The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells
DOI:
https://doi.org/10.2298/ABS240126007CKeywords:
prothrombin, cancer, expression, proliferation, migrationAbstract
Paper description:
- Thrombin influences cancer growth and progression. Although its precursor, prothrombin, is predominantly expressed in the liver, thrombin can be present in the tumor microenvironment.
- We examined the expression of prothrombin in selected colorectal cancer cell lines and its effect on these cells by treating them with different prothrombin concentrations and monitoring cell proliferation and migration.
- All analyzed cell lines expressed prothrombin, with prothrombin exerting an effect on cell proliferation and migration.
- Prothrombin could impact colon cancer development. Further research into prothrombin’s potential as a diagnostic and therapeutic biomarker is proposed.
Abstract: Thrombotic disorders are some of the main comorbidities in cancer patients. So far, research has indicated that thrombin, a key regulator of hemostasis, contributes to cancer progression. However, data on its origin in tumor microenvironments remain elusive. Based on previous research, we analyzed the RNA and protein expression of prothrombin, a precursor of thrombin, in selected colorectal cancer (CRC) cell lines. Since the effect of prothrombin in cancer development has not been previously reported, we treated the cells for 24 h and 48 h with different prothrombin concentrations and assessed the effect on cell proliferation and migration. Our results show that the tested CRC cell lines expressed prothrombin and that prothrombin inhibited proliferation and migration. The presented results suggest that prothrombin may contribute to CRC etiopathology and could serve as a potential diagnostic biomarker and therapeutic target. The mechanisms underlying prothrombin expression in cancer cells, potential prothrombin activation, and the underlying processes driving the described effects warrant further investigation.
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References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. https://doi.org/10.3322/caac.21660
Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res. 2010;125(6):490-3. https://doi.org/10.1016/j.thromres.2009.12.023
Abdol Razak N, Jones G, Bhandari M, Berndt M, Metharom P. Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment. Cancers. 2018;10(10):380. https://doi.org/10.3390/cancers10100380
Colman RW, M. D. Clowes AW, Goldhaber SZ, Marder VJ, George JN, editors. Hemostasis And Thrombosis: Basic Principles And Clinical Practice. 5th edition. Philadelphia, Pa. London: Lippincott Williams & Wilkins; 2005. 1827 p.
Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Thrombin-unique coagulation system protein with multifaceted impacts on cancer and metastasis. Cancer Metastasis Rev. 2016;35(2):213-33. https://doi.org/10.1007/s10555-016-9626-0
Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258-64. https://doi.org/10.1038/35025229
Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Protease-activated receptors (PARs)-biology and role in cancer invasion and metastasis. Cancer Metastasis Rev. 2015;34(4):775-96. https://doi.org/10.1007/s10555-015-9599-4
Tsopanoglou NE, Maragoudakis ME. Thrombin's central role in angiogenesis and pathophysiological processes. Eur Cytokine Netw. 2009;20(4):171-9. https://doi.org/10.1684/ecn.2009.0166
Danckwardt S, Hentze MW, Kulozik AE. Pathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer, and beyond. J Mol Med. 2013;91(11):1257-71. https://doi.org/10.1007/s00109-013-1074-5
Kohli M, Williams K, Yao JL, Dennis RA, Huang J, Reeder J, Ricke WA. Thrombin expression in prostate: a novel finding. Cancer Invest. 2011;29(1):62-7. https://doi.org/10.3109/07357907.2010.535057
Shaker H, Bundred NJ, Landberg G, Pritchard SA, Albadry H, Nicholson SL, Harries LJ, Heah JYE, Castle J, Kirwan CC. Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion. Cancer Med. 2020;9(5):1768-78. https://doi.org/10.1002/cam4.2748
Wojtukiewicz MZ, Rucinska M, Zimnoch L, Jaromin J, Piotrowski Z, Rózanska-Kudelska M, Kisiel W, Kudryk BJ. Expression of Prothrombin Fragment 1+2 in Cancer Tissue as an Indicator of Local Activation of Blood Coagulation. Thromb Res. 2000;97(5):335-42. https://doi.org/10.1016/S0049-3848(99)00169-3
Tape CJ. The Heterocellular Emergence of Colorectal Cancer. Trends Cancer. 2017;3(2):79-88. https://doi.org/10.1016/j.trecan.2016.12.004
Dunjic S, Cumbo M, Gvozdenov M, Tomic B, Pruner I, Radojkovic D, Djordjevic V. Prothrombin expression in cancer-derived cell lines. Arch Biol Sci. 2019;71(1):49-54. https://doi.org/10.2298/ABS180829046D
Malki A, ElRuz RA, Gupta I, Allouch A, Vranic S, Al Moustafa A-E. Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements. Int J Mol Sci. 2020;22(1):130. https://doi.org/10.3390/ijms22010130
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671-5. https://doi.org/10.1038/nmeth.2089
Fair D, Bahnak B. Human hepatoma cells secrete single chain factor X, prothrombin, and antithrombin III. Blood. 1984;64(1):194-204. https://doi.org/10.1182/blood.V64.1.194.194
Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood. 2004;104(9):2746-51. https://doi.org/10.1182/blood-2004-03-1047
Sierko E, Wojtukiewicz MZ, Zimnoch L, Thorpe PE, Brekken RA, Kisiel W. Co-localization of prothrombin fragment F1+2 and VEGF-R2-bound VEGF in human colon cancer. Anticancer Res. 2011;31(3):843-7.
Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus Trasfus Sangue. 2010;8(3):149-54.
Ahmed D, Eide PW, Eilertsen IA, Danielsen SA, Eknæs M, Hektoen M, Lind GE, Lothe RA. Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis. 2013;2(9):e71-e71. https://doi.org/10.1038/oncsis.2013.35
Leibovitz A, Stinson JC, McCombs WB, McCoy CE, Mazur KC, Mabry ND. Classification of human colorectal adenocarcinoma cell lines. Cancer Res. 1976;36(12):4562-9.
Fogh J, editor. Human Tumor Cells in Vitro. Boston, MA: Springer US; 1975. https://doi.org/10.1007/978-1-4757-1647-4
Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE. Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res. 1981;41(5):1751-6.
Caro I, Boulenc X, Rousset M, Meunier V, Bourrié M, Julian B, Joyeux H, Roques C, Berger Y, Zweibaum A, Fabre G. Characterisation of a newly isolated Caco-2 clone (TC-7), as a model of transport processes and biotransformation of drugs. Int J Pharm. 1995;116(2):147-58. https://doi.org/10.1016/0378-5173(94)00280-I
Murphy N, Ward HA, Jenab M, Rothwell JA, Boutron-Ruault M-C, Carbonnel F, Kvaskoff M, Kaaks R, Kühn T, Boeing H, Aleksandrova K, Weiderpass E, Skeie G, Borch KB, Tjønneland A, Kyrø C, Overvad K, Dahm CC, Jakszyn P, Sánchez M-J, Gil L, Huerta JM, Barricarte A, Quirós JR, Khaw K-T, Wareham N, Bradbury KE, Trichopoulou A, La Vecchia C, Karakatsani A, Palli D, Grioni S, Tumino R, Fasanelli F, Panico S, Bueno-de-Mesquita B, Peeters PH, Gylling B, Myte R, Jirström K, Berntsson J, Xue X, Riboli E, Cross AJ, Gunter MJ. Heterogeneity of Colorectal Cancer Risk Factors by Anatomical Subsite in 10 European Countries: A Multinational Cohort Study. Clin Gastroenterol Hepatol. 2019;17(7):1323-1331.e6. https://doi.org/10.1016/j.cgh.2018.07.030
Sobral D, Martins M, Kaplan S, Golkaram M, Salmans M, Khan N, Vijayaraghavan R, Casimiro S, Fernandes A, Borralho P, Ferreira C, Pinto R, Abreu C, Costa AL, Zhang S, Pawlowski T, Godsey J, Mansinho A, Macedo D, Lobo-Martins S, Filipe P, Esteves R, Coutinho J, Costa PM, Ramires A, Aldeia F, Quintela A, So A, Liu L, Grosso AR, Costa L. Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development. Commun Biol. 2022;5(1):937. https://doi.org/10.1038/s42003-022-03884-x
Buikhuisen JY, Torang A, Medema JP. Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges. Oncogenesis. 2020;9(7):66. https://doi.org/10.1038/s41389-020-00250-6
Patkulkar PA, Subbalakshmi AR, Jolly MK, Sinharay S. Mapping Spatiotemporal Heterogeneity in Tumor Profiles by Integrating High-Throughput Imaging and Omics Analysis. ACS Omega. 2023;8(7):6126-38. https://doi.org/10.1021/acsomega.2c06659
Beitia M, Romano P, Larrinaga G, Solano-Iturri JD, Salis A, Damonte G, Bruzzone M, Ceppi M, Profumo A. The Activation of Prothrombin Seems to Play an Earlier Role than the Complement System in the Progression of Colorectal Cancer: A Mass Spectrometry Evaluation. Diagnostics. 2020;10(12):1077. https://doi.org/10.3390/diagnostics10121077
Wiebe JP, Dinsdale CJ. Inhibition of cell proliferation by glycerol. Life Sci. 1991;48(16):1511-7. https://doi.org/10.1016/0024-3205(91)90275-G
