Metaplasia in the stomach—precursor of gastric Cancer?

International Journal of Molecular Sciences

Volumn 18, Issue 10, 2017, Pages

  Kinoshita, Hiroto ^a   Hayakawa, Yoku ^a   Koike, Kazuhiko ^a  

^a UNIVERSITY OF TOKYO   (Japan)

Author keywords

Gastric cancer; Helicobacter pylori; Intestinal metaplasia; Lineage tracing; Spasmolytic polypeptide expressing metaplasia (SPEM); Stem cells

Indexed keywords

B RAF KINASE; DNA METHYLTRANSFERASE 1; EPIDERMAL GROWTH FACTOR RECEPTOR; GAMMA INTERFERON; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; INTERLEUKIN 8; MITOGEN ACTIVATED PROTEIN KINASE; MUCIN 1; MUCIN 2; MUCIN 5AC; MUCIN 6; PROTEIN P53; STROMAL CELL DERIVED FACTOR 1; TAMOXIFEN; TOLL LIKE RECEPTOR; TRANSCRIPTION FACTOR CDX1; TRANSCRIPTION FACTOR CDX2; TREFOIL FACTOR 2; TREFOIL FACTOR 3; VILLIN; BIOLOGICAL MARKER;

ANTINEOPLASTIC ACTIVITY; ATROPHY; BACTERIAL COLONIZATION; CANCER RISK; CELL DIFFERENTIATION; CELL PROLIFERATION; DNA METHYLATION; GASTRIC CELL LINE; GENE; HELICOBACTER INFECTION; HUMAN; IMMUNOHISTOCHEMISTRY; INFLAMMATION; INTESTINE METAPLASIA; METAPLASIA; NONHUMAN; PRECURSOR; PROTEIN EXPRESSION; REVIEW; STOMACH; STOMACH CANCER; STOMACH EPITHELIUM; TFF2 GENE; ANIMAL; CANCER GRADING; COMPLICATION; DISEASE MODEL; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; HELICOBACTER PYLORI; METABOLISM; MICROBIOLOGY; MOUSE; PATHOLOGY; PRECANCER; SIGNAL TRANSDUCTION; STOMACH MUCOSA; STOMACH TUMOR;

ANIMALS; BIOMARKERS; DISEASE MODELS, ANIMAL; EPIGENESIS, GENETIC; GASTRIC MUCOSA; GENE EXPRESSION REGULATION, NEOPLASTIC; HELICOBACTER INFECTIONS; HELICOBACTER PYLORI; HUMANS; METAPLASIA; MICE; NEOPLASM GRADING; PRECANCEROUS CONDITIONS; SIGNAL TRANSDUCTION; STOMACH; STOMACH NEOPLASMS;

EID: 85030154877     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms18102063     Document Type: Review

References (155)

1. Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in globocan 2012. Int. J. Cancer 2015, 136, E359-E386.
2. Uemura, N.; Okamoto, S.; Yamamoto, S.; Matsumura, N.; Yamaguchi, S.; Yamakido, M.; Taniyama, K.; Sasaki, N.; Schlemper, R.J. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001, 345, 784-789.
3. Correa, P.; Shiao, Y.H. Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res. 1994, 54, 1941s-1943s.
4. Correa, P. Human gastric carcinogenesis: A multistep and multifactorial process-First american cancer society award lecture on cancer epidemiology and prevention. Cancer Res. 1992, 52, 6735-6740.
5. Giroux, V.; Rustgi, A.K. Metaplasia: Tissue injury adaptation and a precursor to the dysplasia-cancer sequence. Nat. Rev. Cancer 2017, 17, 594-604.
6. Kimura, K.; Satoh, K.; Ido, K.; Taniguchi, Y.; Takimoto, T.; Takemoto, T. Gastritis in the Japanese stomach. Scand. J. Gastroenterol. 1996, 31, 17-20.
