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634050, . , , 2, e-mail: zavyalovamv@mail.ru1
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CLINICAL-MORPHOLOGICAL AND MOLECULAR-GENETIC CHARACTERISTICS
OF INTESTINAL AND DIFFUSE TYPES OF GASTRIC CARCINOMAS
I.V. Stepanov1, M.V. Zavyalova1,2, E.S. Grigoryeva3, Yu.A. Bukurova3, S.G. Afanasyev2, N.V. Cherdyntseva2
Siberian State Medical University, Tomsk1
Cancer Research Institute, SB RAMS, Tomsk2
V.A. Engelgardt Institute of Molecular Biology of the RAS, Moscow3
2, Moskovsky Tract, 634050-Tomsk, e-mail: zavyalovamv@mail.ru1
The review presents the data on clinical characteristics of two different histological types of gastric cancer and molecular
factors of pathogenesis including Helicobacter pylori infection, inherited and somatic mutations and other genetic disturbances.
The analysis of relation of the markers of proliferation, apoptosis, growth factors and regulators of intercellular interactions to the
tumor progression was carried out. The results of proteomic studies on the search for diagnostic markers and prognosis of intestinal
and diffuse types of gastric cancer were presented.
Key words: intestinal and diffuse gastric cancer, pathogenesis, molecular markers, prognosis.

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TP53 //
, 2010. . 56, 2. . 156161.
2. .., .., .., ..
// . 2010.
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3. .., .., .. .
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4. .., .. 2001 . .:
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14. Araujo-Filho I., Brandao-Neto J. Prevalence of helicobacter
pylori infection in advanced gastric carcinoma // Arq. Gastroenterol.
2006. Vol. 43. P. 288292.
15. Brooks-Wilson A.R., Kaurah P., Suriano G. Germline Ecadherin mutations in hereditary diffuse gastric cancer: Assessment
of 42 new families and review of genetic screening criteria // J. Med.
Genet. 2004. Vol. 41. P. 508517.
16. Caca K., Kolligs F.T., Ji X. et al. Beta- and gamma-catenin
mutations, but not E-cadherin inactivation, underlie T-cell factor/
lymphoid enhancer factor transcriptional deregulation in gastric and
pancreatic cancer // Cell Growth Differ. 1999. Vol. 10. P. 369376.
17. Cheng Y., Zhang J., Li Y. et al. Proteome analysis of human
gastric cardia adenocarcinoma by laser capture microdissection // BMC
Cancer. 2007. Vol. 7. P. 191.
18. Dinis-Ribeiro M., Lopes C., Costa-Pereira A. A follow up
model for patients with atrophic chronic gastritis and intestinal metaplasia // J. Clin. Pathol. 2004. Vol. 57. P. 177182.
19. Elpek G.O., Gelen T., Aksoy N.H. Microvessel count, proliferating cell nuclear antigen and Ki-67 indices in gastric adenocarcinoma
// Pathol. Oncol. Res. 2000. Vol. 6. P. 5964.
20. Feakins R.M., Nickols C.D., Bidd H., Walton S.J. Abnormal
expression of pRb, p16 and cyclin D1 in gastric adenocarcinoma and
lymph node metastases:relationship with pathological features and
survival // Hum. Pathol. 2003. Vol. 34. P. 12761282.
21. Fischbach W., Chan A., Wong B. Helicobacter pylori and
Gastric Malignancy // Helicobacter. 2005. Vol. 10. P. 3439.
22. Grady W.M., Willis J., Guilford P.J. Methylation of the CDH1
promoter as the second genetic hit in hereditary diffuse gastric cancer
// Nat. Genet. 2000. Vol. 26. P. 1617.
23. Gutierrez-Gonzalez L., Wright N.A. Biology of intestinal
metaplasia in 2008: More than a simple phenotypic alteration // Dig.
Liver Dis. 2008. Vol. 40. P. 510522.
24. Itoh K. Proteomic alteration in gastric adenocarcinomas from
Japanese patients // Mol. Cancer. 2006. Vol. 5. P. 75.
25. Jass J.R., Walsh M.D. Altered mucin expression in the
gastrointestinal tract: a review // J. Cell. Mol. Med. 2001. Vol. 5.
P. 327351.
26. Joo Y.E., Oh W.T., Rew J.S., Park C.S. Cyclooxygenase-2
expression is associated with well-differentiated and intestinaltype

65

pathways in gastric carcinogenesis // Digestion. 2002. Vol. 66.

