Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Abstract

• Anticoagulants inhibit release of angiogenic proteins from platelets.Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 59-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. (Blood. 2014;123(1):101-112) IntroductionCancer cells are surrounded by and interact with a complex milieu consisting of but not limited to endothelial cells, mast cells, macrophages, stromal cells, and lymphocytes. In fact, tumor cells live in intimate symbiosis with the rest of the body and appear to hijack normal physiological processes to aid their progression and growth. The recognition that tumor growth and metastasis is not exclusively an independent process for tumor cells suggests that disrupting the tumor microenvironment might provide a novel treatment modality for malignancy.Although platelets are best known for their role in hemostasis and thrombosis, a substantial amount of data supports the idea that platelets play important roles in tumorigenesis, contributing to inflammation, angiogenesis, and metastatic dissemination of tumor cells.1 Platelet count can be a prognostic factor in cancer, patients presenting with thrombocytosis having a poor survival in a variety of cancers including breast cancer.2-5 Conversely, the presence of thrombocytopenia is associated with a survival benefit and decreased metastasis.6-9 For tumors to grow beyond 1 to 2 mm 3 , they must establish their own blood supply through angiogenesis, and there is substantial evidence that angiogenesis is regulated by platelets. [10][11][12] In malignancy, platelets are the major serum source of many potent proangiogenic proteins, including more than 80% of circulating vascul...

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

“…[49][50][51] Finally, we previously showed in mouse models that leukocyte extravasation in mesenteric vessels is dependent on VWF-mediated permeability. 52,53 This step could be related to vascular dissemination of cancer cells facilitated by VWF-recruited platelets mediating vascular permeability and tumor-associated activation of the coagulation.…”

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

“…This is somewhat puzzling, as thrombin is known to enhance angiogenesis (44), and anticoagulants inhibit tumor cell-mediated angiogenesis (45). Interestingly, however, low thrombin levels (i.e., 0.1-0.3 U/ mL) more potently induce angiogenesis as compared with high (i.e., 1 U/mL) thrombin levels (46), suggesting that residual thrombin activity in dabigatran-treated mice might actually induce angiogenesis.…”

Paraneoplastic thrombocytosis: the secrets of tumor self-promotion

“…20 Finally, for tumors to grow to sizes larger than 2 mm, they must establish their own blood supply through angiogenesis, a process regulated by platelets and their a granules that contain both proangiogenic and antiangiogenic proteins, including more than 80% of circulating vascular endothelial growth factor. 21 Contact with tumor cells activates platelets to preferentially release proangiogenic proteins. However, the mechanism of this selective release process through the possible organization of pro-and antiangiogenic proteins into separate a granules or platelet populations remains ill-defined.…”

“…45 Interestingly, recent evidence suggests that these anticoagulants can also selectively inhibit platelet release of proangiogenic proteins and diminish platelet-mediated angiogenic response. 21 Finally, blockade of platelet Fcg receptor IIa and a IIb b 3 receptors would also be logical approaches, 7 in addition to blockade of the P2Y 2 receptor on endothelial cells or its downstream signaling pathway. 20 However, these too will require rigorous preclinical testing, especially as prasugrel, a potent P2Y 12 receptor blocker used in the treatment of cardiovascular disease, was found to be associated with a higher rate of colonic malignancy in a large study.…”