N.V. Danilova1

1 Medical Research and Educational Center, Lomonosov Moscow State University (Moscow, Russia)

Gastric cancer is one of the most common malignant neoplasms in humans. Carcinogenesis is a specific process with the progressive accumulation of mutations in the cell genome, leading to disruption of cell growth and differentiation. Disturbances in the differentiation of gastric cells are reflected, in particular, in changes in the expression of markers of gastric and intestinal differentiation, and its clinical behavior and the prognosis of patient survival may depend on the tumor phenotype. Markers of gastric and intestinal differentiation (MUC2, MUC5AC, CD10 and CDX2) are often used to determine whether tumors belong to the intestinal or gastric type, but their prognostic role and relationship with clinical and morphological parameters of the tumor have not been fully determined. The purpose of this literature review is to collect and systematize the latest data on the expression of markers of gastric and intestinal differentiation in gastric cancer and their prognostic significance.

The latest literature data on markers of intestinal and gastric differentiation are systematized. Depending on the expression of mucins and other markers of intestinal differentiation, gastric cancer is divided into intestinal phenotype (positive expression of MUC2 and/or CD10), gastric phenotype (positive expression of MUC5AC and/or MUC6 positive), mixed phenotype (positive expression of both MUC2 and/or CD10 , and MUC5AC and/or MUC6), as well as the null phenotype (MUC2, CD10, MUC5AC and MUC6 negative). The gastric phenotype of gastric cancer has more favorable prognostic characteristics compared to the intestinal phenotype; the most promising prognostic markers are CDX2 (high expression of CDX2 is associated with a positive prognosis in gastric cancer) and MUC5AС (decreased expression of MUC5AC in early-stage gastric cancer is an independent negative prognostic factor). Structured information on markers of gastric and intestinal differentiation will accelerate the search for new prognostic and predictive markers to improve the diagnosis and treatment of patients with gastric cancer.

Danilova N.V. Markers of gastric and intestinal differentiation in gastric cancer: a literature review. Technologies of Living Systems. 2023. V. 20. № 1. Р. 16-26. DOI: https://doi.org/10.18127/j20700997-202301-02 (In Russian)

1. Nemtsova M.V., Bykov I.I., Chekunova N.V., Zaletayev D.V., Glukhov A.I., Khorobrykh T.V. Molekulyarno-geneticheskaya patologiya pri rake zheludka. Tekhnologii zhivykh sistem. 2013. T. 10. № 3. S. 36–47. (in Russian).
2. Chekunova N.V., Bykov I.I., Khorobrykh T.V., Nemtsova M.V. Molekulyarno-geneticheskiye izmeneniya v slizistoy kulti zheludka bolnykh. perenesshikh subtotalnuyu distalnuyu rezektsiyu zheludka po povodu raka. Tekhnologii zhivykh sistem. 2014. T. 11. № 3. S. 46–51. (in Russian).
3. Danilova N.V., Anikina K.A. i dr. Ekspressiya klaudina-4 v kletkakh adenokartsinomy zheludka. Tekhnologii zhivykh sistem. 2020. T. 17. № 3. S. 46–52. (in Russian).
4. Ridley C., Kouvatsos N., Raynal B.D., Howard M., Collins R.F., Desseyn J.L., Jowitt T.A., Baldock C., Davis C.W., Hardingham T.E., Thornton D.J. Assembly of the respiratory mucin MUC5B: a new model for a gel-forming mucin. J. Biol. Chem. 2014. V. 289(23). P. 16409–16420.
5. Bu X.D., Li N., Tian X.Q., Huang P.L. Caco-2 and LS174T cell lines provide different models for studying mucin expression in colon cancer. Tissue Cell. 2011. V. 43(3). P. 201–206.
6. Hoorens P.R., Rinaldi M., Li R.W., Goddeeris B., Claerebout E., Vercruysse J., Geldhof P. Genome wide analysis of the bovine mucin genes and their gastrointestinal transcription profile. BMC Genomics. 2011. V. 12. P. 140.
7. Johansson M.E., Sjövall H., Hansson G.C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 2013. V. 10(6). P. 352–361.
8. Pérez-Sánchez J., Estensoro I., Redondo M.J., Calduch-Giner J.A., Kaushik S., Sitjà-Bobadilla A. Mucins as diagnostic and prognostic biomarkers in a fish-parasite model: transcriptional and functional analysis. PLoS One. 2013. V. 8(6). P. e65457.
