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The High Affinity IIbß3 Integrin Is Involved in Invasion of Human Melanoma Cells¹

Departments of Radiation Oncology [M. T., S. K. L., K. S., Y. C., A. T. P., K. V. H.] and Pathology and Chemistry [K. V. H.], Wayne State University, and Barbara Ann Karmanos Cancer Center, The Detroit Medical Center [K. V. H.], Detroit, Michigan 48202, and First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, H-1085, Hungary [J. T.]

Integrins play an important role in mediating tumor cell-extracellular matrix (ECM) and tumor cell-endothelial cell interactions. The integrin IIbß3 (GPIIb-IIIa) is expressed on the surface of platelets in an inactive state and requires a conformational change to recognize extracellular matrix proteins such as fibrinogen, fibronectin, vitronectin, and others. In this study, we questioned whether human melanoma cells express the IIbß3 integrin. Reverse transcription-PCR/Southern blotting, Northern blotting, and dot blotting demonstrated the presence of the platelet-type IIbß3 integrin in human melanoma WM 983B, WM 983A, and WM 35 cells. AP-2, a monoclonal antibody (mAb) to IIbß3, positively stained two human melanoma specimens, indicating expression of this integrin in vivo. Phorbol 12-myristate 13-acetate and 12(S)-hydroxyeicosatetraenoic acid, two activators of protein kinase C, stimulated adhesion of melanoma cells to immobilized fibronectin and PAC-1, a mAb to IIbß3. PAC-1 specifically recognizes the conformationally active form of platelet IIbß3. Phorbol 12-myristate 13-acetate-stimulated adhesion of WM 983B cells to PAC-1 was completely blocked by an RGD peptide, thus providing evidence that tumor cell adhesion to PAC-1 is mediated via the IIbß3 integrin but not the Fc receptor. Confocal immunofluorescent studies demonstrated that fibronectin-adherent melanoma cells possess an intracellularly localized pool of high-affinity IIbß3. Invasion of WM 983B cells through fibronectin was stimulated by 12(S)-hydroxyeicosatetraenoic acid, and this stimulated invasion was blocked by the mAb PAC-1. The data suggest that melanoma cells express the high-affinity IIbß3 integrin, which is involved in tumor invasion.

¹ This work was supported by NIH Department of Health and Human Services Grants CA-47115-08 (to K. V. H.), CA-29997-14 (to K. V. H.), Harper Developmental Fund (to K. V. H.) TW-285-03 (to K. V. H. and J. T.), NATO CRG950287 (to K. V. H. and J. T.), Hungarian Ministry of Welfare 343/93 (to J. T.), the Hungarian National Science Fund T21149 (J. T.), and a National Cancer Institute fellowship (to M. T.).

² To whom requests for reprints should be addressed, at Wayne State University, 431 Chemistry Building, Detroit, MI 48202. Phone: (313) 577-1018; Fax (313) 577-0798.

Received 10/30/96. Accepted 4/15/97.

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