Колоректальный рак: эпидемиология, канцерогенез, молекулярно-генетические и клеточные механизмы резистентности к терапии (аналитический обзор)
https://doi.org/10.33878/2073-7556-2023-22-2-160-171
Аннотация
В этой статье анализируются статистические данные о колоректальном раке в России и в мире, включая заболеваемость, смертность и выживаемость. Рассматриваются основные пути канцерогенеза колоректального рака, молекулярные подтипы и их влияние на различие при поражении проксимальных и дистальных отделов толстой кишки. В статье приводится обзор ведущих препаратов для химио- и таргетной терапии при колоректальном раке, а также основные причины развития терапевтической резистентности, в том числе изменение клеточного микроокружения опухоли.
Ключевые слова
Об авторах
П. Е. Максимова
Институт «Медицинская академия имени С.И. Георгиевского» ФГАОУ ВО «Крымский федеральный университет имени В.И. Вернадского»
Россия
Россия
Максимова П.Е. — студентка шестого курса Первого медицинского факультета
бул. Ленина, д. 5/7, Республика Крым, г. Симферополь, 295051, Россия
Е. П. Голубинская
Институт «Медицинская академия имени С.И. Георгиевского» ФГАОУ ВО «Крымский федеральный университет имени В.И. Вернадского»
Россия
Россия
Голубинская Е.П. — д.м.н., ведущий научный сотрудник
бул. Ленина, д. 5/7, Республика Крым, г. Симферополь, 295051, Россия
Б. Д. Сеферов
ООО «Центр Клинической онкологии и гематологии»
Россия
Россия
Сеферов Б.Д. — к.м.н., ассистент кафедры онкологии
ул. Луговая, д. 16/2, Cимферопольский р-н, с.Мирное, 297503, Россия
Е. Ю. Зяблицкая
Институт «Медицинская академия имени С.И. Георгиевского» ФГАОУ ВО «Крымский федеральный университет имени В.И. Вернадского»
Россия
Россия
Зяблицкая Е.Ю. — д.м.н., ведущий научный сотрудник
бул. Ленина, д. 5/7, Республика Крым, г. Симферополь, 295051, Россия
Список литературы
1. Cho YA, Lee J, OhJ H, et al. Genetic Risk Score, Combined Lifestyle Factors and Risk of Colorectal Cancer. Cancer Res Treat. 2019;51(3):1033–1040. doi: 10.4143/crt.2018.447
2. Baidoun F, Elshiwy K, Elkeraie Y, et al. Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets. 2021;22(9):9981009. doi: 10.2174/1389450121999201117115717
3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660
4. Bray F. Transitions in human development and the global cancer burden. In: BW Stewart, CP Wild, eds. World Cancer Report 2014. WHO Press; 2014:42–55.
5. Fidler MM, Soerjomataram I, Bray F. A global view on cancer incidence and national levels of the Human Development Index. Int J Cancer. 2016;139:2436–2446
6. Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159:335–349.e15.
7. Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–691.
8. Женщины и мужчины России. 2020: Стат.сб./ Росстат., М. 2020; 239 с.
9. Каприн А.Д., Старинский В.В., Шахзадова А.О. Злокачественные новообразования в России в 2020 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2021.
10. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–164.
11. Clinton SK, Giovannucci EL, Hursting SD. The World Cancer Research Fund/American Institute for Cancer Research Third Expert Report on Diet, Nutrition, Physical Activity, and Cancer: Impact and Future Directions. J Nutr. 2020 Apr 1;150(4):663–671. doi: 10.1093/jn/nxz268
12. Sullivan T, Sullivan R, Ginsburg OM. Screening for Cancer: Considerations for Low- and Middle-Income Countries. Cancer: Disease Control Priorities. 3rd ed. Volume 3. The International Bank for Reconstruction and Development/The World Bank. 2015: 211–222. doi: 10.1596/978-1-4648-0349-9_ch12
13. Navarro M, Nicolas A, Ferrandez A, et al. Colorectal cancer population screening programs worldwide in 2016: an update. World J Gastroenterol. 2017;23:3632–3642.
14. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–573.
15. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250–281. doi: 10.3322/caac.21457
16. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–732. doi: 10.1038/s41575-019-0189-8
17. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–193. doi: 10.3322/caac.21395
18. Li J, Ma X, Chakravarti D, et al. Genetic and biological hallmarks of colorectal cancer. Genes Dev. 2021;35(11-12):787–820. doi: 10.1101/gad.348226.120
19. Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer. Lancet. 2019;394(10207):1467–1480. doi: 10.1016/S0140-6736(19)32319-0
20. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i
21. Boutin AT, Liao WT, Wang M, et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev. 2017;31(4):370–382. doi: 10.1101/gad.293449.116
22. Liao W, Overman MJ, Boutin AT, et al. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer. Cancer Cell. 2019;35(4):559–572.e7. doi: 10.1016/j.ccell.2019.02.008
23. Rashtak S, Rego R, Sweetser SR, et al. Sessile Serrated Polyps and Colon Cancer Prevention. Cancer Prev Res (Phila). 2017;10(5):270–278. doi: 10.1158/1940-6207.CAPR-16-0264
24. Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017;17(2):79–92. doi: 10.1038/nrc.2016.126
25. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356. doi: 10.1038/nm.3967
26. Müller MF, Ibrahim AE, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Arch. 2016;469(2):125–134. doi: 10.1007/s00428-016-1956-3
27. Zhong M, Wu B, Zhongguo Yi, et al. Recent Advances on the Differences between Left- and Right-sided. Colorectal Cancer. 2021;43(6):980–985. doi: 10.3881/j.issn.1000-503X.12867
28. LaPointe LC, Dunne R, Brown GS, et al. Map of differential transcript expression in the normal human large intestine. Physiol Genomics. 2008;33(1):50–64. doi: 10.1152/physiolgenomics.00185.2006
29. Hansen IO, Jess P. Possible better long-term survival in left versus right-sided colon cancer — a systematic review. Dan Med J. 2012;59(6):A4444.
30. Augustus GJ, Ellis NA. Colorectal Cancer Disparity in African Americans: Risk Factors and Carcinogenic Mechanisms. Am J Pathol. 2018;188(2):291–303. doi: 10.1016/j.ajpath.2017.07.023
31. Dienstmann R, Mason MJ, Sinicrope FA, et al. Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol. 2017;28(5):1023–1031. doi: 10.1093/annonc/mdx052
32. Aguiar Junior S, Oliveira MM, Silva DRME, et al. Survival of patients with colorectal cancer in a cancer center. Arq Gastroenterol. 2020;57(2):172–177. doi: 10.1590/S0004-2803.202000000-32
33. Lee MS, Menter DG, Kopetz S. Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes. J Natl Compr Canc Netw. 2017;15(3):411–419. doi: 10.6004/jnccn.2017.0038
34. Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3):dju427. doi: 10.1093/jnci/dju427
35. Lee GH, Malietzis G, Askari A, et al. Is right-sided colon cancer different to left-sided colorectal cancer? — a systematic review. Eur J Surg Oncol. 2015;41(3):300–8. doi: 10.1016/j.ejso.2014.11.001
36. Baran B, Mert Ozupek N, Yerli Tetik N, et al. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterology Res. 2018;11(4):264–273. doi: 10.14740/gr1062w
37. Федянин М.Ю., Ачкасов С.И., Болотина Л.В. и соавт. Практические рекомендации по лекарственному лечению рака ободочной кишки и ректосигмоидного соединения. Злокачественные опухоли. 2021;11(3s2–1):330–372. doi: 10.18027/2224-5057-
38. -11-3s2-22
39. Park SC, Sohn DK, Kim MJ, et al. Phase II Clinical Trial to Evaluate the Efficacy of Transanal Endoscopic Total Mesorectal Excision for Rectal Cancer. Dis Colon Rectum. 2018;61(5):554–560. doi: 10.1097/DCR.0000000000001058
40. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363–385. doi: 10.3322/caac.21565