9. Lang T., Klasson S., Larsson E., Johansson M.E., Hansson G.C., Samuelsson T. Searching the Evolutionary Origin of Epithelial Mucus Protein Components-Mucins and FCGBP. Mol. Biol. Evol. 2016. V. 33(8). P. 1921–1936.
10. Pigny P., Guyonnet-Duperat V., Hill A.S., Pratt W.S., Galiegue-Zouitina S., d'Hooge M.C., Laine A., Van-Seuningen I., Degand P., Gum J.R., Kim Y.S., Swallow D.M., Aubert J.P., Porchet N. Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes. Genomics. 1996. V. 38(3). P. 340–352.
11. Chen Y., Zhao Y.H., Kalaslavadi T.B., Hamati E., Nehrke K., Le A.D., Ann D.K., Wu R. Genome-wide search and identification of a novel gel-forming mucin MUC19/Muc19 in glandular tissues. Am. J. Respir. Cell. Mol. Biol. 2004. V. 30(2). P. 155–165.
12. de Bustros A., Nelkin B.D., Silverman A., Ehrlich G., Poiesz B., Baylin S.B. The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia. Proc. Natl. Acad. Sci. USA. 1988. V. 85(15). P. 5693–5697.
13. Pinto-de-Sousa J., David L., Reis C.A., Gomes R., Silva L., Pimenta A. Mucins MUC1, MUC2, MUC5AC and MUC6 expression in the evaluation of differentiation and clinico-biological behaviour of gastric carcinoma. Virchows. Arch. 2002. V. 440(3). P. 304–310.
14. Reis C.A., David L., Carvalho F., Mandel U., de Bolós C., Mirgorodskaya E., Clausen H., Sobrinho-Simões M. Immunohistochemical study of the expression of MUC6 mucin and co-expression of other secreted mucins (MUC5AC and MUC2) in human gastric carcinomas. J. Histochem. Cytochem. 2000. V. 48(3). P. 377–388.
15. Teixeira A., David L., Reis C.A., Costa J., Sobrinho-Simões M. Expression of mucins (MUC1, MUC2, MUC5AC, and MUC6) and type 1 Lewis antigens in cases with and without Helicobacter pylori colonization in metaplastic glands of the human stomach. J. Pathol. 2002. V. 197(1). P. 37–43.
16. Ferreira B., Marcos N.T., David L., Nakayama J., Reis C.A. Terminal alpha1,4-linked N-acetylglucosamine in Helicobacter pylori-associated intestinal metaplasia of the human stomach and gastric carcinoma cell lines. J. Histochem. Cytochem. 2006. V. 54(5).
17. P. 585–591.
18. Craanen M.E., Blok P., Dekker W., Ferwerda J., Tytgat G.N. Subtypes of intestinal metaplasia and Helicobacter pylori. Gut. 1992. V. 33(5). P. 597–600.
19. Kawakubo M., Ito Y., Okimura Y., Kobayashi M., Sakura K., Kasama S., Fukuda M.N., Fukuda M., Katsuyama T., Nakayama J. Natural antibiotic function of a human gastric mucin against Helicobacter pylori infection. Science. 2004. V. 305(5686). P. 1003–1006.
20. Wi D.H., Cha J.H., Jung Y.S. Mucin in cancer: a stealth cloak for cancer cells. BMB Rep. 2021. V. 54(7). P. 344–355.
21. Akyürek N., Akyol G., Dursun A., Yamaç D., Günel N. Expression of MUC1 and MUC2 mucins in gastric carcinomas: their relationship with clinicopathologic parameters and prognosis. Pathol. Res. Pract. 2002. V. 198(10). P. 665–674.
22. Cozzi P.J., Wang J., Delprado W., Perkins A.C., Allen B.J., Russell P.J., Li Y. MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer. Clin. Exp. Metastasis. 2005. V. 22(7). P. 565–573.
23. Shi D., Xi X.X. Regulation of MUC6 Methylation Correlates with Progression of Gastric Cancer. Yonsei. Med. J. 2021. V. 62(11). P. 1005–1015.
24. Terada T. An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: II. Expression of MUC1, MUC2, MUC5AC, and MUC6 in normal mucosa and in 42 cases. Int. J. Clin. Exp. Pathol. 2013. V. 6(4). P. 613–621.
25. Hondo F.Y., Kishi H., Safatle-Ribeiro A.V., Pessorrusso F.C.S., Ribeiro U., Maluf-Filho F. Characterization of the mucin phenotype can predict gastric cancer recurrence after endoscopic mucosal resection. Arq. Gastroenterol. 2017. V. 54(4). P. 308–314.
