Platelet phenotype changes associated with breast cancer and its treatment

Abstract

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-β1). Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-β1 were measured using standard ELISA. Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-β1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-β1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-β1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-β1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied. While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

“…The assessment of short-term effects of aspirin from the analyses of 51 randomized controlled trials that were designed to evaluate the role of aspirin in the primary and secondary prevention of vascular events demonstrated that aspirin reduced the incidence of several cancers from 3 years onwards [ 104 ]. In addition to having a preventive role in cancer, depending on the duration of treatment, aspirin also improves the results of treatment among cancer patients [ 7 , 17 , 24 ].…”

“…The differences in results may be associated with the length of time aspirin is taken [ 17 ] Shiao]. A prospective observational study of 4164 women with breast cancer showed that decreased risk of distant recurrence and breast cancer death is observed when aspirin is taken at least 12 months [ 7 ]. The newest retrospective analysis of 222 stage II and III triple-negative breast cancer (TNBC) patients demonstrates improvement in 5-year DFS (80.1 vs 62.6%, p = 0.04) and 5-year DMR (9.0 vs 31.6%, p = 0.007) in the aspirin group compared with the control group.…”

“… Prostate cancer Choe [ 4 ] n = 6000 A multi-institutional registry Lower prostate cancer-specific mortality (3 v 8%). Increased risk of upper gastrointestinal bleeding Hepatocellular carcinoma Lee 2016 [ 20 ] Retrospective analysis, n = 442 Improvement of recurrence-free survival and overall survival, reduced the risk of HCC recurrence and overall mortality Breast cancer Holmes 2010 [ 7 ] Prospective observational study, n = 4164 Decreased risk of distant recurrence and breast cancer death Gastrointestinal, esophageal, pancreatic, brain, and lung cancers Rothel 2011 [ 24 ] Analysis of eight randomized trials Reduced deaths due to cancer …”

“…The most important processes contributing to cancer progression regulated by platelets and their granular contents are adhesion and tumor cell-induced platelet aggregation (TCIPA), which result in tumor emboli in microvasculature, tumor cell migration, intra-/extravasation and angiogenesis [ 3 , 7 ]. Additionally, platelets are critical for survival of tumor cells within solid mass as they regulate intratumoral vasculature and hemostasis, and they protect circulating tumor cells (CTCs) in the blood stream from NK cell lysis [ 8 – 10 ].…”

The “Janus Face” of Platelets in Cancer

“…A recent study performed on twenty-four women with active breast cancer and ten healthy controls showed that breast cancer and its chemotherapeutic treatment influence platelet phenotype, by increasing VEGF release and modulating the response to antiplatelet therapy [119]. Noticeably, an autocrine-paracrine loop, occurring in the bone marrow microenvironment and involving VEGFR-1-dependent megakaryocyte maturation has been documented [120]. Such evidence, together with the finding that tumor-derived IL-6 leads to enhanced megakaryocyte VEGF expression and a higher platelet VEGF load (concomitantly associated with fast tumor growth kinetics and poor diagnosis), strongly suggest a cooperation between platelets and cancer in promoting angiogenesis [121].…”