Platelets are versatile cells with known functions in hemostasis, thrombosis, inflammation, and several pathological situations, such as cancer [1,2]. The relationship between platelets and cancer progression has been known since the 19th century when Trousseau described the presence of spontaneous coagulation in cancer patients . Indeed, platelets participate in all stages of cancer: from localized growth to distant metastasis formation . As such, multifunctional cells have been in the center of many research efforts to treat and/or prevent cancer.
Tumor cells have the capability to activate platelets through tumor cell-induced platelet aggregation . It can occur through direct contact, with the binding of platelet αIIbβ3 to tumor αVβ3, binding platelet α6β1 to tumor ADAM9, or through P-selectins, platelet TLR4 or CLEC-2 interactions [1,4–6]. Tumor cell-induced platelet aggregation may also be induced by indirect contact, by tumor secretion into the microenvironment of platelet activators, such as ADP or thromboxane A2 [7,8].
Microvesicle (MV) production by tumor cells can also activate platelets and trigger granule content release . Platelet granules contain a myriad of growth and pro-angiogenic factors, which provide pro-survival signals for the tumor cells. When activated, they secrete transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) [6,10]. Platelets also sustain pro-angiogenic signaling that induces formation of tumor-infiltrating blood vessels, as well as proliferation/differentiation of cancer-associated pericytes and fibroblasts in the tumor microenvironment [1,6].
Cancer cells can also affect platelet messenger RNA (mRNA) profiles. While the exact molecular mechanisms have not been elucidated, it has been proposed that cancer MVs could be the acting vehicles. Researchers have shown that platelets from cancer patients contain tumor-associated RNA biomarkers (e.g., EGFRvIII and PCA3 for glioma and prostate cancer) . Additionally, mRNA sequencing of tumor-educated-platelets can not only identify cancer patients, but also distinguish between six primary tumor types (non-small-cell lung cancer, glioblastoma, colorectal, pancreatic, hepatobiliary and breast cancer) with high accuracy .
The concept of tumor-educated-platelets refers to these platelets whose function has been “kidnapped” by tumor cells [13,14]. While this concept has become quite popular in recent years, it is important to bear in mind that it is not a one-way relationship. Platelets can also affect cancer cell behavior through different direct or indirect mechanisms, creating a vicious circle that could ultimately enhance cancer cell proliferation.
Platelets affect cancer cells by degranulating in the tumor microenvironment, as we have previously stated . They can also affect tumor cell phenotype and induce the epithelial–mesenchymal transition (EMT) in situ by downregulating cancer E-cadherin expression, upregulating pro-EMT molecules, such as Snail, vimentin, fibronectin and matrix metalloproteinase-9 and, overall, upregulating a pro-metastatic gene signature . Interestingly, MVs issued from platelet-cancer interaction can also stimulate EMT .
During the metastatic process, platelets also affect cancer cells and participate in molecule exchanges that result in survival advantages for cancer cells. Platelets facilitate immune evasion by releasing high quantities of TGF-β, which downregulates the expression of NKG2D, the major receptor on natural killer cells and results in diminished natural killer activation [15,17]. Platelets also transfer major histocompatibility complex I (MHC-I) to platelets in circulation, as well as other platelet markers to further shroud cancer cells from the immune system.
Platelet cancer cell interactions also mediate tumor cell arrest on the endothelium during the metastatic progression [1,6]. After cancer–platelet interaction, MVs containing membrane proteins from both cancer cells and platelets can activate the endothelium, which increases expression of adhesion molecules facilitating cancer cell rolling and adhesion . Furthermore, platelet-derived CXCL5 and CXCL7 can recruit granulocytes to guide the pre-metastatic niche formation [1,19].
As this short but concise literature review shows, platelets and cancer cells seem to be incessantly interacting with each other. We propose that there are not only “tumor-educated-platelets” or “cancer-educated-platelets” but more likely, a continuous interaction, which alters the phenotype and secretome of both cell types involved. While this is a promising therapeutic target, there is still much work to be done in order to fully comprehend these mechanisms.
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