Overcoming Fas-mediated apoptosis accelerates Helicobacter-induced gastric cancer in mice

The interactions between cancer cells and the extracellular matrix (ECM) regulate cancer progression. The B1C and B1A integrins, two cytoplasmic variants of the B1 integrin subfamily, are differentially expressed in prostate cancer. Using gene expression analysis, we show here that the B1C variant, an inhibitor of cell proliferation, which is down-regulated in prostate cancer, up-regulates insulin-like growth factor-II (IGFII) mRNA and protein levels. In contrast, B1A does not affect IGF-II levels. We provide evidence that B1C-mediated upregulation of IGF-II levels increases adhesion to Laminin-1, a basement membrane protein down-regulated in prostate cancer, and that the B1C cytoplasmic domain contains the structuralmotif sufficient to increase cell adhesion to Laminin-1. This autocrine mechanism that locally supports cell adhesion to Laminin-1 via IGF-II is selectively regulated by the B1 cytoplasmic domain via activation of the growth factor receptor binding protein 2–associated binder-1/SH2-containing protein-tyrosine phosphatase 2/phosphatidylinositol 3-kinase pathway. Thus, the concurrent local loss of B1C integrin, of its ligand Laminin-1, and of IGF-II in the tumormicroenvironment may promote prostate cancer cell invasion and metastasis by reducing cancer cell adhesive properties. It is, therefore, conceivable that reexpression of B1C will be sufficient to revert a neoplastic phenotype to a nonproliferative and highly adherent normal phenotype. (Cancer Res 2006; 66(1): 331-42)