There are fundamental issues regarding the role of integrins in human disease which remain to be elucidated. Human cutaneous melanoma is an attractive model for studying integrin involvement in tumor progression because it generally follows a sequential series of definable stages. Furthermore, the most specific marker for the transition of cells from the more benign, non-metastatic radial growth phase stage to the more malignant, metastatically competent vertical growth phase stage is associated with the onset of alpha v beta 3 integrin expression and function. This same pattern, however, does not hold true for human ocular/uveal melanomas which do not progress through these stages, but preferentially metastasize to the liver by dissemination of the cells via a direct hematogenous pathway. It is also unclear whether the alpha v beta 3 integrin is functionally involved in uveal melanoma metastasis or not. Our results show that perturbation of the alpha v beta 3 integrin on moderately invasive A375M human cutaneous melanoma cells with either specific antibodies or ligands results in an increase in the cells' ability to invade in vitro coincident with an increase in the cells' expression and extracellular levels of matrix metalloproteinase-2 (MMP-2, gelatinase A). The highly invasive C8161 human cutaneous melanoma cells express little-to-no alpha v beta 3 integrin, but are more invasive and express higher levels of MMPs after perturbation of their alpha 5 beta 1 integrin. This augmented invasiveness could subsequently be abrogated with a function-blocking anti-MMP-2 antibody. Primary uveal melanoma cells and cells derived from uveal metastases appear to grow in either a spindle or epithelioid morphology. The less invasive uveal melanoma cells are spindle shaped and express higher levels of the alpha v beta 3 integrin, while the more invasive cell lines are epithelioid shaped and express reduced levels of the alpha v beta 3 integrin. The apparent conflict between these results and the current model for cutaneous melanoma progression may be addressed as follows: The expression and function of the alpha v beta 3 integrin plays an important role(s) during the transition of cells from the radial growth phase stage to the vertical growth phase stage. However, further progression leading to metastases may require changes in the cells' integrins that would facilitate their ability to leave the primary tumor, and aid in their ability to invade and ultimately form metastases. It is also conceivable that the alpha v beta 3 integrin is reexpressed during various stages of metastatic dissemination, and, in particular, during tumor reestablishment.