Molecular role(s) for integrins in human melanoma invasion

There are fundamental issues regarding the role of integrins in human disea se which remain to be elucidated. Human cutaneous melanoma is an attractive model for studying integrin involvement in tumor progression because it ge nerally follows a sequential series of definable stages. Furthermore, the m ost specific marker for the transition of cells from the more benign, non-m etastatic radial growth phase stage to the more malignant, metastatically c ompetent vertical growth phase stage is associated with the onset of alpha( v)beta(3) integrin expression and function. This same pattern, however, doe s not hold true for human ocular/uveal melanomas which do not progress thro ugh these stages, but preferentially metastasize to the liver by disseminat ion of the cells via a direct hematogenous pathway. It is also unclear whet her 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 wit h either specific antibodies or ligands results in an increase in the cells ' ability to invade in vitro coincident with an increase in the cells' expr ession and extracellular levels of matrix metalloproteinase-2 (MMP-2, gelat inase A). The highly invasive C8161 human cutaneous melanoma cells express little-to-no alpha(v)beta(3) integrin, but are more invasive and express hi gher levels of MMPs after perturbation of their alpha(5)beta(1) integrin. T his augmented invasiveness could subsequently be abrogated with a function- blocking anti-MMP-2 antibody. Primary uveal melanoma cells and cells derive d from uveal metastases appear to grow in either a spindle or epithelioid m orphology. The less invasive uveal melanoma cells are spindle shaped and ex press higher levels of the alpha(v)beta(3) integrin, while the more invasiv e cell lines are epithelioid shaped and express reduced levels of the alpha (v)beta(3) integrin. The apparent conflict between these results and the cu rrent model for cutaneous melanoma progression may be addressed as follows: The expression and function of the alpha(v)beta(3) integrin plays an impor tant role(s) during the transition of cells from the radial growth phase st age to the vertical growth phase stage. However, further progression leadin g to metastases may require changes in the cells' integrins that would faci litate their ability to leave the primary tumor, and aid in their ability t o invade and ultimately form metastases. It is also conceivable that the al pha(v)beta(3) integrin is reexpressed during various stages of metastatic d issemination, and, in particular, during tumor reestablishment.