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The occurrence of aberrations in cell adhesion is a critical phase in the invasion and metastasis of human cancer. A tumor suppressor gene, TSLC1/IGSF4, from chromosomal region 11q23 was identified in non-small cell lung cancer (NSCLC) by its tumor suppressor activity in nude mice. TSLC1/IGSF4 is expressed in most tissues except for peripheral blood lymphocytes, but it is inactivated in 44% of NSCLC and 30–60% of various cancers, including liver, pancreatic, and prostate cancers, especially in those with invasion or metastasis. Inactivation occurs by two hits: through promoter methylation, and through loss of heterozygosity at the gene locus. TSLC1/IGSF4 encodes an immunoglobulin superfamily cell adhesion molecule and associates with an actin-binding protein, DAL-1/4.1B, and members of the membrane-associated guanylate kinase homologue (MAGuK) group, providing a novel tumor suppressor cascade that is inactivated in more than 80% of NSCLC. TSLC1/IGSF4 appears to be involved in the formation of an epithelial cell structure with DAL-1/4.1B and MAGuK. Furthermore, TSLC1/IGSF4 may act as a tumor antigen recognized by activated NK or CD8+ T cells. These two distinct mechanisms based on homophilic and heterophilic interactions would be responsible for tumor suppression by TSLC1/IGSF4. TSLC1/IGSF4 is ectopically expressed in adult T-cell leukemia (ATL) cells, providing not only a diagnostic marker for ATL, but also a possible therapeutic target against its invasion. The distinct roles of TSLC1/IGSF4 in the oncogenesis of carcinomas and ATL could be due to tissue-specific differences in the downstream cascades, and is a novel concept with respect to cell adhesion in human oncogenesis. (Cancer Sci 2005; 96: 543 –552)