Naghmeh Ahmadiankia - Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
Hojjat Naderi-Meshkin - Stem Cells and Regenerative Medicine Research Group, Iranian Academic Center for Education, Culture Research (ACECR), Khorasan Razavi Branch, Mashhad, Iran

The blood stream is a hostile environment for tumor cells. This may be due to three challenging factors: (i) shearing forces, (ii) immunologic deletion and (iii) anoikis. However, cancer cells employ platelets to overcome these hurdles in favor of metastasis. Cancer cells must be able to withstand shearing forces generated by blood flow in the vascular microenvironment. Platelets have been shown to bind to and form a physical barrier which limits cancer cells exposure to shear stress.One of the other challenges tumor cells are confronted in the circulatory system is attack by the immune cells especially natural killer (NK) cells. There is data indicating that activation of platelets by tumor cells contributes to overcome immunologic deletion. After platelet activation, the P-selectin which is present in platelet α-particles can be rapidly inserted into the membrane and expressed on the platelet surface. Activated platelets react with their ligand, PSGL-1, on cancer cells via P-selectin, and help to formation of platelets aggregate to protect cancer cells. Aggregation of platelets around tumor cells acts like a physical barrier to NK cells and protect them from immunologic deletion. Moreover, platelets exert paracrine suppression of NK-mediated cytolytic activity by secretion of factors like transforming growth factor-β (TGF-β). There is evidence that NK cells express TGF-β receptor family members, and NK cell-mediated cytotoxicity is impaired in the presence of soluble TGF-β by repressing the mTOR pathway.It is proved that cells after detachment from the extracellular matrix (ECM) undergo a particular type of apoptosis, termed anoikis. However, one of the hallmarks of cancer cells is that they evade cell death after detachment. It was revealed that some signaling pathways like PI3K/AKT, Ras–Erk, NF-B, and Rho GTPase, EGFR, and Mek–Erk, that regulate cell growth and survival are downregulated in cells undergoing anoikis. Previous studies revealed that microvesicles arise after platelet activation help cancer cells to maintain these signaling pathways active and promote anoikis resistance.Accordingly, platelet-targeted anti-cancer strategy may bring in novel anti-cancer treatments that can synergize the therapeutic effects of chemotherapies and surgical treatments of cancer.

platelets, cancer cell survival, shearing forces, immunologic deletion, anoikis, circulatory system