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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 19, 2006; DOI: 10.1124/jpet.105.098384

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Received for publication November 9, 2005.
Revised January 17, 2006.
Accepted for publication January 18, 2006.

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

Carlos Medina 1, Paul Jurasz 1, Maria Jose Santos-Martinez 1, Soon Seog Jeong 2, Timothy Mitsky 2, Ridong Chen 2, Marek Radomski 1*

1 Institute of Molecular Medicine, University of Texas-Houston 2 APT Therapeutics Inc

* Address correspondence to: E-mail: mradomsk{at}yahoo.com

Abstract

Background: 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. Aim: To investigate mechanisms of TCIPA induced by colon adenocarcinoma cells in vitro. Methods: Human Caco-2 cells were used to study their interactions with platelets using aggregometry, zymography, phase-contrast microscopy and flow cytometry. Results: Caco-2 induced platelet aggregation in a concentration-dependent manner. This aggregation resulted in the release of 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. Conclusion: 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.


Key words: ADP, Caco-2, Human colon cancer, MMP-2, platelet receptors, tumor cell-induced platelet aggregation


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