26. Kim D.H., Shin N., Kim G.H., Song G.A., Jeon T.Y., Kim D.H., Lauwers G.Y., Park D.Y. Mucin expression in gastric cancer: reappraisal of its clinicopathologic and prognostic significance. Int. J. Mol. Sci. 2013. V. 137(8). P. 1047–1053.
27. Oue N., Sentani K., Sakamoto N., Uraoka N., Yasui W. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. Int. J. Clin. Oncol. 2019. V. 24(7). P. 771–778.
28. Setia N., Agoston A.T., Han H.S., Mullen J.T., Duda D.G., Clark J.W., Deshpande V., Mino-Kenudson M., Srivastava A., Lennerz J.K., Hong T.S., Kwak E.L., Lauwers G.Y. A protein and mRNA expression-based classification of gastric cancer. Mod. Pathol. 2016. V. 29(7). P. 772–784.
29. Xiong Z.F., Shi J., Fu Z.H., Wan H.P., Tu L.X. Phenotypic classification of gastric signet ring cell carcinoma and its relationship with K-ras mutation. Genet. Mol. Res. 2017. V. 16(2).
30. Kabashima A., Yao T., Sugimachi K., Tsuneyoshi M. Gastric or intestinal phenotypic expression in the carcinomas and background mucosa of multiple early gastric carcinomas. Histopathology. 2000. V. 37(6). P. 513–522.
31. Egashira Y., Shimoda T., Ikegami M. Mucin histochemical analysis of minute gastric differentiated adenocarcinoma. Pathol. Int. 1999. V. 49(1). P. 55–61.
32. Nakamura T., Yao T., Kabashima A., Nishiyama K., Maehara Y., Tsuneyoshi M. Loss of phenotypic expression is related to tumour progression in early gastric differentiated adenocarcinoma. Histopathology. 2005. V. 47(4). P. 357–367.
33. Oue N., Sentani K., Sakamoto N., Yasui W. Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype. Cancer Sci. 2015. V. 106(8). P. 951–958.
34. Gaganov L.E., Kazantseva I.A., Gurevich L.E., Ustinova E.I. Immunogistokhimicheskaya ekspressiya galektina-3 i e-kadkherina v razlichnykh immunofenotipicheskikh variantakh raka zheludka. Tekhnologii zhivykh sistem. 2012. T. 9. № 3. S. 28–31. (in Russian).
35. Ma J., Rubin B.K., Voynow J.A. Mucins, Mucus, and Goblet Cells. Chest. 2018. V. 154(1). P. 169–176.
36. Van der Sluis M., De Koning B.A., De Bruijn A.C., Velcich A., Meijerink J.P., Van Goudoever J.B., Büller H.A., Dekker J., Van Seuningen I., Renes I.B., Einerhand A.W. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006. V. 131(1). P. 117–129.
37. Johansson M.E., Phillipson M., Petersson J., Velcich A., Holm L., Hansson G.C. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl. Acad. Sci. U S A. 2008. V. 105(39). P. 15064–15069.
38. Aslam F., Palumbo L., Augenlicht L.H., Velcich A. The Sp family of transcription factors in the regulation of the human and mouse MUC2 gene promoters. Cancer Res. 2001. V. 61(2). P. 570–576.
39. Yamashita M.S.A., Melo E.O. Mucin 2 (MUC2) promoter characterization: an overview. Cell Tissue Res. 2018. V. 374(3). P. 455–463.
40. Xiao L.J., Zhao S., Zhao E.H., Zheng X., Gou W.F., Xing Y.N., Takano Y., Zheng H.C. Clinicopathological and prognostic significance of MUC-2, MUC-4 and MUC-5AC expression in japanese gastric carcinomas. Asian Pac. J. Cancer Prev. 2012. V. 13(12). P. 6447–6453.
41. Geramizadeh B., Mokhtari M., Sefidbakht S., Rahsaz M. Mucin profile expression in gastric adenocarcinoma. Middle East J. Dig. Dis. 2012. V. 4(4). P. 211–215.
42. İlhan Ö., Han Ü., Önal B., Çelık S.Y. Prognostic significance of MUC1, MUC2 and MUC5AC expressions in gastric carcinoma. Turk. J. Gastroenterol. 2010. V. 21(4). P. 345–352.
43. Machlowska J., Maciejewski R., Sitarz R. The Pattern of Signatures in Gastric Cancer Prognosis. Gastric. Cancer. 2018. V. 19(6). P. 1658.