7. Shichijo, S.; Hirata, Y.; Sakitani, K.; Yamamoto, S.; Serizawa, T.; Niikura, R.; Watabe, H.; Yoshida, S.; Yamada, A.; Yamaji, Y.; et al. Distribution of intestinal metaplasia as a predictor of gastric cancer development. J. Gastroenterol. Hepatol. 2015, 30, 1260-1264.
8. Rugge, M.; de Boni, M.; Pennelli, G.; de Bona, M.; Giacomelli, L.; Fassan, M.; Basso, D.; Plebani, M.; Graham, D.Y. Gastritis olga-staging and gastric cancer risk: A twelve-year clinico-pathological follow-up study. Aliment. Pharmacol. Ther. 2010, 31, 1104-1111.
9. Capelle, L.G.; de Vries, A.C.; Haringsma, J.; Ter Borg, F.; de Vries, R.A.; Bruno, M.J.; van Dekken, H.; Meijer, J.; van Grieken, N.C.; Kuipers, E.J. The staging of gastritis with the olga system by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointest. Endosc. 2010, 71, 1150-1158.
10. Kato, I.; Tominaga, S.; Ito, Y.; Kobayashi, S.; Yoshii, Y.; Matsuura, A.; Kameya, A.; Kano, T.; Ikari, A. A prospective study of atrophic gastritis and stomach cancer risk. Jpn. J. Cancer Res. 1992, 83, 1137-1142.
11. Cassaro, M.; Rugge, M.; Gutierrez, O.; Leandro, G.; Graham, D.Y.; Genta, R.M. Topographic patterns of intestinal metaplasia and gastric cancer. Am. J. Gastroenterol. 2000, 95, 1431-1438.
12. De Vries, A.C.; van Grieken, N.C.; Looman, C.W.; Casparie, M.K.; de Vries, E.; Meijer, G.A.; Kuipers, E.J. Gastric cancer risk in patients with premalignant gastric lesions: A nationwide cohort study in the Netherlands. Gastroenterology 2008, 134, 945-952.
13. Sakitani, K.; Hirata, Y.; Watabe, H.; Yamada, A.; Sugimoto, T.; Yamaji, Y.; Yoshida, H.; Maeda, S.; Omata, M.; Koike, K. Gastric cancer risk according to the distribution of intestinal metaplasia and neutrophil infiltration. J. Gastroenterol. Hepatol. 2011, 26, 1570-1575.
14. Lim, J.H.; Kim, N.; Lee, H.S.; Choe, G.; Jo, S.Y.; Chon, I.; Choi, C.; Yoon, H.; Shin, C.M.; Park, Y.S.; et al. Correlation between endoscopic and histological diagnoses of gastric intestinal metaplasia. Gut Liver 2013, 7, 41-50.
15. Shichijo, S.; Hirata, Y.; Niikura, R.; Hayakawa, Y.; Yamada, A.; Ushiku, T.; Fukayama, M.; Koike, K. Histological intestinal metaplasia and endoscopic atrophy are predictors of gastric cancer development after Helicobacter pylori eradication. Gastrointest. Endosc. 2016, 84, 618-624.
16. Fukase, K.; Kato, M.; Kikuchi, S.; Inoue, K.; Uemura, N.; Okamoto, S.; Terao, S.; Amagai, K.; Hayashi, S.; Asaka, M. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: An open-label, randomised controlled trial. Lancet 2008, 372, 392-397.
17. Ogura, K.; Hirata, Y.; Yanai, A.; Shibata, W.; Ohmae, T.; Mitsuno, Y.; Maeda, S.; Watabe, H.; Yamaji, Y.; Okamoto, M.; et al. The effect of Helicobacter pylori eradication on reducing the incidence of gastric cancer. J. Clin. Gastroenterol. 2008, 42, 279-283.
18. Mera, R.M.; Bravo, L.E.; Camargo, M.C.; Bravo, J.C.; Delgado, A.G.; Romero-Gallo, J.; Yepez, M.C.; Realpe, J.L.; Schneider, B.G.; Morgan, D.R.; et al. Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 2017.
