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Role of the ₅ß₁ Integrin Receptor in the Proliferative Response of Quiescent Human Melanoma Cells to Fibronectin¹

Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan [R. M., G. P., A. A.]; Laboratory of Experimental Medicine, Università La Sapienza, Rome [A. G., A. S.]; and Laboratory of Pathophysiology, Regina Elena Cancer Institute, Rome [A. S.], Italy

The possible mitogenic activity of fibronectin (FN) in human primary and metastatic melanoma lines and clones and the involvement of integrins in mediating this effect were evaluated. Quiescent human melanoma cells cultured in serum-free medium proliferated in a dose- and time-dependent fashion to immobilized FN as indicated by [³H]thymidine incorporation, increment of cell number, and cell cycle analysis. This response to FN was observed with tumor clones isolated from a subcutaneous metastasis and with primary or metastatic melanomas from different patients, but only when tumor cells expressed the ₅ subunit of the FN receptor (i.e., VLA-5). Proliferation to FN by a primary tumor (Me4405) expressing all FN receptors and by a tumor clone (2/60) lacking only the ₄ subunit was inhibited by monoclonal antibodies to the ₅ and ß₁ but not by monoclonal antibodies to other subunits of FN receptors. Mapping of FN regions responsible for the proliferative signal was performed by stimulating melanoma cells with different FN proteolytic fragments and indicated that a significant mitogenic signal was provided by the M_r 120,000 -chymotrypsin fragment containing the Arg-Gly-Asp sequence. The proliferation of melanoma cells to FN and to FN fragments was also significantly inhibited by peptides containing the Arg-Gly-Asp sequence. These data indicate that FN can stimulate the proliferation of quiescent melanoma cells and that integrins as ₅ß₁ are involved in the response of tumor cells to this extracellular matrix protein.

¹ Supported in part by the Italian Association for Cancer Research, Milan, Italy.

² To whom requests for reprints should be addressed, at Division of Experimental Oncology D, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.

Received 3/ 2/92. Accepted 6/ 8/92.

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