44. Park K.K., Yang S.I., Seo K.W., Yoon K.Y., Lee S.H., Jang H.K., Shin Y.M. Correlations of Human Epithelial Growth Factor Receptor 2 Overexpression with MUC2, MUC5AC, MUC6, p53, and Clinicopathological Characteristics in Gastric Cancer Patients with Curative Resection. Gastroenterol. Res. Pract. 2015. V. 2015. P. 946359.
45. Baldus S.E., Zirbes T.K., Engel S., Hanisch F.G., Mönig S.P., Lorenzen J., Glossmann J., Fromm S., Thiele J., Pichlmaier H., Dienes H.P. Correlation of the immunohistochemical reactivity of mucin peptide cores MUC1 and MUC2 with the histopathological subtype and prognosis of gastric carcinomas. Int. J. Cancer. 1998. V. 79(2). P. 133–138.
46. Fujimoto A., Ishikawa Y., Ishii T., Yamada A., Igarashi Y., Ohmoto Y., Kaise M. Differences between gastric signet-ring cell carcinoma and poorly differentiated adenocarcinoma: A comparison of histopathologic features determined by mucin core protein and trefoil factor family peptide immunohistochemistry. Pathol. Int. 2017. V. 67(8). P. 398–403.
47. Zhang H.K., Zhang Q.M., Zhao T.H., Li Y.Y., Yi Y.F. Expression of mucins and E-cadherin in gastric carcinoma and their clinical significance. World J. Gastroenterol. 2004. V. 10(20). P. 3044–3047.
48. Leteurtre E., Zerimech F., Piessen G., Wacrenier A., Leroy X., Copin M.C., Mariette C., Aubert J.P., Porchet N., Buisine M.P. Relationships between mucinous gastric carcinoma, MUC2 expression and survival. World J. Gastroenterol. 2006. V. 12(21). P. 3324–3331.
49. Utsunomiya T., Yonezawa S., Sakamoto H., Kitamura H., Hokita S., Aiko T., Tanaka S., Irimura T., Kim Y.S., Sato E. Expression of MUC1 and MUC2 mucins in gastric carcinomas: its relationship with the prognosis of the patients. Clin. Cancer Res. 1998. V. 4(11). P. 2605–2614.
50. Kerckhoffs K.G.P., Liu D.H.W., Saragoni L., van der Post R.S., Langer R., Bencivenga M., Iglesias M., Gallo G., Hewitt L.C., Fazzi G.E., Vos A.M., Renaud F., Yoshikawa T., Oshima T., Tomezzoli A., de Manzoni G., Arai T. Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer. Gastric Cancer. 2020. V. 23(5). P. 765–779.
51. Mikhaleva L.M., Biryukov A.E. Morfologicheskiye i immunogistokhimicheskiye osobennosti tyazheloy displazii i rannego raka zheludka. Arkhiv patologii. 2017. T. 79(4). S. 22–28. (in Russian).
52. Zhang C.T., He K.C., Pan F., Li Y., Wu J. Prognostic value of Muc5AC in gastric cancer: A meta-analysis. World J. Gastroenterol. 2015. V. 21(36). P. 10453–10460.
53. Gürbüz Y., Kahlke V., Klöppel G. How do gastric carcinoma classification systems relate to mucin expression patterns? An immunohistochemical analysis in a series of advanced gastric carcinomas. Virchows. Arch. 2002. V. 440(5). P. 505–511.
54. Kim S.M., Kwon C.H., Shin N., Park D.Y., Moon H.J., Kim G.H., Jeon T.Y. Decreased Muc5AC expression is associated with poor prognosis in gastric cancer. Int. J. Cancer. 2014. V. 134(1). P. 114–124.
55. Wang X., Yan F., Shi R., Huang X., Lu S., Xu L., Ren B. Hyper Expression of Mucin 5ac Indicates Poor Cancer Prognoses: A Meta-Analysis. Medicine (Baltimore). 2016. V. 95(1). P. e2396.
56. Jiang K., Liu H., Xie D., Xiao Q. Differentially expressed genes ASPN, COL1A1, FN1, VCAN and MUC5AC are potential prognostic biomarkers for gastric cancer. Oncol. Lett. 2019. V. 17(3). P. 3191–3202.
57. Papandreou C.N., Nanus D.M. Is methylation the key to CD10 loss?. J. Pediatr. Hematol. Oncol. 2010. V. 32(1). P. 2–3.
58. Ruemmele F.M., Schmitz J., Goulet O. Microvillous inclusion disease (microvillous atrophy). Orphanet. J. Rare Dis. 2006. V. 1. P. 22.
