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[Cancer Research 62, 2824-2833, May 15, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Multiple Roles for Platelet GPIIb/IIIa and {alpha}vß3 Integrins in Tumor Growth, Angiogenesis, and Metastasis

Mohit Trikha1, Zhao Zhou, Jozsef Timar, Erzebet Raso, Margaret Kennel, Eva Emmell and Marian T. Nakada

Department of Biology Research, Centocor, Inc., Malvern, Pennsylvania 19355 [M. T., Z. Z., M. K., E. E., M. T. N.], and Department of Tumor Progression, National Institute of Oncology, Budapest, Hungary H-1122 [J. T., E. R.]

In vivo tumor cells interact with a variety of host cells such as endothelial cells and platelets, and these interactions are mediated by integrins GPIIb/IIIa and {alpha}vß3. We used chimeric (c) 7E3 Fab (ReoPro) and murine (m) 7E3 F(ab')2 to elucidate the role of these integrins in angiogenesis, tumor growth, and metastasis. These antibodies are potent inhibitors of GPIIb/IIIa and {alpha}vß3. c7E3 Fab inhibited {alpha}vß3-mediated human umbilical vein endothelial (HUVEC) and melanoma cell adhesion, migration, invasion, and basic fibroblast growth factor stimulated proliferation of HUVECs (IC50 values range from 0.15 to 5 µg/ml for different assays). In an in vitro angiogenesis assay, c7E3 Fab inhibited basic fibroblast growth factor and platelet-stimulated capillary formation of HUVECs (IC50 = 10 µg/ml and 15 µg/ml, respectively), demonstrating that endothelial {alpha}vß3 is important for sprouting, and platelet-stimulated sprouting is mediated by GPIIb/IIIa. In an experimental metastasis assay, a single pretreatment of human melanoma cells with c7E3 Fab (2.5 µg/ml) inhibited lung colonization of the tumor cells in severe combined immunodeficient mice. In vivo, m7E3 F(ab')2 partially inhibited growth of human melanoma tumors in nude mice compared with control-treated animals. These data suggest that tumor cell-expressed integrins are important but not the only component involved in tumor growth. Because c7E3 Fab and m7E3 F(ab')2 do not cross-react with murine integrins, this inhibition of metastasis and tumor growth is attributable to direct blockade of human tumor {alpha}vß3 integrins. m7E3 F(ab')2 completely blocked tumor formation and growth of human melanoma tumors growing in nude rats. In this xenograft model, m7E3 F(ab')2 simultaneously binds to both human tumor and host platelet GPIIb/IIIa and endothelial {alpha}vß3 integrins, thus participating as an antiangiogenic and an antitumor agent. Collectively, these results indicate that combined blockade of GPIIb/IIIa and {alpha}vß3 affords significant antiangiogenic and antitumor benefit.




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