Expression of alpha and beta subunits of VLA and VNR integrins was analyzed by cytofluorimetric analysis on 6 different human primary and metastatic melanoma cell cultures. Marked inter-tumor heterogeneity was observed, and expression of VLA-alpha I, VLA-alpha 2 and VLA-alpha 6 was lower on primary melanomas than on metastatic lesions. The function of VLA products on melanoma cells was assessed by adhesion assays to extracellular matrix (ECM) proteins using a panel of melanoma clones previously characterized for the presence and heterogeneity of expression of the distinct VLA-alpha subunits. These experiments indicated that intra-tumor heterogeneity in the integrin profile can influence the interaction of neoplastic cells with ECM proteins. Inhibition of adhesion with antibodies to VLA-alpha subunits revealed that the presence on melanoma cells of VLA-alpha 2, VLA-alpha 5 and VLA-alpha 6 is relevant for the adhesion to type-IV collagen, fibronectin and laminin respectively. Culture of tumor cells in the presence of cytokines such as rIL-I beta, rTNF-alpha, rIFN-gamma or TGF-beta I could induce up- or down-modulation in the level of expression of multiple VLA integrins. Cytokine-mediated antigenic shifts in the VLA profile of melanoma cells were detected by cytofluorimetric analysis as early as 24 hr after cytokine exposure. The cytokine-dependent change in the matrix receptor profile of melanoma cells also affected the adhesion to ECM proteins as revealed by the enhanced adhesion of rTNF-alpha-treated cells to fibronectin. These data indicate that constitutive heterogeneity in the integrin profile or cytokine-mediated shifts in VLA expression can affect the ability of human melanoma cells to interact with different ECM components.