The human melanoma cell line A375M expresses the vitronectin receptor (aP3 integrin) on its cell surface. Treatment of A375M cells with either polyclonal or monoclonal anti-a,43 antibodies resulted in stimulation of invasion through basement membrane matrices in vitro. Similar treatment of these cells with a monoclonal anti-el antibody, which does not inhibit the adhesive function of the a,#3antigen, also stimulated invasion; however, anti-,83 antibody treatment had no effect. Furthermore, pretreatment of the cells with vitronectin or addition of vitronectin to the basement membrane matrix also resulted in stimulation of invasion. Similar treatments with fibronectin receptor antibody or fibronectin had no effect on invasion. Analysis of type IV collagenase expression in cells treated with anti-a4,33 antibody showed higher levels of both the secreted 72-kDa enzyme and its mRNA. Signal transduction through the a413 integrin could underlie the elevated expression of metalloproteinase and the enhanced invasion of A375M cells through basement membrane matrices.The three-step model for tumor cell invasion describes the initial process of the complex metastatic cascade in relatively simple terms: cell attachment to the extracellular matrix, proteolytic dissolution of the matrix, and movement of cells through the digested barrier (1). This process can occur repeatedly during the course of intra-and extravasation and can result in metastases at sites distant from the original tumor. The integrins, which are a family of cell-surface proteins that mediate cell-substratum and cell-cell adhesion, are important mediators of some of the interactions that constitute the metastatic process. The integrins are heterodimers of noncovalently linked a and ,8 subunits, each of which is a transmembrane protein (2-4). Eleven a and six 3 subunits have been identified; in various combinations they can produce at least 16 distinct integrins (5-7). Furthermore, a,B subunit can associate with multiple a subunits, and a single a subunit can become paired with more than one /3 subunit. In addition, more than one ligand can be bound by most integrins (5-8).While in vitro and in vivo comparisons between normal and malignant cells suggest that changes in integrin expression accompany malignant transformation (9), little correlation exists between the altered pattern of integrin expression and tumorigenesis (7). However, elevated expression of the a5/31 fibronectin receptor integrin is associated with lowered tumorigenicity (9,(10)(11)(12). Moreover, inhibition of integrin functions has suggested that integrins are important components of the metastatic process (7,(13)(14)(15)(16)(17)(18). Earlier, correlative observations suggest that the avI33 integrin (also known as the vitronectin receptor) is one of the integrins that plays a role in tumorigenicity and metastasis. Thus, elevated expression of this integrin is associated with invasive melanoma in vitro (7). We have explored the relationship between the function and expression of the av...