19. Wang, J.; Xu, L.; Shi, R.; Huang, X.; Li, S.W.; Huang, Z.; Zhang, G. Gastric atrophy and intestinal metaplasia before and after Helicobacter pylori eradication: A meta-analysis. Digestion 2011, 83, 253-260.
20. Kodama, M.; Murakami, K.; Okimoto, T.; Sato, R.; Uchida, M.; Abe, T.; Shiota, S.; Nakagawa, Y.; Mizukami, K.; Fujioka, T. Ten-year prospective follow-up of histological changes at five points on the gastric mucosa as recommended by the updated sydney system after Helicobacter pylori eradication. J. Gastroenterol. 2012, 47, 394-403.
21. Correa, P.; Fontham, E.T.; Bravo, J.C.; Bravo, L.E.; Ruiz, B.; Zarama, G.; Realpe, J.L.; Malcom, G.T.; Li, D.; Johnson,W.D.; et al. Chemoprevention of gastric dysplasia: Randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J. Natl. Cancer Inst. 2000, 92, 1881-1888.
22. Zullo, A.; Rinaldi, V.; Hassan, C.; Diana, F.;Winn, S.; Castagna, G.; Attili, A.F. Ascorbic acid and intestinal metaplasia in the stomach: A prospective, randomized study. Aliment. Pharmacol. Ther. 2000, 14, 1303-1309.
23. Kong, Y.J.; Yi, H.G.; Dai, J.C.; Wei, M.X. Histological changes of gastric mucosa after Helicobacter pylori eradication: A systematic review and meta-analysis. World J. Gastroenterol. 2014, 20, 5903-5911.
24. Heilmann, K.L.; Hopker, W.W. Loss of differentiation in intestinal metaplasia in cancerous stomachs. A comparative morphologic study. Pathol. Res. Pract. 1979, 164, 249-258.
25. Filipe, M.I.; Munoz, N.; Matko, I.; Kato, I.; Pompe-Kirn, V.; Jutersek, A.; Teuchmann, S.; Benz, M.; Prijon, T. Intestinal metaplasia types and the risk of gastric cancer: A cohort study in Slovenia. Int. J. Cancer 1994, 57, 324-329.
26. Shiotani, A.; Iishi, H.; Ishiguro, S.; Tatsuta, M.; Nakae, Y.; Merchant, J.L. Epithelial cell turnover in relation to ongoing damage of the gastric mucosa in patients with early gastric cancer: Increase of cell proliferation in paramalignant lesions. J. Gastroenterol. 2005, 40, 337-344.
27. Pittayanon, R.; Rerknimitr, R.; Klaikaew, N.; Sanpavat, A.; Chaithongrat, S.; Mahachai, V.; Kullavanijaya, P.; Barkun, A. The risk of gastric cancer in patients with gastric intestinal metaplasia in 5-year follow-up. Aliment. Pharmacol. Ther. 2017, 46, 40-45.
28. Gonzalez, C.A.; Sanz-Anquela, J.M.; Companioni, O.; Bonet, C.; Berdasco, M.; Lopez, C.; Mendoza, J.; Martin-Arranz, M.D.; Rey, E.; Poves, E.; et al. Incomplete type of intestinal metaplasia has the highest risk to progress to gastric cancer: Results of the spanish follow-up multicenter study. J. Gastroenterol. Hepatol. 2016, 31, 953-958.
29. Wang, X.T.; Wei, W.Y.; Kong, F.B.; Lian, C.; Luo, W.; Xiao, Q.; Xie, Y.B. Prognostic significance of Cdx2 immunohistochemical expression in gastric cancer: A meta-analysis of published literatures. J. Exp. Clin. Cancer Res. 2012, 31, 98.
30. Correa, P.; Piazuelo, M.B.; Wilson, K.T. Pathology of gastric intestinal metaplasia: Clinical implications. Am. J. Gastroenterol. 2010, 105, 493-498.