41. Ogura A, Konishi T, Cunningham C, et al. Neoadjuvant (Chemo) radiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer. J Clin Oncol. 2019;37(1):33–43. doi: 10.1200/JCO.18.00032
42. Zacharakis M, Xynos ID, Lazaris A, et al. Predictors of survival in stage IV metastatic colorectal cancer. Anticancer Res. 2010;30(2):653–660
43. Johdi NA, Sukor NF. Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol. 2020;11:1624. doi: 10.3389/fimmu.2020.01624
44. Piawah S, Venook AP. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 2019;125(23):4139–4147. doi: 10.1002/cncr.32163
45. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol. 1992;10:896–903 45. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl 16):15–18. doi: 10.1053/sonc.2002.37263
46. Riechelmann R, Grothey A. Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies. Ther Adv Med Oncol. 2017;9(2):106–126. doi: 10.1177/1758834016676703
47. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. doi: 10.1056/NEJMoa032691
48. Rosen LS, Jacobs IA, Burkes RL. Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Target Oncol. 2017;12(5):599–610. doi: 10.1007/s11523-017-0518-1
49. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–19. 97. doi: 10.1200/JCO.2007.14.9930
50. Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an openlabel, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85. doi: 10.1016/S1470-2045(13)70154-2
51. Tang PA, Cohen SJ, Kollmannsberger C, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. 2012;18:6023–6031. doi: 10.1158/1078-0432.CCR-11-3252
52. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–3506. doi: 10.1200/JCO.2012.42.8201
53. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499–508. doi: 10.1016/S1470-2045(15)70127-0
54. Carter N. Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Drugs Aging. 2014;31:67–78. doi: 10.1007/s40266-013-0140-6
55. Kasi PM, Kotani D, Cecchini M, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016;16:467. doi: 10.1186/s12885-016-2491-y
56. Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412–420. doi: 10.1016/S1470-2045(19)30827-7
57. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587–594. doi: 10.1016/j.ejca.2015.01.054
58. Seshacharyulu P, Ponnusamy MP, Haridas D, et al. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):15–31. doi: 10.1517/14728222.2011.648617
59. Yarom N, Jonker DJ. The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med. 2011;11:95–105.
60. Fakih M, Vincent M. Adverse events associated with antiEGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17 Suppl 1(Suppl 1):S18–S30. doi: 10.3747/co.v17is1.615
61. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861–2868. doi: 10.1200/JCO.2011.40.9243
62. Lenz HJ. Anti-EGFR mechanism of action: antitumor effect and underlying cause of adverse events. Oncology (Williston Park). 2006;20(5 Suppl 2):5–13.
63. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on thePETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol. 2010;28:466–74. doi: 10.1200/JCO.2009.23.3452
64. Zhao B, Wang L, Qiu H, et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2017;8(3):3980–4000. doi: 10.18632/oncotarget.14012
65. Kopetz S, Guthrie KA, Morris VK, et al. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAFMutant Metastatic Colorectal Cancer (SWOG S1406). J Clin Oncol. 2021;39(4):285–294. doi: 10.1200/JCO.20.01994
66. Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7(2):122–136. doi: 10.1177/1758834014566428
67. Sinicrope FA, Sargent DJ. Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol. 2009;21(4):369–373. doi: 10.1097/CCO.0b013e32832c94bd
68. Benson AB, Venook AP, Cederquist L, et al. Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Colon Cancer. National Comprehensive Cancer. Network. 2018:1–132.
69. Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16(7):30. doi: 10.1007/s11864-015-0348-22
70. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596
71. Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361–375. doi: 10.1038/s41575-019-0126-x
72. Johnson DB, Chandra S, Sosman JA. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA. 2018;320(16):1702–1703. doi: 10.1001/jama.2018.13995
73. Siena S, Sartore-Bianchi A, Marsoni S, et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018;29(5):1108–1119. doi: 10.1093/annonc/mdy100
74. Van der Jeught K, Xu HC, Li YJ, Lu XB, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834–3848. doi: 10.3748/wjg.v24.i34.3834
75. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as firstline treatment for metastatic colorectal cancer: a multicentre randomised trial [published correction appears in Lancet 2000 Apr 15;355(9212):1372]. Lancet. 2000;355(9209):1041–1047. doi: 10.1016/s0140-6736(00)02034-1
76. Abdallah EA, Fanelli MF, Buim ME, et al. Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients. Int J Cancer. 2015;137(6):1397–1405. doi: 10.1002/ijc.29495
77. Che J, Pan L, Yang X, et al. Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5-fluorouracil-based chemotherapy: A meta-analysis. Mol Clin Oncol. 2017;7(6):943–952. doi: 10.3892/mco.2017.1436
78. Sakowicz-Burkiewicz M, Przybyla T, Wesserling M, et al. Suppression of TWIST1 enhances the sensitivity of colon cancer cells to 5-fluorouracil. Int J Biochem Cell Biol. 2016;78:268–278. doi: 10.1016/j.biocel.2016.07.024
79. Hicks LD, Hyatt JL, Stoddard S, et al. Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity. J Med Chem. 2009;52(12):3742–3752. doi: 10.1021/jm9001296
80. Palshof JA, Høgdall EV, Poulsen TS, et al. Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer. BMC Cancer. 2017;17(1):48.. doi: 10.1186/s12885-016-3001-y
81. Nielsen DL, Palshof JA, Brünner N, et al. Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review. Int J Mol Sci. 2017;18(9):1926. doi: 10.3390/ijms18091926
82. de Man FM, Goey AKL, van Schaik RHN, et al. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet. 2018;57(10):1229–1254. doi: 10.1007/s40262-018-0644-7
83. Meisenberg C, Ashour ME, El-Shafie L, et al. Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan. Nucleic Acids Res. 2017;45(3):1159–1176. doi: 10.1093/nar/gkw1026
84. Gnoni A, Russo A, Silvestris N, et al. Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients. Curr Drug Metab. 2011;12(10):918–931. doi: 10.2174/138920011798062300
85. Yan D, Tu L, Yuan H, et al. WBSCR22 confers oxaliplatin resistance in human colorectal cancer. Sci Rep. 2017;7(1):15443. doi: 10.1038/s41598-017-15749-z
86. Mao L, Li Y, Zhao J, et al. Transforming growth factor-β1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol Lett. 2017;14(1):647–654. doi: 10.3892/ol.2017.6209
87. Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307
88. Zeuner A, Todaro M, Stassi G, et al. Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell. 2014;15(6):692–705. doi: 10.1016/j.stem.2014.11.012
89. Paquet-Fifield S, Koh SL, Cheng L, et al. Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stemlike Cells. Cancer Res. 2018;78(11):2925–2938. doi: 10.1158/0008-5472.CAN-17-1869
90. Hu J, Li J, Yue X, et al. Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget. 2017;8(17):28463–28470. doi: 10.18632/oncotarget.15307
Рецензия
Для цитирования:
Максимова П.Е., Голубинская Е.П., Сеферов Б.Д., Зяблицкая Е.Ю. Колоректальный рак: эпидемиология, канцерогенез, молекулярно-генетические и клеточные механизмы резистентности к терапии (аналитический обзор). Колопроктология. 2023;22(2):160-171. https://doi.org/10.33878/2073-7556-2023-22-2-160-171
For citation:
Maksimova P.E., Golubinskaya E.P., Seferov B.D., Zyablitskaya E.Yu. Colorectal cancer: epidemiology, carcinogenesis, molecular subtypes and cellular mechanisms of therapy resistance (analytical review). Koloproktologia. 2023;22(2):160-171. https://doi.org/10.33878/2073-7556-2023-22-2-160-171
Просмотров:
1882
Послать статью по эл. почте 
