Abstract

Tumor cell adherence to and migration on the extracellular matrix is an important aspect of cancer progression. This interaction with the extracellular matrix is mediated primarily through the integrin class of cell adhesion molecules. We identified a restricted expression of alphavbeta3 in highly metastatic K1735M2 and of alphavbeta5 in poorly metastatic K1735C23 murine melanoma cells. The highly metastatic cells were ten times more motile on vitronectin and fibronectin and approximately three times more invasive through a reconstituted basement membrane than the poorly metastatic cells. This motility was inhibited by addition of anti-beta3 antibodies. Injection of the alphavbeta3-negative K1735C23 cells into syngeneic mice resulted in the generation of a metastatic variant (K1735C23PM) that neo expressed the alphavbeta3 complex, indicating that expression of alphavbeta3 is required for K1735 melanoma metastasis. Injection of highly metastatic K1735M2 cells in the presence of blocking antibody to beta3 reduced tumor size by approximately 80%. Treatment of the K1735M2 cells with a retroviral antisense beta3 construct significantly reduced their expression of alphavbeta3 and also reduced their motility on extracellular matrix ligands and their invasion through a reconstituted basement membrane. In contrast, when the K1735C23 cells were treated with a construct containing the full-length beta3 cDNA, their motility on extracellular matrix proteins and invasion of a reconstituted basement membrane were significantly increased. These results indicate that alphavbeta3 is required for migration and invasion of K1735 melanoma cells in vitro and primary tumor growth and metastasis in vivo.