31. Rokkas, T.; Filipe, M.I.; Sladen, G.E. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991, 32, 1110-1113.
32. Gutierrez-Gonzalez, L.; Graham, T.A.; Rodriguez-Justo, M.; Leedham, S.J.; Novelli, M.R.; Gay, L.J.; Ventayol-Garcia, T.; Green, A.; Mitchell, I.; Stoker, D.L.; et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 2011, 140, 1251-1260.
33. Ochiai, A.; Yamauchi, Y.; Hirohashi, S. P53 mutations in the non-neoplastic mucosa of the human stomach showing intestinal metaplasia. Int. J. Cancer 1996, 69, 28-33.
34. Hayakawa, Y.; Sethi, N.; Sepulveda, A.R.; Bass, A.J.;Wang, T.C. Oesophageal adenocarcinoma and gastric cancer: Should we mind the gap? Nat. Rev. Cancer 2016, 16, 305-318.
35. Leung, W.K.; Yu, J.; To, K.F.; Go, M.Y.; Ma, P.K.; Chan, F.K.; Sung, J.J. Apoptosis and proliferation in Helicobacter pylori-associated gastric intestinal metaplasia. Aliment. Pharmacol. Ther. 2001, 15, 1467-1472.
36. Hayakawa, Y.; Fox, J.G.; Gonda, T.; Worthley, D.L.; Muthupalani, S.; Wang, T.C. Mouse models of gastric cancer. Cancers 2013, 5, 92-130.
37. Wang, T.C.; Goldenring, J.R.; Dangler, C.; Ito, S.; Mueller, A.; Jeon, W.K.; Koh, T.J.; Fox, J.G. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with helicobacter felis infection. Gastroenterology 1998, 114, 675-689.
38. Wang, T.C.; Dangler, C.A.; Chen, D.; Goldenring, J.R.; Koh, T.; Raychowdhury, R.; Coffey, R.J.; Ito, S.; Varro, A.; Dockray, G.J.; et al. Synergistic interaction between hypergastrinemia and helicobacter infection in a mouse model of gastric cancer. Gastroenterology 2000, 118, 36-47.
39. Roth, K.A.; Kapadia, S.B.; Martin, S.M.; Lorenz, R.G. Cellular immune responses are essential for the development of helicobacter felis-associated gastric pathology. J. Immunol. 1999, 163, 1490-1497.
40. Lee, Y.; Urbanska, A.M.; Hayakawa, Y.; Wang, H.; Au, A.S.; Luna, A.M.; Chang, W.; Jin, G.; Bhagat, G.; Abrams, J.A.; et al. Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett’s-like esophagus. Oncotarget 2017, 8, 203-214.
41. Takaishi, S.; Tu, S.; Dubeykovskaya, Z.A.; Whary, M.T.; Muthupalani, S.; Rickman, B.H.; Rogers, A.B.; Lertkowit, N.; Varro, A.; Fox, J.G.; et al. Gastrin is an essential cofactor for helicobacter-associated gastric corpus carcinogenesis in C57BL/6 mice. Am. J. Pathol. 2009, 175, 365-375.
42. Hayakawa, Y.; Chang, W.; Jin, G.; Wang, T.C. Gastrin and upper GI cancers. Curr. Opin. Pharmacol. 2016, 31, 31-37.
43. Hayakawa, Y.; Jin, G.; Wang, H.; Chen, X.; Westphalen, C.B.; Asfaha, S.; Renz, B.W.; Ariyama, H.; Dubeykovskaya, Z.A.; Takemoto, Y.; et al. CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. Gut 2015, 64, 544-553.
44. Tomita, H.; Takaishi, S.; Menheniott, T.R.; Yang, X.; Shibata, W.; Jin, G.; Betz, K.S.; Kawakami, K.; Minamoto, T.; Tomasetto, C.; et al. Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing. Gastroenterology 2011, 140, 879-891.
