma has also been suggested. Taken together, we suggest that the different effect of METCAM/MUC18 on tumor formation and metastasis is dependent on the intrinsic properties of each tumor cell line. This paper will review previous experiments and results and present some possible mechanisms of METCAM/MUC18-mediated tumorigenesis and metastasis for future studies.

Dual Roles of the Melanoma CAM (MelCAM/METCAM) in Malignant Progression of Melanoma

“…No metastasis was found when METCAMexpressing melanoma cells were injected subcutaneously (spontaneous metastasis assay) either in immune-deficient mouse models [3,17] or in immune-competent syngeneic mouse models [18]. Taken together, METCAM promotes the metastasis of melanoma cells, but at later stages [7]; thus over-expression of METCAM did not initiate the metastasis of melanoma cells. This result is consistent with the recent observation that fibroblast growth factor 2, but not huMETCAM, nor integrin, actually initiates the malignant progression of subcutaneous melanocyte into melanoma [19].…”

“…We may be able to find some common clues to begin understanding its mechanisms by deducing knowledge learned from the tumorigenesis of other tumors [10][11][12][13][14]22] [7]. Among these potential regulators, it is well documented that the AP2transcription factor plays a crucial tumor suppressor role in the progression of melanoma [25].…”

“…Among these potential regulators, it is well documented that the AP2transcription factor plays a crucial tumor suppressor role in the progression of melanoma [25]. However, the roles of other transcription regulators, tissue specific enhancers and repressors, epigenetic control, and control at the level of chromatin remodeling of the gene have still yet to be investigated [7]. Second, since the cytoplasmic tail of METCAM contains consensus sequences potentially to be phosphorylated by PKA, PKC, and CK2, it may manifest its functions by cross-talk with various signaling pathways mediated by these protein kinases [7].…”

“…However, the roles of other transcription regulators, tissue specific enhancers and repressors, epigenetic control, and control at the level of chromatin remodeling of the gene have still yet to be investigated [7]. Second, since the cytoplasmic tail of METCAM contains consensus sequences potentially to be phosphorylated by PKA, PKC, and CK2, it may manifest its functions by cross-talk with various signaling pathways mediated by these protein kinases [7]. For example, METCAM expression in melanoma cells is reciprocally regulated by AKT, in which AKT up-regulates the level METCAM and over-expression of METCAM activates endogenous AKT, which in turn inhibits apoptosis and increases survival ability [23].…”

“…Based on the above information, aberrant expression of huMETCAM may also affect the motility and invasiveness of many tumor cells in vitro and metastasis in vivo. It is logical to hypothesize that HuMETCAM should play an important role in regulating the malignant progression of many cancer types [7,13]. Nevertheless, in this chapter we will only review its positive or negative roles in the tumorigenesis and metastasis of human and mouse melanoma cells.…”