Sakurai S, Okada Y, Mataga I. Inhibitory Effects of Glycerol on Growth and Invasion of Human Oral Cancer Cell Lines. J Hard Tissue Biol. 2011;20(1):37-46. https://doi.org/10.2485/jhtb.20.37
Hansen CB, van Deurs B, Petersen LC, Rao LV. Discordant expression of tissue factor and its activity in polarized epithelial cells. Asymmetry in anionic phospholipid availability as a possible explanation. Blood. 1999;94(5):1657-64. https://doi.org/10.1182/blood.V94.5.1657
Zhou H, Hu H, Shi W, Ling S, Wang T and Wang H: The expression and the functional roles of tissue factor and protease-activated receptor-2 on SW620 cells. Oncol Rep 2008;20:1069-76. https://doi.org/10.3892/or_00000111
Hisada Y, Mackman N. Tissue Factor and Cancer: Regulation, Tumor Growth, and Metastasis. Semin Thromb Hemost. 2019;45(04):385-95. https://doi.org/10.1055/s-0039-1687894
Mackman N. Role of Tissue Factor in Hemostasis, Thrombosis, and Vascular Development. Arterioscler Thromb Vasc Biol. 2004;24(6):1015-22. https://doi.org/10.1161/01.ATV.0000130465.23430.74
Pozzi N, Chen Z, Zapata F, Niu W, Barranco-Medina S, Pelc LA, Di Cera E. Autoactivation of Thrombin Precursors. J Biol Chem. 2013;288(16):11601-10. https://doi.org/10.1074/jbc.M113.451542
Zain J, Huang YQ, Feng X, Nierodzik ML, Li JJ, Karpatkin S. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Blood. 2000;95(10):3133-8. https://doi.org/10.1182/blood.V95.10.3133
Degani G, Altomare A, Digiovanni S, Arosio B, Fritz G, Raucci A, Aldini G, Popolo L. Prothrombin is a binding partner of the human receptor of advanced glycation end products. J Biol Chem. 2020;295(35):12498-511. https://doi.org/10.1074/jbc.RA120.013692
Younessi P, Yoonessi A. Advanced glycation end-products and their receptor-mediated roles: inflammation and oxidative stress. Iran J Med Sci. 2011;36(3):154-66.
Fuentes MK, Nigavekar SS, Arumugam T, Logsdon CD, Schmidt AM, Park JC, Huang EH. RAGE Activation by S100P in Colon Cancer Stimulates Growth, Migration, and Cell Signaling Pathways. Dis Colon Rectum. 2007;50(8):1230-40. https://doi.org/10.1007/s10350-006-0850-5
Schulze EB, Hedley BD, Goodale D, Postenka CO, Al-Katib W, Tuck AB, Chambers AF, Allan AL. The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms. Breast Cancer Res Treat. 2008;112(2):243-54. https://doi.org/10.1007/s10549-007-9865-4
Vianello F, Sambado L, Goss A, Fabris F, Prandoni P. Dabigatran antagonizes growth, cell‐cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines. Cancer Med. 2016;5(10):2886-98. https://doi.org/10.1002/cam4.857
DeFeo K, Hayes C, Chernick M, Van Ryn J, Gilmour SK. Use of dabigatran etexilate to reduce breast cancer progression. Cancer Biol Ther. 2010;10(10):1001-8. https://doi.org/10.4161/cbt.10.10.13236
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Copyright (c) 2024 Marija Cumbo, Sofija Dunjic Manevski, Maja Gvozdenov, Martina Mia Mitic, Valentina Djordjevic, Branko Tomic
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