45. Soutto, M.; Belkhiri, A.; Piazuelo, M.B.; Schneider, B.G.; Peng, D.; Jiang, A.;Washington, M.K.; Kokoye, Y.; Crowe, S.E.; Zaika, A.; et al. Loss of TFF1 is associated with activation of NF-_B-mediated inflammation and gastric neoplasia in mice and humans. J. Clin. Investig. 2011, 121, 1753-1767.
46. Lee, A.; O’Rourke, J.; de Ungria, M.C.; Robertson, B.; Daskalopoulos, G.; Dixon, M.F. A standardized mouse model of Helicobacter pylori infection: Introducing the sydney strain. Gastroenterology 1997, 112, 1386-1397.
47. Arnold, I.C.; Lee, J.Y.; Amieva, M.R.; Roers, A.; Flavell, R.A.; Sparwasser, T.; Muller, A. Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology 2011, 140, 199-209.
48. Serizawa, T.; Hirata, Y.; Hayakawa, Y.; Suzuki, N.; Sakitani, K.; Hikiba, Y.; Ihara, S.; Kinoshita, H.; Nakagawa, H.; Tateishi, K.; et al. Gastric metaplasia induced by Helicobacter pylori is associated with enhanced SOX9 expression via interleukin-1 signaling. Infect. Immun. 2015, 84, 562-572.
49. Sayi, A.; Kohler, E.; Toller, I.M.; Flavell, R.A.; Müller, W.; Roers, A.; Müller, A. TLR-2-activated b cells suppress helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J. Immunol. 2011, 186, 878-890.
50. Banerjee, A.; Thamphiwatana, S.; Carmona, E.M.; Rickman, B.; Doran, K.S.; Obonyo, M. Deficiency of the myeloid differentiation primary response molecule MyD88 leads to an early and rapid development of helicobacter-induced gastric malignancy. Infect. Immun. 2014, 82, 356-363.
51. Ericksen, R.E.; Rose, S.;Westphalen, C.B.; Shibata,W.; Muthupalani, S.; Tailor, Y.; Friedman, R.A.; Han,W.; Fox, J.G.; Ferrante, A.W., Jr.; et al. Obesity accelerates helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response. Gut 2014, 63, 385-394.
52. Lofgren, J.L.; Whary, M.T.; Ge, Z.; Muthupalani, S.; Taylor, N.S.; Mobley, M.; Potter, A.; Varro, A.; Eibach, D.; Suerbaum, S.; et al. Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology 2011, 140, 210-220.
53. Tu, S.; Bhagat, G.; Cui, G.; Takaishi, S.; Kurt-Jones, E.A.; Rickman, B.; Betz, K.S.; Penz-Oesterreicher, M.; Bjorkdahl, O.; Fox, J.G.; et al. Overexpression of interleukin-1_ induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 2008, 14, 408-419.
54. Syu, L.J.; El-Zaatari, M.; Eaton, K.A.; Liu, Z.; Tetarbe, M.; Keeley, T.M.; Pero, J.; Ferris, J.; Wilbert, D.; Kaatz, A.; et al. Transgenic expression of interferon- in mouse stomach leads to inflammation, metaplasia, and dysplasia. Am. J. Pathol. 2012, 181, 2114-2125.
55. Shibata, W.; Ariyama, H.; Westphalen, C.B.; Worthley, D.L.; Muthupalani, S.; Asfaha, S.; Dubeykovskaya, Z.; Quante, M.; Fox, J.G.; Wang, T.C. Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors. Gut 2013, 62, 192-200.
56. Asfaha, S.; Dubeykovskiy, A.N.; Tomita, H.; Yang, X.; Stokes, S.; Shibata, W.; Friedman, R.A.; Ariyama, H.; Dubeykovskaya, Z.A.; Muthupalani, S.; et al. Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis. Gastroenterology 2013, 144, 155-166.
