РОЛЬ ФАКТОРОВ ВРОЖДЕННОГО ИММУНИТЕТА В ПРОЦЕССЕ ОПУХОЛЕОБРАЗОВАНИЯ

Одной из важнейших теорий канцерогенеза является теория о полиэтиологичности опухолеобразования. Большое место в этой теории отводится роли воспалительного компонента, который реализуется посредством факторов врожденного иммунитета.

К факторам врожденного иммунитета, участвующим в опухолеобразовании, относятся TLRs, хемокины и их рецепторы. Активация TLRs может приводить как к снижению прогрессии онкологического процесса, так и, наоборот, к усилению. Известно, что TLR3, TLR5, TLR7, TLR9 обладают наибольшим противоопухолевым эффектом через DCs-опосредованную активацию Тh1, активацию макрофагов М1-типа и ингибирование Treg. Стимуляция TLR4 и TLR2 обладает опухоль-активирующим эффектом, путем гиперактивации MyD88 и выработки IL-6 и TNFα, однако механизмы до конца не изучены. Помимо TLRs, большое влияние на развитие онкологического процесса оказывают хемокины и их рецепторы. Показано, что CCL2, CCL4, CCL17, CCL22 и CXCL12, выделяемые клетками микроокружения опухоли, активно влияют на хемотаксис опухолевых клеток. Также известно, что CXCR4 и CCR7, экспрессируемые опухолевыми клетками, активируются хемокинами, что ведет к метастазированию. Также показаны ассоциации некоторых полиморфизмов генов TLRs, хемокинов и их рецепторов с развитием опухолевого процесса. Таким образом, на основании литературных данных, можно сделать заключение о том, что TLR и хемокины имеют большое значение при онкогенезе. Дальнейшее изучение влияния факторов врожденного иммунитета на онкогенез имеет больше значение для обоснования новых подходов терапии рака, а также потенциал для создания вакцин против рака. 

1. Филина А.Б., Свитич О.А., Ганковская Л.В., Лабжинов П.А., Парфенова Т.М., Зверев В.В. Изучение лиганд-опосредованного хемотаксиса клеток макрофагальной линии U93 // Медицинская иммунология, 2014. № 5. C. 443-448. [Filina A.B., Svitich O.A., Gankovskaya L.V., Labzhinov P.A., Parfenova T.M., Zverev V.V. The study of ligand-mediated chemotaxis of macrophage line cells U93. Meditsinskaya immunologiya = Medical Immunology (Russia), 2014, no. 5, pp. 443-448. (In Russ.)] doi: 10.15789/1563-0625-2014-5-443-448.

2. Bauer A.K., Dixon D., DeGraff L.M., Cho H.Y., Walker C.R., Malkinson A.M., Kleeberger S.R. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. Journal of the National Cancer Institute, 2005, Vol. 97, no. 23, pp. 1778-1781.

3. Barbieri F., Bajetto A., Thellung S., Würth R., Florio T. Drug design strategies focusing on the CXCR4/ CXCR7/CXCL12 pathway in leukemia and lymphoma. Expert Opin. Drug. Discov., 2016, Vol. 11, no. 11, pp. 1093-1109.

4. Bednarczyk M., Muc-Wierzgoń M., Walkiewicz K., Kokot T., Fatyga E., Mazurek U. Profile of gene expression of TLR-signaling pathways in colorectal cancer tissues. Int. J. Immunopathol. Pharmacol., 2017, Vol. 30, no. 3, pp. 322-326.

5. Ben-Baruch A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin. Exp. Metastasis., 2008, Vol. 25, no. 4, pp. 345-356.

6. Cai Z., Sanchez A., Shi Z., Zhang T., Liu M., Zhang D. Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Research, 2011, Vol. 71, no. 7, pp. 2466-2475.

7. Cannova J., Breslin S.J.P., Zhang J. Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases. Front Med., 2015, Vol. 9, no. 3, pp. 288-303.

