Tumor-Educated Platelet Extracellular Vesicles: Proteomic Profiling and Crosstalk with Colorectal Cancer Cells

Simple Summary The most life-threatening events in colorectal cancer (CRC) are metastasis and thrombosis. Platelets can play a role in these outcomes via the release of medium-sized extracellular vesicles (mEVs). Thus, we aimed to study the EVs released from activated platelets of CRC patients and healthy controls (HS) for their size composition, protein content, and the capacity to influence the expression of genes involved in malignancy and the synthesis of a prothrombotic lipid mediator such as thromboxane (TX)A(2). Our findings show that the protein content of thrombin-stimulated mEVs is modulated in CRC. Its evaluation may represent a noninvasive tool to discriminate patients from healthy subjects. Moreover, our findings show that characterizing the regulation of the expression of promalignant genes and prothrombotic phenotypes in cancer cells by the crosstalk with platelet mEVs could provide prognostic information on cancer patients, which could help in developing an appropriate anticancer strategy. Background: Platelet-cancer cell interactions modulate tumor metastasis and thrombosis in cancer. Platelet-derived extracellular vesicles (EVs) can contribute to these outcomes. Methods: We characterized the medium-sized EVs (mEVs) released by thrombin-stimulated platelets of colorectal cancer (CRC) patients and healthy subjects (HS) on the capacity to induce epithelial-mesenchymal transition (EMT)-related genes and cyclooxygenase (COX)-2(PTGS2), and thromboxane (TX)B-2 production in cocultures with four colorectal cancer cell lines. Platelet-derived mEVs were assessed for their size distribution and proteomics signature. Results: The mEV population released from thrombin-activated platelets of CRC patients had a different size distribution vs. HS. Platelet-derived mEVs from CRC patients, but not from HS, upregulated EMT marker genes, such as TWIST1 and VIM, and downregulated CDH1. PTGS2 was also upregulated. In cocultures of platelet-derived mEVs with cancer cells, TXB2 generation was enhanced. The proteomics profile of mEVs released from activated platelets of CRC patients revealed that 119 proteins were downregulated and 89 upregulated vs. HS. Conclusions: We show that mEVs released from thrombin-activated platelets of CRC patients have distinct features (size distribution and proteomics cargo) vs. HS and promote prometastatic and prothrombotic phenotypes in cancer cells. The analysis of platelet-derived mEVs from CRC patients could provide valuable information for developing an appropriate treatment plan.