Abstract
A long-standing postulate in oncology is that platelets facilitate cancer metastasis (Menter et al. Cancer Metastasis Rev 33:231–269, 2014; Menter et al. Invasion Metastasis 7:109–128, 1987; Gasic et al. Proc Natl Acad Sci USA 61:46–52, 1968; Woods Bulletin der Schweizerischen Akademie der Medizinischen Wissenschaften 20:92–121, 1964). As their most critical biological response, platelets serve as “first responders” during the wounding process and hemostasis. As a part of the metastatic process, platelet receptors recognize complexes of tumor cell receptors and surface-bound matrix proteins or cellular products as they invade blood vessels. This recognition triggers platelet activation and platelet-tumor cell interactions. Once activated by tumor cells, platelets change shape, degranulate, and release proteins, growth factors, bioactive lipids, and other factors that recruit additional platelets and immune cells along with initiating thrombogenesis. Extensive membrane changes occur at bilayer interfaces between platelets and tumor cells. Tumor cells form extensive membrane/cytoskeletal processes that heavily interdigitate with a central platelet aggregate and involves the uptake of platelet fragments and mitochondria. These interactions are thought to result in the suppression of immune recognition/cytotoxicity or the promotion of cell arrest at the endothelium or entrapment in the microvasculature. These responses all support survival and spread of cancer cells and the establishment of secondary lesions. Additional mechanisms of the platelet-metastasis relationship may include the production of platelet exosomes or extravascular migratory behavior of platelets helping to drive cancer progression or preconditioning of secondary metastatic sites. In contrast to the many mechanisms involved in platelet-metastasis relationships, little is known about the role of platelets in precancerous lesion development. This paucity of knowledge exists despite numerous large randomized clinical trials illustrating the cancer preventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin in reducing the cancer incidence, mortality, and metastasis. Aspirin covalently acetylates and inactivates platelet cyclooxygenase 1 and thereby eliminates all downstream prostaglandin production from arachidonic acid (AA) by platelets. This includes the key bioactive lipid involved in platelet activation, thromboxane A2 (TxA2). Another prostaglandin, prostacyclin (PGI2), counterbalances and inhibits platelet activation (Honn et al. Science 212:1270–1272, 1981). Metabolically, the genesis of TxA2 and other bioactive lipids are also impacted by ω-3 polyunsaturated fatty acid substrate substitution for AA. Although not well studied, this places platelets not only at the center of the metastasis discussion but also the progression of premalignancies. Since neoangiogenesis produces leaky blood vessels during early cancer progression, it stands to reason that platelets are the “first responders” to extravasate, activate, and release their stroma-stimulating, proangiogenic, chemoattractive, and immunomodulatory contents. These normal platelet functions and products undoubtedly promote precancerous lesion progression as a series of cyclic amplification events. Platelets are suspected to have a key role within the full spectrum of the cancer progression continuum, which makes limiting their first response an important target for both prevention and therapy.
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Acknowledgments
Grant and other support: Boone Pickens Distinguished Chair for Early Prevention of Cancer to EH, the Duncan Family Institute, Colorectal Cancer Moon Shot, 1R01CA187238-01, 5R01CA172670-03 and 1R01CA184843-01A1, and CA177909. Many thanks to Kenneth Dunner Jr. for his electron microscopy expertise and effort.
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Menter, D.G. et al. (2017). Platelets: “First Responders” in Cancer Progression and Metastasis. In: Gresele, P., Kleiman, N., Lopez, J., Page, C. (eds) Platelets in Thrombotic and Non-Thrombotic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-47462-5_74
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