8. Cataisson C., Salcedo R., Hakim S., Moffitt B.A., Wright L., Yi M., Stephens R., Dai R.M., Lyakh L., Schenten D., Yuspa H.S., Trinchieri G. IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. The Journal of Experimental Medicine, 2012, Vol. 209, no. 9, pp. 1689-1702.

9. Cherfils-Vicini J., Platonova S., Gillard M., Laurans L., Validire P., Caliandro R., Magdeleinat P., MamiChouaib F., Dieu-Nosjean M.C., Fridman W.H., Damotte D., Sautès-Fridman C., Cremer I. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. The Journal of Clinical Investigation, 2010, Vol. 120, no. 4, pp. 1285-1297.

10. Chin A.I., Miyahira A.K., Covarrubias A., Teague J., Guo B., Dempsey P.W., Cheng G. Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance. Cancer Research, 2010, Vol. 70. no. 7, pp. 2595-2603.

11. Chew V., Tow C., Huang C., Bard-Chapeau E., Copeland N.G., Jenkins N.A., Weber A., Lim K.H., Toh H.C., Heikenwalder M., Ng I.O., Nardin A., Abastado J.P. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. Journal of the National Cancer Institute, 2012, Vol. 104, no. 23, pp. 1796-1807.

12. D’Alterio C., Nasti G., Polimeno M., Ottaiano A., Conson M., Circelli L., Botti G., Scognamiglio G., Santagata S., De Divitiis C., Nappi A., Napolitano M., Tatangelo F., Pacelli R., Izzo F., Vuttariello E., Botti G., Scala S. CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvanttreated patients. Oncoimmunology, 2016, Vol. 5, no. 12, e1254313. doi: 10.1080/2162402X.2016.1254313.

13. Dapito D.H., Mencin A., Gwak G.Y., Pradere J.P., Jang M.K., Mederacke I., Caviglia J.M., Khiabanian H., Adeyemi A., Bataller R., Lefkowitch J.H., Bower M., Friedman R., Sartor R.B., Rabadan R., Schwabe R.F. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell, 2012, Vol. 21, no. 4, pp. 504-516.

14. Diamond M.S., Kinder M., Matsushita H. Mashayekhi M., Dunn G.P., Archambault J.M., Lee H., Arthur C.D., White J.M., Kalinke U., Murphy K.M., Schreiber R.D. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med., 2011, Vol. 208, no. 10, pp. 1989-2003.

15. Dommange F., Cartron G., Espanel C., Gallay N., Domenech J., Benboubker L., Ohresser M., Colombat P., Binet C., Watier H., Herault O. CXCL12 polymorphism and malignant cell dissemination/tissue infiltration in acute myeloid leukemia. FASEB Journal, 2006, Vol. 20, no. 11, pp. 1913-1915.

16. Elmusrati A.A., Pilborough A.E., Khurram S.A., Lambert D.W. Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma. Br. J. Cancer, 2017, Vol. 117, no. 6, pp. 867-875.

17. El-Omar E.M., Ng M.T., Hold G.L. Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene, 2008, Vol. 27, no. 2, pp. 244-252.

18. Fabbri M., Paone A., Calore F., Galli R., Gaudio E., Santhanam R., Lovat F., Fadda P., Mao C., Nuovo G.J., Zanesi N., Crawford M., Ozer G.H., Wernicke D., Alder H., Caligiuri M.A., Nana-Sinkam P., Perrotti D., Croce C.M. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl. Acad. Sci. USA, 2012, Vol. 109, no. 31, pp. 2110-2116.

19. Fuertes M.B., Kacha A.K., Kline J. Seng-Ryong Woo, David M. Kranz, Kenneth M. Murphy, Thomas F. Gajewskicorresponding. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J. Exp. Med., 2011, Vol. 208, no. 10, pp. 2005-2016.

