Inhibition of MCF-7 breast cancer cell-induced platelet aggregation using a combination of antiplatelet drugs

Abstract

Cancer metastasis is a highly coordinated and dynamic multistep process in which cancer cells interact with a variety of host cells. Morphological studies have documented the association of circulating tumor cells with host platelets. Tumor cell-induced platelet aggregation (TCIPA) contributes significantly to hematogenous metastasis; however, the molecular mechanisms involved in breast cancer TCIPA are poorly characterized. In this study, MCF-7 metastatic human breast cancer cells induced dose-dependent aggregation of washed platelets. Four major platelet activation pathways, glycoprotein (GP)-Ib-IX, GPIIb/IIIa, thromboxane (TX)-A2 and adenosine diphosphate (ADP) were activated during TCIPA and were inhibited by their respective inhibitors, 7E3, SZ-1, aspirin and apyrase. Pretreatment of platelets with 7E3, SZ-1 or apyrase significantly inhibited TCIPA, while pretreatment with aspirin had no effect. Moreover, combined pretreatment of platelets with 7E3, SZ-1 and apyrase significantly inhibited TCIPA, compared to single inhibitors. Combinations of antiplatelet drugs may represent a promising strategy to prevent cancer metastasis.

Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology

“…At the site of injury, tumor cell-induced platelet activation (TCIPA) is characterized by PLT aggregation, adhesion, and a strong increase of PLT-derived pro-angiogenic factors [25]. PLTs are activated by their essential pathways, such as thromboxane (TX)-A2, glycoprotein (GP)-Ib-IX, ADP, and GPIIb/IIIa [26], leading to a dramatic increase in PLT-activation markers, such as P-selectin (CD62P) and angiogenesis mediators. Literature evidence reported that PLTs from breast cancer patients contained significantly higher levels of VEGF, angiopoietin-1, and P-selectin compared to normal controls [27]; similarly, the concentrations of VEGF and platelet-derived growth factor (PDGF) were increased in colorectal cancer patients compared to controls [28], as well as in GBM patients [20].…”

Platelets surrounding primary tumor cells are related to chemoresistance

“…Therefore, the presence of platelet aggregation around primary tumor cells is difficult to recognize. Cancer cells were shown to have the ability to interact with platelets in vitro several decades ago (19)(20)(21)(22). Furthermore, the interaction between circulating tumor cells (CTCs) and circulating platelets is now recognized as a hallmark of the metastatic potential of cancer (6,8).…”

“…Other studies have reported the interaction between intrinsic subtype and tumor cell-platelet interactions. Luminal-type breast cancer cells have been reported to induce greater aggregation of platelets than other types of breast cancer cells in vitro (19,24). Moreover, in addition to facilitating tumor invasiveness, migration, tumor growth, cell survival, and angiogenesis, circulating platelets also play a crucial role in inducing EMT in malignancy (10).…”

Platelet function beyond hemostasis and thrombosis

“…A long held observation of tumor cells supporting platelet aggregation highlights the tumor cells ability to exert a thrombotic effect likely contributing to the Trousseau syndrome [32]. The aggregation mechanisms are the well characterized receptor-ligand interactions and pathways that are exquisitely described for hemostasis, such as glycoprotein (GP) Ib-IX, GPIIb/IIIa, ADP, and thromboxane [51]. …”