αv   β3-mediated regulation of TSP-1 in tumor cells depends on PI3 kinase signaling Free

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Integrin-mediated cellular communication with extracellular matrix (ECM) is thought to contribute to the regulation of angiogenesis and tumor progression. Tumor angiogenesis depends in part on the coordinated activity of both pro and anti-angiogenic factors derived from a number of cellular compartments within the local microenvironment of the tumor. Thus, a more in depth understanding of molecular mechanisms that regulate the balance of pro and anti-angiogenic factors may lead to the development of more strategies for controlling malignant tumor growth. In this regard, significant progress has been made in understanding the contributions of growth factors and proteolytic enzymes in the regulation of the tumor angiogenic switch. In contrast, less is known concerning the mechanisms by which integrin-mediated interactions with the tumor ECM may contribute to this process. Here we provide evidence that inhibition of integrin αvβ3 but not β1-mediated tumor cell interactions with a cryptic epitope within collagen can up-regulate TSP-1, a well known endogenous angiogenesis inhibitor. Importantly, αvβ3-mediated regulation of TSP-1 in these tumor cells appears to depend on PI3kinase signaling since inhibition of PI3kinase activity blocks the ability of αvβ3 to regulate TSP-1 in vitro. To this end, studies have suggested that the PI3kinase signaling cascade can modulate the relative levels of c-Myc, an oncogene thought to repress TSP-1 and regulate angiogenesis in vivo. Here we provide evidence that αvβ3-mediated tumor cell interactions with denatured collagen was associated with increased levels of c-Myc and reduced levels of TSP-1. Interestingly, specific targeting of αvβ3 expressed within tumor cells in vivo, but not in host blood vessels, resulted in inhibition of tumor angiogenesis and up-regulated TSP-1 within these tumors. Taken together, these findings are consistent with the possibility that selective targeting of αvβ3 within the tumor compartment may contribute indirectly to the inhibition of angiogenesis in vivo, by a mechanism involving up-regulating the endogenous angiogenesis inhibitor TSP-1.