20. Fridlender Z.G., Sun J., Kim S., Veena K., Guanjun C., Leona L., G. Scott W., Steven M. Albelda1 Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell, 2009, Vol. 16, no. 3, pp. 183-194

21. Garaude J., Kent A., van Rooijen N., Blander J.M. Simultaneous targeting of toll- and nod-like receptors induces effective tumor-specific immune responses. Science Translational Medicine, 2012, Vol. 4, no. 120, 120ra16. doi: 10.1126/scitranslmed.3002868.

22. Ignatz-Hoover J.J., Wang H, Moreton S.A., Chakrabarti A., Agarwal M.K.., Sun K.., Gupta K., Wald D.N. The role of TLR8 signaling in acute myeloid leukemia differentiation. Leukemia, 2015, Vol. 29, no. 4, pp. 918-926.

23. Itoh G., Chida S., Yanagihara K., Yashiro M., Aiba N., Tanaka M. Cancer-associated fibroblasts induce cancer cell apoptosis that regulates invasion mode of tumours. Oncogene, 2017, Vol. 36, no. 31, pp. 4434-4444.

24. Jing Yang, Min Li, Qi Chang Zheng. Emerging role of Toll-like receptor 4 in hepatocellular carcinoma. J. Hepatocell Carcinoma, 2015, Vol. 2, pp. 11-17.

25. Johdi N.A., Mazlan L., Sagap I., Jamal R. Profiling of cytokines, chemokines and other soluble proteins as a potential biomarker in colorectal cancer and polyps. Cytokine, 2017, Vol. 99, pp. 35-42.

26. Gomes Lopes J.A., Borges-Canha M., Pimentel-Nunes P. Innate immunity and hepatocarcinoma: Can tolllike receptors open the door to oncogenesis? World J. Hepatol., 2016, Vol. 8, no. 3, pp. 162-182.

27. Joyce J.A., Pollard J.W. Microenvironmental regulation of metastasis. Nature Rev. Cancer, 2009, Vol. 9, no. 4, pp. 239-252.

28. Kim H.Y., Lee S.Y., Kim D.Y., Moon J.Y., Choi Y.S., Song I.C., Lee H., Yun H.J., Kim S., Jo D.Y. Expression and functional roles of the chemokine receptor CXCR7 in acute myeloid leukemia cells. Blood Res., 2015, Vol. 50, no. 4, pp. 218-226.

29. Kim S., Takahashi H., Lin W.W. Descargues P., Grivennikov S., Kim Y., Luo J.L., Karin M. Carcinomaproduced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature, 2009, Vol. 457, no. 7225, pp. 102-106.

30. Krieg A.M. Development of TLR9 agonists for cancer therapy. The Journal of Clinical Investigation, 2007, Vol. 117, no. 5, pp. 1184-1194.

31. Lazennec G., Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. A comprehensive review of the role of chemokines and their receptors in cancer and cancer-associated inflammation. Trends Mol. Med., 2010, Vol. 16, no. 3, pp. 133-144.

32. Lee M.S., Kim Y.J. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem., 2007, Vol. 76, pp. 447-480.

33. Li N., Zhou P., Zheng J. Jieqiong D., Hongchun W., Wei L., Fang L., Hongbin L., Jiachun L., Yifeng Z. and Chun Z. A polymorphism rs12325489C>T in the lincRNA-ENST00000515084 exon was found to modulate breast cancer risk via GWAS-based association analyses. PLoS ONE, 2014, Vol. 9, no. 5, e98251. doi: 10.1371/journal. pone.0098251.

34. Li Y., Kundu P., Seow S.W. de Matos C.T., Aronsson L., Chin K.C., Kärre K., Pettersson S., Greicius G. Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis, 2012, Vol. 33, no. 6, pp. 1231-1238.

35. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature, 2008, Vol. 454, no. 7203, pp. 436-444.