59. Tian M.M., Zhao A.L., Li Z.W., Li J.Y. Phenotypic classification of gastric signet ring cell carcinoma and its relationship with clinicopathologic parameters and prognosis. World J. Gastroenterol. 2007. V. 13(23). P. 3189–3198.
60. Sato Y., Itoh F., Hinoda Y., Ohe Y., Nakagawa N., Ueda R., Yachi A., Imai K. Expression of CD10/neutral endopeptidase in normal and malignant tissues of the human stomach and colon. J. Gastroenterol. 1996. V. 31(1). P. 12–17.
61. Han J.P., Hong S.J., Kim H.K., Kim H.S., Lee Y.N., Lee T.H., Lee J.S. Expression of immunohistochemical markers according to histological type in patients with early gastric cancer. Scand. J. Gastroenterol. 2016. V. 51(1). P. 60–66.
62. Park D.Y., Srivastava A., Kim G.H., Mino-Kenudson M., Deshpande V., Zukerberg L.R., Song G.A., Lauwers G.Y. CDX2 expression in the intestinal-type gastric epithelial neoplasia: frequency and significance. Mod. Pathol. 2010. V. 23(1). P. 54–61.
63. Huang W.B., Zhou X.J., Chen J.Y., Zhang L.H., Meng K., Ma H.H., Lu Z.F. CD10-positive stromal cells in gastric carcinoma: correlation with invasion and metastasis. Jpn. J. Clin. Oncol. 2005. V. 35(5). P. 245–250.
64. Guo R.J., Suh E.R., Lynch J.P. The role of Cdx proteins in intestinal development and cancer. Cancer Biol. Ther. 2004. V. 3(7). P. 593–601.
65. Roessler K., Mönig S.P., Schneider P.M., Hanisch F.G., Landsberg S., Thiele J., Hölscher A.H., Dienes H.P., Baldus S.E. Co-expression of CDX2 and MUC2 in gastric carcinomas: correlations with clinico-pathological parameters and prognosis. World J. Gastroenterol. 2005. V. 11(21). P. 3182–3188.
66. Bai Y.Q., Yamamoto H., Akiyama Y., Tanaka H., Takizawa T., Koike M., Kenji Yagi O., Saitoh K., Takeshita K., Iwai T., Yuasa Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett. 2002. V. 176(1). P. 47–55.
67. Seno H., Oshima M., Taniguchi M.A., Usami K., Ishikawa T.O., Chiba T., Taketo M.M. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications. Int. J. Oncol. 2002. V. 21(4). P. 769–774.
68. Carneiro F., Moutinho-Ribeiro M., David L., Seixas M., Sansonetty F., Soares P., Serrano A., Sobrinho-Simões M. Signet ring cell carcinoma of the stomach: a morphometric, ultrastructural, and DNA cytometric study. Ultrastruct. Pathol. 1992. V. 16(6). P. 603–614.
69. Yamamoto H., Bai Y.Q., Yuasa Y. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem. Biophys. Res. Commun. 2003. V. 300(4). P. 813–818.
70. Masood M.A., Loya A., Yusuf M.A. CDX2 as a prognostic marker in gastric cancer. Gastric Cancer. 2016. V. 79(2). P. 197–200.
71. Fernández Aceñero, M.J., Sánchez de Molina M.L., Caso A., Vorwald P., Olmo D.G., Palomar J., Estrada L., Díaz Del Arco C. CDX2 expression can predict response to neoadjuvant therapy in gastric carcinoma. Rom. J. Morphol. Embryol. 2017. V. 58(4). P. 1275–1278.
72. Yan L.H., Wei W.Y., Xie Y.B., Xiao Q. New insights into the functions and localization of the homeotic gene CDX2 in gastric cancer. World J. Gastroenterol. 2014. V. 20(14). P. 3960–3966.
73. Lu L., Wu M., Sun L., Li W., Fu W., Zhang X., Liu T. Clinicopathological and prognostic significance of cancer stem cell markers CD44 and CD133 in patients with gastric cancer: A comprehensive meta-analysis with 4729 patients involved. Medicine (Baltimore). 2016.
74. V. 95(42). P. e5163.
75. Saito M., Okayama H., Saito K., Ando J., Kumamoto K., Nakamura I., Ohki S., Ishi Y., Takenoshita S. CDX2 is involved in microRNA-associated inflammatory carcinogenesis in gastric cancer. Oncol. Lett. 2017. V. 14(5). P. 6184–6190.