57. Buzzelli, J.N.; Chalinor, H.V.; Pavlic, D.I.; Sutton, P.; Menheniott, T.R.; Giraud, A.S.; Judd, L.M. IL33 is a stomach alarmin that initiates a skewed TH2 response to injury and infection. Cell. Mol. Gastroenterol. Hepatol. 2015, 1, 203-221.
58. -/- C57BL6 × Sv129 Helicobacter pylori-infected mice. Am. J. Pathol. 2007, 171, 1520-1528.
59. Hayakawa, Y.; Fox, J.G.; Wang, T.C. Isthmus stem cells are the origins of metaplasia in the gastric corpus. Cell. Mol. Gastroenterol. Hepatol. 2017, 4, 89-94.
60. Schmidt, P.H.; Lee, J.R.; Joshi, V.; Playford, R.J.; Poulsom, R.; Wright, N.A.; Goldenring, J.R. Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma. Lab. Investig. 1999, 79, 639-646.
61. Goldenring, J.R.; Nam, K.T.; Wang, T.C.; Mills, J.C.; Wright, N.A. Spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia: Time for reevaluation of metaplasias and the origins of gastric cancer. Gastroenterology 2010, 138, 2207-2210.
62. Peterson, A.J.; Menheniott, T.R.; O’Connor, L.; Walduck, A.K.; Fox, J.G.; Kawakami, K.; Minamoto, T.; Ong, E.K.; Wang, T.C.; Judd, L.M.; et al. Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans. Gastroenterology 2010, 139, 2005-2017.
63. Silberg, D.G.; Sullivan, J.; Kang, E.; Swain, G.P.; Moffett, J.; Sund, N.J.; Sackett, S.D.; Kaestner, K.H. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 2002, 122, 689-696.
64. Mutoh, H.; Hakamata, Y.; Sato, K.; Eda, A.; Yanaka, I.; Honda, S.; Osawa, H.; Kaneko, Y.; Sugano, K. Conversion of gastric mucosa to intestinal metaplasia in cdx2-expressing transgenic mice. Biochem. Biophys. Res. Commun. 2002, 294, 470-479.
65. Mutoh, H.; Sakurai, S.; Satoh, K.; Osawa, H.; Hakamata, Y.; Takeuchi, T.; Sugano, K. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: Comparative study with Cdx2 transgenic mice. Gut 2004, 53, 1416-1423.
66. Mutoh, H.; Sakurai, S.; Satoh, K.; Tamada, K.; Kita, H.; Osawa, H.; Tomiyama, T.; Sato, Y.; Yamamoto, H.; Isoda, N.; et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 2004, 64, 7740-7747.
67. Okumura, T.; Ericksen, R.E.; Takaishi, S.; Wang, S.S.; Dubeykovskiy, Z.; Shibata, W.; Betz, K.S.; Muthupalani, S.; Rogers, A.B.; Fox, J.G.; et al. K-ras mutation targeted to gastric tissue progenitor cells results in chronic inflammation, an altered microenvironment, and progression to intraepithelial neoplasia. Cancer Res. 2010, 70, 8435-8445.
68. Ray, K.C.; Bell, K.M.; Yan, J.; Gu, G.; Chung, C.H.; Washington, M.K.; Means, A.L. Epithelial tissues have varying degrees of susceptibility to krasG12D-initiated tumorigenesis in a mouse model. PLoS ONE 2011, 6, e16786.
69. Matkar, S.S.; Durham, A.; Brice, A.;Wang, T.C.; Rustgi, A.K.; Hua, X. Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice. Am. J. Cancer Res. 2011, 1, 432-445.
70. Hayakawa, Y.; Ariyama, H.; Stancikova, J.; Sakitani, K.; Asfaha, S.; Renz, B.W.; Dubeykovskaya, Z.A.; Shibata, W.; Wang, H.; Westphalen, C.B.; et al. Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche. Cancer Cell 2015, 28, 800-814.