P. 222229.
27. Kumar V., Cotran R.S., Robbins S.L. Robbins Basic Pathology, 7th Edition. Philadelphia: Saunders, 2003. 873 p.
28. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal type carcinoma // Acta Pathol.
Microbiol. Scand. 1965. Vol. 64 (1). P. 3149.
29. Lee K.E., Lee H-J., Kim Y.H. Prognostic Significance of p53,
nm23, PCNA and c-erbB-2 in Gastric Cancer // Jap. J. Clin. Oncol.
2003. Vol. 33. P. 173179.
30. Lee W-S., Kim H.-S., Choi S-K., Rew J-S. Expression of Cyclooxygenase-2, p53 and Ki-67 in Gastric Cancer // J. Korean Med.
Sci. 2006. Vol. 21. P. 871876.
31. Levine A.J., Hu W., Feng Z. The p53 pathway: what questions remain to be explored? // Cell Death Differ. 2006. Vol. 13.
P. 10271036.
32. Mesquita P., Raquel A., Nuno L. Metaplasia a transdifferentiation process that facilitates cancer development: the model of gastric
intestinal metaplasia // Crit. Rev. Oncog. 2006. Vol. 12. P. 326.
33. Mutoh H., Sakurai S., Satoh K. Perycriptal fibroblast sheath
in intestinal metaplasia and gastric carcinoma // Gut. 2005. Vol. 54.
P. 3339.
34. Nardone G., Rocco A., Malfertheiner P. Review article: Helicobacter pylori and molecular events in precancerous gastric lesions
// Aliment. Pharmacol. Ther. 2004. Vol. 20. P. 261270.
35. Nogueira ., Silva A.S., Santos J.N. Early Gastric Cancer:
Ten years of Experience // World J. Surg. 2002. Vol. 26, Suppl. 3.
P. 330334.
36. Pharoah P.D.P., Guilford P., Caldas C. International Gastric
Cancer Linkage Consortium. Incidence of gastric cancer and breast
cancer in CDH1 (E-adherin) mutation carriers from hereditary
diffuse gastric cancer families // Gastroenterology. 2001. Vol. 121.
P. 13481353.
37. Qiang L., Ming T., KoseiI. CDX2 expression is progressively
decreased in human gastric intestinal metaplasia, dysplasia and cancer
// Modern Pathol. 2007. Vol. 20. P. 12861297.
38. Scartozzi M., Galizia E., Freddari F. Molecular biology of
sporadic gastric cancer: Prognostic indicators and novel therapeutic
approaches // Cancer Treat. Rev. 2004. Vol. 30. P. 451459.
39. Seno H., Oshima M., Taniguchi M.A. CDX2 expression in the
stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications // Int. J. Oncol. 2002. Vol. 21 (4). P. 769774.
40. Takehana T., Kunimoto K., Kono K. Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry,
fluorescence in situ hybridization and enzyme-linked immuno-sorbent
assay // Int. J. Cancer. 2002. Vol. 98. P. 833837.
41. Tamura G. Alterations of tumor suppressor and tumor-related
genes in the development and progression of gastric cancer // World
J. Gastroenterol. 2006. Vol. 12 (2). P. 192198.
42. Tamura G. Promoter methylation status of tumor suppressor and tumor-related genes in neoplastic and non-neoplastic gastric
epithelia // Histol. Histopathol. 2004. Vol. 19. P. 221228.
43. Varis A., Zaika A., Puolakkainen P. Coamplied and overexpressed genes at ERBB2 locus in gastric cancer // Int. J. Cancer. 2004.
Vol. 109. P. 548553.
44. Veenstra T.D., Conrads T.P., Hood B.L. et al. Biomarkers:
mining the biofluid proteome // Mol. Cell Proteomics. 2005. Vol. 4
(4). P. 409418.
45. Werling R.W., Yaziji H., Bacchi C.E. CDX2, a highly sensitive
and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas
// Am. J. Surg. Pathol. 2003. Vol. 27 (3). P. 303330.
46. Wiksten J.P., Lundin J., Nordling S. Comparison of the
prognostic value of a panel of tissue tumor markers and established
clinico-pathological factors in patients with gastric cancer // Anticancer
Res. 2008. Vol. 28. P. 22792287.

. 2010. 4 (40)

66

.. , .. , .. .

47. Yamazaki K., Tajima Y., Makino R. Tumor differentiation

phenotype in gastric differentiated type tumors and its relation to
tumor invasion and genetic alterations // World J. Gastroenterol. 2006.
Vol. 12 (24). P. 38033809.
48. Yoshihara T., Kadota Y., Yoshimura Y. et al. Proteomic alteration in gastic adenocarcinomas from Japanese patients // Mol. Cancer.
2006. Vol. 5. P. 75.
49. Zheng H., Takahashi H. Pathobiological characteristics of
intestinal and diffuse-type gastric carcinoma in Japan: an immu-

. 2010. 4 (40)

nostaining study on the tissue microarray // J. Clin. Pathol. 2007.

Vol. 60. P. 273277.
50. Zhu C.-Q., Shih W., Ling C.-H., Tsao M.-S. Immunohistochemical markers of prognosis in non-small cell lung cancer: a
review and proposal for a multiphase approach to marker evaluation
// J. Clin. Pathol. 2006. Vol. 59. P. 790800.
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