Anti-Coagulation Agents Provide a Mechanism to Inhibit Tumor Cells From Hijacking the Angiogenic Potential of Platelets
Authors: Battinelli Elisabeth M. , Markens Beth , Italiano Joseph E. 
Published: October 2019

Abstract
Abstract 1149
While an association between cancer and platelets has been long recognized, the cause and effect relationship linking the two remains unclear. Provocatively, recent studies suggest that anti-platelet agents can increase overall survival and decrease metastatic disease in cancer patients. Because angiogenesis is crucial for tumor growth beyond 1–2 mm3, one view is that platelets may regulate new blood vessel growth through release of the vast array of angiogenesis promoters and stimulators stored in platelet alpha granules. We previously demonstrated that physiological agonists as well as tumor cells (MCF-7 breast cancer cells) could direct the preferential release of pro-angiogenic regulatory proteins from platelets, providing a mechanism for how tumor cells may promote new blood vessel growth in the tumor microenvironment (Battinelli et. al Blood, 2011). In line with these observations, we recently showed that the pro-angiogenic potential of platelets could be attenuated by the anti-platelet agent aspirin providing one mechanism by which platelet inhibitors may attenuate metastatic spread. These observations motivated the hypothesis that agents with anti-thrombotic effects, including LMWH, may also alter the release of angiogenesis regulatory proteins from platelets. Our results reveal that platelets pretreated with daltaparin (a LMWH) showed significant decreases in the amount of VEGF released in response to activation by either the platelet agonist ADP (0.633+/−0.63 with dalteparin vs. 55.71+/−13.92 without dalteparin, p<0.05) or the MCF-7 tumor cell line (28.89+/−0.389 with dalteparin vs. 114.0+/− 38.38 without dalteparin, p<0.05). The angiogenic potential of the releasate generated from ADP was significantly decreased as measured by endothelial cell migration (81.25 +/− 8.6 without dalteparin and 0.5 +/− 0.2 with dalteparin). Similar results were observed for the releasate generated from MCF-7 cell exposure (106.6 +/− 14.7 without dalteparin and 2.33 +/− 0.8 with dalteparin). The angiogenic response of the releasate generated from ADP was also significantly decreased as measured by capillary tube formation assay (155.3 +/− 8.9 without dalteparin vs. 38.5 +/− 4.1 with dalteparin). Comparable results were observed for the releasate generated from MCF-7 cell exposure (138.5 +/− 10.6 without dalteparin vs. 23.00 +/− 5.0 with dalteparin). Other anti-coagulants including fondaparinux and unfractionated heparin also produced profound blockade of the platelet angiogenic potential. Taken together, these data underscore the pivotal role of platelets in regulating tumor angiogenesis. Attenuation of platelet angiogenic potential by anti-thrombotic agents may be a mechanism underlying their effects on the improved survival and the decreased metastasis in cancer patients. This study may provide a rationale to search for new cancer drugs by their effects on platelet-mediated angiogenic potential.

Disclosures:
No relevant conflicts of interest to declare.