71. Choi, E.; Hendley, A.M.; Bailey, J.M.; Leach, S.D.; Goldenring, J.R. Expression of activated ras in gastric chief cells of mice leads to the full spectrum of metaplastic lineage transitions. Gastroenterology 2016, 150, 918-930.
72. Thiem, S.; Eissmann, M.F.; Elzer, J.; Jonas, A.; Putoczki, T.L.; Poh, A.; Nguyen, P.; Preaudet, A.; Flanagan, D.; Waring, P.; et al. Stomach-specific activation of oncogenic kRAS and STAT3-dependent inflammation cooperatively promote gastric tumorigenesis in a preclinical model. Cancer Res. 2016, 76, 2277-2287.
73. Matsuo, J.; Kimura, S.; Yamamura, A.; Koh, C.P.; Hossain, M.Z.; Heng, D.L.; Kohu, K.; Chih-Cheng Voon, D.; Hiai, H.; Unno, M.; et al. Identification of stem cells in the epithelium of the stomach corpus and antrum of mice. Gastroenterology 2016, 152, 218-231.
74. Leushacke, M.; Tan, S.H.; Wong, A.; Swathi, Y.; Hajamohideen, A.; Tan, L.T.; Goh, J.; Wong, E.; Denil, S.; Murakami, K.; et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat. Cell. Biol. 2017, 19, 774-786.
75. Goldenring, J.R.; Ray, G.S.; Soroka, C.J.; Smith, J.; Modlin, I.M.; Meise, K.S.; Coffey, R.J., Jr. Overexpression of transforming growth factor-_ alters differentiation of gastric cell lineages. Dig. Dis. Sci. 1996, 41, 773-784.
76. Takagi, H.; Fukusato, T.; Kawaharada, U.; Kuboyama, S.; Merlino, G.; Tsutsumi, Y. Histochemical analysis of hyperplastic stomach of TGF-_ transgenic mice. Dig. Dis. Sci. 1997, 42, 91-98.
77. Nam, K.T.; Lee, H.J.; Mok, H.; Romero-Gallo, J.; Crowe, J.E., Jr.; Peek, R.M., Jr.; Goldenring, J.R. Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia. Gastroenterology 2009, 136, 1288-1296.
78. Nam, K.T.; O’Neal, R.; Lee, Y.S.; Lee, Y.C.; Coffey, R.J.; Goldenring, J.R. Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature. Lab. Investig. 2012, 92, 883-895.
79. Shinohara, M.; Mao, M.; Keeley, T.M.; El-Zaatari, M.; Lee, H.J.; Eaton, K.A.; Samuelson, L.C.; Merchant, J.L.; Goldenring, J.R.; Todisco, A. Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice. Gastroenterology 2010, 139, 2050-2060.
80. Heijmans, J.; van den Brink, G.R. Morphogens and the parietal cell: Shaping up acid secretion. Gastroenterology 2010, 139, 1830-1833.
81. Bleuming, S.A.; He, X.C.; Kodach, L.L.; Hardwick, J.C.; Koopman, F.A.; Ten Kate, F.J.; van Deventer, S.J.; Hommes, D.W.; Peppelenbosch, M.P.; Offerhaus, G.J.; et al. Bone morphogenetic protein signaling suppresses tumorigenesis at gastric epithelial transition zones in mice. Cancer Res. 2007, 67, 8149-8155.
82. Nomura, S.; Yamaguchi, H.; Ogawa, M.; Wang, T.C.; Lee, J.R.; Goldenring, J.R. Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G362-375.
83. Nam, K.T.; Lee, H.J.; Sousa, J.F.; Weis, V.G.; O’Neal, R.L.; Finke, P.E.; Romero-Gallo, J.; Shi, G.; Mills, J.C.; Peek, R.M., Jr.; et al. Mature chief cells are cryptic progenitors for metaplasia in the stomach. Gastroenterology 2010, 139, 2028-2037 e2029.