36. Masayuki F., Yasmin H., Daisy C., Jason C., Anli C., Keith B., Tyralee G., David H., Ruliang X., Maria T.A. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitisassociated tumors. Inflammatory Bowel Diseases, 2009, Vol. 15, no. 7, pp. 997-1006.

37. McGettrick A.F., O’Neill L.A. Toll-like receptors: key activators of leucocytes and regulator of haematopoiesis. Br. J. Haematol., 2007, Vol. 139, pp. 185-193.

38. Mills S.C., Goh P.H., Kudatsih J., Ncube S., Gurung R., Maxwell W., Mueller A. Cell migration towards CXCL12 in leukemic cells compared to breast cancer cells. Cell Signal., 2016, Vol. 28, no. 4, pp. 316-324.

39. Monlish D.A., Bhatt S.T., Schuettpelz L.G. The role of Toll-like receptors in hematopoietic malignancies. Front Immunol., 2016, no. 7, p. 390.

40. Paradis A., Bernier S., Dumais N. TLR4 induces CCR7-dependent monocytes transmigration through the blood-brain barrier. J. Neuroimmunol., 2016, no. 295-296, pp. 12-17.

41. Patsialou A., Wyckoff J., Wang Y. Sumanta G., E. Richard Stanle, J., Condeelis S. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res., 2009, Vol. 69, no. 24, pp. 9498-9506.

42. Peng G., Guo Z., Kiniwa Y. Voo K.S., Peng W., Fu T., Wang D.Y., Li Y., Wang H.Y., Wang R.F. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science, 2005, Vol. 309, no. 5739, pp. 1380-1384.

43. Rakoff-Nahoum S., Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science, 2007, Vol. 317, no. 5834, pp. 124-127.

44. Rhee S.H., Im E., Pothoulakis C. Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology, 2008, Vol. 135, no. 2, pp. 518-528.

45. Salcedo R., Worschech A., Cardone M. Jones Y., Gyulai Z., Dai R.M., Wang E., Ma W., Haines D., O’hUigin C., Marincola F.M., Trinchieri G. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. The Journal of Experimental Medicine, 2010, Vol. 207, no. 8, pp. 1625-1636.

46. Schön M.P., Schön M. TLR7 and TLR8 as targets in cancer therapy. Oncogene, 2008, Vol. 27, no. 2, pp. 190-199.

47. Rousseau S., Martel G. Gain-of-function mutations in the toll-like receptor pathway: TPL2-Mediated ERK1/ ERK2 MAPK activation, a path to tumorigenesis in lymphoid neoplasms? Front. Cell Dev. Biol., 2016, no. 4, p. 50.

48. So E.Y., Ouchi T. The application of Toll like receptors for cancer therapy. International Journal of Biological Sciences, 2010, Vol. 6, no. 7, pp. 675-681.

49. Tazzyman S., Lewis C.E., Murdoch C. Neutrophils: key mediators of tumour angiogenesis. Int. J. Exp Pathol., 2009, Vol. 90, no. 3, pp. 222-231.

50. Yu P., Lübben W., Slomka H. Gebler J., Konert M., Cai C., Neubrandt L., Prazeres da Costa O., Paul S., Dehnert S., Döhne K., Thanisch M., Storsberg S., Wiegand L., Kaufmann A., Nain M., Quintanilla-Martinez L., Bettio S., Schnierle B., Kolesnikova L., Becker S., Schnare M., Bauer S. Author information Nucleic acid-sensing Toll-like receptors are essential for the control of endogenous retrovirus viremia and ERV-induced tumors. Immunity, 2012, Vol. 37, no. 5, pp. 867-879.

51. Yusuf N., Nasti T.H., Long J.A. Mohammed N., Alan P.L., Hui Xu, Craig A. Elmets Protective role of Tolllike receptor 4 during the initiation stage of cutaneous chemical carcinogenesis. Cancer Research, 2008, Vol. 68, pp. 615-622.