Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells

Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin alphavbeta3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin alphavbeta3 supports metastasis of human melanoma cells when injected into the bloodstream of immune deficient mice. Comparing variants of the same melanoma cell type that expressed either alphavbeta3, alphaIIbbeta3 or no beta3 integrin, we found that only alphavbeta3 strongly supported metastasis. Inhibition of tumor cell alphavbeta3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow alphavbeta3, but not alphaIIbbeta3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing alphavbeta3, but not those expressing alphaIIbbeta3 or no beta3 integrin, produced the active form of metalloproteinase MMP-2 and expressed elevated mRNA levels of MT1-MMP and TIMP-2. This indicates an association between alphavbeta3 expression and protease processing. Furthermore, alphavbeta3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin alphavbeta3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin alphaIIbbeta3 cannot substitute for alphavbeta3 in this respect.