We and others have confirmed that this CD133+/CD44+ cell population makes up a subset of prostate cancer cells that are self renewing

or progression of cutaneous melanoma. The role of ALCAM in cutaneous melanoma was first addressed directly by the laboratory of Guido Swart. An amino terminal-truncated form of ALCAM was transfected into cutaneous melanoma cells, and was found to diminish cell clustering and enhance both motility in vitro and the transition from primary tumor to tissue invasion in vivo. It appeared that the disruption of homophilic ALCAM contacts thus resulted in increased metastatic potential in cutaneous melanoma cell lines; this was, however, in contrast to previous expression data that predicted ALCAM would promote invasion and metastasis. When other cancer types are considered, the picture becomes murkier one study by Kristiansen and colleagues found that ALCAM protein expression is high in low-grade prostate cancer, and is lost in higher-grade tumors. A study of colorectal cancer demonstrated overexpression of ALCAM neoplastic regions compared to normal surrounding tissue; membranous ALCAM staining correlated with reduced patient survival. Studies of breast carcinoma also provide seemingly conflicting results: one study found that low ALCAM expression correlated with high tumor grade and metastasis, while another showed that ALCAM is associated with smaller tumor diameter and grade. ALCAM in Melanoma Motility and Adhesion Studies describing ALCAM function in uveal melanoma, the most common form of primary intraocular cancer, are lacking. Our aim in initiating this study was to determine the role that ALCAM plays in modulating invasiveness and motility in uveal melanoma, and to provide mechanistic data that will contribute to an understanding of why ALCAM up- and down-regulation might be associated with different stages of different cancers. We describe a correlation between ALCAM expression and motility in a gap closure assay in uveal melanoma cells. These data suggested that ALCAM plays a role in promoting motility and migration. We further find that silencing of ALCAM in the invasive MUM-2B line results in decreased motility, invasiveness, and MMP-2 activation. ALCAM in Melanoma Motility and Adhesion 11 ALCAM in Melanoma Motility and Adhesion Our results have implicated ALCAM as a regulator of cadherinbased adherens junctions in uveal melanoma cells. The disruption of N-cadherin/-catenin-positive junctions we observe in ALCAM-silenced sh5 cells is striking. Typically, N-cadherin and catenin localize strongly to cell-cell contacts, colocalizing with ALCAM. In ALCAM-silenced cells, however, both N-cadherin and -catenin localization at cell contacts is markedly reduced it appears as if adherens junctions ��fall apart��in the absence of ALCAM. This is consistent with earlier findings by Ofori-Acquah and colleagues, in which ALCAM co-immunoprecipitated in multiple adherens junction complexes. We were not, however, able to co-immunoprecipitate ALCAM with N-cadherin in uveal melanoma cells, suggesting that any interaction may not be direct or may be sensitive to our lysis RO4929097 custom synthesis conditions. The cadherins have long been implicated PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22203956 in invasion and metastasis, with N-cadherin/E-cadherin expression often dictating invasive potential in cancer cells. In addition to mediating intercellular and cell-matrix adhesive interactions, cell adhesion molecules also modulate signaling pathways. Thus, changes in the expression and localization of cell adhesion molecules can influence tumor progression by both modulating the adhesion status of a cell and by altering cell signal