Abstract
Pharmacologically and genetically induced thrombocytopenia is associated with decreased metastasis, highlighting the importance of platelets in the bloodborne dissemination of cancer cells. It is frequently suggested that platelets support metastasis, in part, by protecting cancer cells from shear stress, a biomechanical force generated by blood flow. However, there is currently no evidence to support this hypothesis. To address this, we investigated the effect of shear stress on A2780 ovarian cancer cells in the presence and absence of platelets. Using a cone and plate viscometer, suspensions of A2780 cells with and without platelets were exposed to shear rates representing venous (200 s−1) and arterial (1,500 s−1) blood flow. Lactate dehydrogenase (LDH) release was used to quantify shear induced membrane damage. Both venous and arterial shear rates induced the release of LDH from A2780 cells, demonstrating their susceptibility to shear forces. In contrast, platelets released minimal levels of LDH in response to similar conditions. In the presence of platelets, there was a significant decrease in LDH release by A2780 cells under shear conditions, suggesting that platelets can confer protection against shear induced damage. The disruption of platelet–cancer cell interactions could increase the shear stress induced destruction of cancer cells in vivo.
Similar content being viewed by others
References
Stone RL et al (2012) Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 366(7):610–618
Ho-Tin-Noe B et al (2008) Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res 68(16):6851–6858
Camerer E et al (2004) Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104(2):397–401
Gasic GJ, Gasic TB, Stewart CC (1968) Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA 61(1):46–52
Jain S, Russell S, Ware J (2009) Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J Thromb Haemost 7(10):1713–1717
Jain S et al (2007) Platelet glycoprotein Ib alpha supports experimental lung metastasis. Proc Natl Acad Sci USA 104(21):9024–9028
Kim YJ et al (1998) P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci USA 95(16):9325–9330
Alonso-Escolano D et al (2004) Membrane type-1 matrix metalloproteinase stimulates tumour cell-induced platelet aggregation: role of receptor glycoproteins. Br J Pharmacol 141(2):241–252
Jurasz P, Alonso-Escolano D, Radomski MW (2004) Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 143(7):819–826
Jurasz P et al (2003) Matrix metalloproteinase-2 contributes to increased platelet reactivity in patients with metastatic prostate cancer: a preliminary study. Thromb Res 112(1–2):59–64
Jurasz P et al (2001) Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide. Cancer Res 61(1):376–382
Karpatkin S, Ambrogio C, Pearlstein E (1988) The role of tumor-induced platelet aggregation, platelet adhesion and adhesive proteins in tumor metastasis. Prog Clin Biol Res 283:585–606
Karpatkin S et al (1988) Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest 81(4):1012–1019
Karpatkin S et al (1982) Platelet aggregating material (PAM) of two virally-transformed tumors: SV3T3 mouse fibroblast and PW20 rat renal sarcoma. Role of cell surface sialylation. Prog Clin Biol Res 89:445–477
Nieswandt B et al (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59(6):1295–1300
Zheng S et al (2009) Platelets and fibrinogen facilitate each other in protecting tumor cells from natural killer cytotoxicity. Cancer Sci 100(5):859–865
Palumbo JS et al (2005) Platelets and fibrin (ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105(1):178–185
Placke T et al (2011) Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res 72(2):440–448
Placke T, Kopp HG, Salih HR (2011) Modulation of natural killer cell anti-tumor reactivity by platelets. J Innate Immun 3(4):374–382
Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis. Cancer Cell 20(5):576–590
Lowe KL, Navarro-Nunez L, Watson SP (2012) Platelet CLEC-2 and podoplanin in cancer metastasis. Thromb Res 129(Suppl 1):S30–S37
Dvoretsky PM et al (1988) Distribution of disease at autopsy in 100 women with ovarian cancer. Hum Pathol 19(1):57–63
Egan K et al (2011) Platelet adhesion and degranulation induce pro-survival and pro-angiogenic signalling in ovarian cancer cells. PLoS ONE 6(10):e26125
Nylander S et al (2004) Synergistic action between inhibition of P2Y12/P2Y1 and P2Y12/thrombin in ADP- and thrombin-induced human platelet activation. Br J Pharmacol 142(8):1325–1331
Cattaneo M et al (1993) Shear-induced platelet aggregation is potentiated by desmopressin and inhibited by ticlopidine. Arterioscler Thromb 13(3):393–397
Berezovskaya O et al (2005) Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res 65(6):2378–2386
Rhim AD et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361
Zong W (2006) Thompson, CB, Necrotic death as a cell fate. Genes Dev 20(1):1–15
Coleman ML et al (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3(4):339–345
Lawler K et al (2006) Mobility and invasiveness of metastatic esophageal cancer are potentiated by shear stress in a ROCK- and Ras-dependent manner. Am J Physiol Cell Physiol 291(4):C668–C677
Lawler K et al (2009) Shear stress induces internalization of E-cadherin and invasiveness in metastatic oesophageal cancer cells by a Src-dependent pathway. Cancer Sci 100(6):1082–1087
Qazi H, Shi ZD, Tarbell JM (2011) Fluid shear stress regulates the invasive potential of glioma cells via modulation of migratory activity and matrix metalloproteinase expression. PLoS ONE 6(5):e20348
Chang SF et al (2008) Tumor cell cycle arrest induced by shear stress: roles of integrins and Smad. Proc Natl Acad Sci USA 105(10):3927–3932
Brooks DE (1984) The biorheology of tumor cells. Biorheology 21(1–2):85–91
Wei X et al (2005) Real-time detection of circulating apoptotic cells by in vivo flow cytometry. Mol Imaging 4(4):415–416
Wyckoff JB et al (2000) A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res 60(9):2504–2511
Corti R et al (2004) Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis. J Thromb Thrombolysis 17(1):35–44
Fuster V et al (2005) Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 46(6):937–954
Malek AM, Alper SL, Izumo S (1999) Hemodynesamic shear stress and its role in atherosclerosis. JAMA 282(21):2035–2042
Cunningham KS, Gotlieb AI (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 85(1):9–23
Lawler K et al (2004) Shear stress modulates the interaction of platelet-secreted matrix proteins with tumor cells through the integrin alphavbeta3. Am J Physiol Cell Physiol 287(5):C1320–C1327
Dupire J, Socol M, Viallat A (2012) Full dynamics of a red blood cell in shear flow. Proc Natl Acad Sci USA 109(51):20808–20813
Trabert B et al (2014) Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst 106(2):djt431
Acknowledgments
This research is supported through the National Biophotonics and Imaging Platform, Ireland, and funded by the Irish Government’s Programme for Research in Third Level Institutions, Cycle 4, and National Development Plan 2007–2013. NC is funded by a grant from Science Foundation Ireland (SFI) as part of the Biomedical Diagnostics Institute for Science Excellence and Technology (CSET), Grant Number: 10/CE/B1821.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Karl Egan and Niamh Cooke are joint first author
Rights and permissions
About this article
Cite this article
Egan, K., Cooke, N. & Kenny, D. Living in shear: platelets protect cancer cells from shear induced damage. Clin Exp Metastasis 31, 697–704 (2014). https://doi.org/10.1007/s10585-014-9660-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10585-014-9660-7