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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Platelet Aggregation-Induced by Caco-2 Cells: Regulation by Matrix Metalloproteinase-2 and Adenosine Diphosphate

Department of Integrative Biology and Pharmacology and Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas, Houston, Texas (C.M., P.J., M.J.S.-M., M.W.R.); APT Therapeutics Inc., St. Louis, Missouri (S.S.J., T.M., R.C.); and Gastroenterology Department, Hospital Universitario de Canarias, Tenerife, Spain (C.M.)

Formation of tumor cell-platelet aggregates facilitates hematogenous metastases. However, molecular mechanisms implicated in tumor cell-induced platelet aggregation (TCIPA) in colon cancer are unclear. To investigate mechanisms of TCIPA induced by colon adenocarcinoma cells in vitro, human Caco-2 cells were used to study their interactions with platelets using aggregometry, zymography, phase-contrast microscopy, and flow cytometry. Caco-2-induced platelet aggregation in a concentration-dependent manner. This aggregation resulted in the release of matrix metalloproteinase (MMP)-2, as measured by zymography. In addition, flow cytometry showed a significant up-regulation of activated GpIIb/IIIa, total GpIIb/IIIa, GpIb, and P-selectin receptors on platelets. Inhibition of MMP-2 by phenantroline and degradation of ADP by APT102, respectively, resulted in inhibition of TCIPA. Furthermore, both phenantroline and APT102 significantly down-regulated the surface abundance of platelet receptors. Caco-2 cells aggregate platelets, at least in part, via releasing MMP-2 and ADP. Modulation of MMP-2 and ADP actions could have therapeutic value in colonic cancer.

Address correspondence to: Dr. Marek W. Radomski, School of Pharmacy and Pharmaceutical Sciences, University of Dublin Trinity College, Dublin 2, United Kingdom. E-mail: radomskm{at}tcd.ie

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