84. Huh,W.J.; Khurana, S.S.; Geahlen, J.H.; Kohli, K.;Waller, R.A.; Mills, J.C. Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach. Gastroenterology 2012, 142, 21-24.
85. Burclaff, J.; Osaki, L.H.; Liu, D.; Goldenring, J.R.; Mills, J.C. Targeted apoptosis of parietal cells is insufficient to induce metaplasia in stomach. Gastroenterology 2016, 152, 762-766.
86. Petersen, C.P.; Weis, V.G.; Nam, K.T.; Sousa, J.F.; Fingleton, B.; Goldenring, J.R. Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells. Gastroenterology 2014, 146, 1727-1738.
87. Petersen, C.P.; Meyer, A.R.; DeSalvo, C.; Choi, E.; Schlegel, C.; Petersen, A.; Engevik, A.C.; Prasad, N.; Levy, S.E.; Peebles, R.S.; et al. A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut 2017.
88. Choi, E.; Lantz, T.L.; Vlacich, G.; Keeley, T.M.; Samuelson, L.C.; Coffey, R.J.; Goldenring, J.R.; Powell, A.E. Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 2017.
89. Menheniott, T.R.; O’Connor, L.; Chionh, Y.T.; Dabritz, J.; Scurr, M.; Rollo, B.N.; Ng, G.Z.; Jacobs, S.; Catubig, A.; Kurklu, B.; et al. Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression. J. Clin. Investig. 2016, 126, 1383-1400.
90. G12D mice. Gastroenterology 2017, 152, 2078-2079.
91. Hayakawa, Y.; Fox, J.G.;Wang, T.C. The origins of gastric cancer from gastric stem cells: Lessons from mouse models. Cell. Mol. Gastroenterol. Hepatol. 2017, 3, 331-338.
92. Mills, J.C.; Goldenring, J.R. Metaplasia in the stomach arises from gastric chief cells. CMGH 2017, 4, 85-88.
93. Spechler, S.J.; Merchant, J.L.; Wang, T.C.; Chandrasoma, P.; Fox, J.G.; Genta, R.M.; Goldenring, J.R.; Hayakawa, Y.; Kuipers, E.J.; Lund, P.K.; et al. A summary of the 2016 james W. Freston conference of the american gastroenterological association: Intestinal metaplasia in the esophagus and stomach: Origins, differences, similarities and significance. Gastroenterology 2017, 153, e6-e13.
94. Nam, K.T.; O’Neal, R.L.; Coffey, R.J.; Finke, P.E.; Barker, N.; Goldenring, J.R. Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells. Gut 2012, 61, 1678-1685.
95. Westphalen, C.B.; Asfaha, S.; Hayakawa, Y.; Takemoto, Y.; Lukin, D.J.; Nuber, A.H.; Brandtner, A.; Setlik, W.; Remotti, H.; Muley, A.; et al. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J. Clin. Investig. 2014, 124, 1283-1295.
96. Liu, J.; Willet, S.G.; Bankaitis, E.D.; Xu, Y.; Wright, C.V.; Gu, G. Non-parallel recombination limits cre-loxP-based reporters as precise indicators of conditional genetic manipulation. Genesis 2013, 51, 436-442.
97. Polk, D.B.; Peek, R.M., Jr. Helicobacter pylori: Gastric cancer and beyond. Nat. Rev. Cancer 2010, 10, 403-414.
98. Backert, S.; Naumann,M. What a disorder: Proinflammatory signaling pathways induced by Helicobacter pylori. Trends Microbiol. 2010, 18, 479-486.
99. Backert, S.; Clyne, M.; Tegtmeyer, N. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell. Commun. Signal. 2011, 9, 28.
100. Hatakeyama, M. Helicobacter pylori CagA and gastric cancer: A paradigm for hit-and-run carcinogenesis. Cell. Host Microbe 2014, 15, 306-316.
101. Sue, S.; Shibata, W.; Maeda, S. Helicobacter pylori-induced signaling pathways contribute to intestinal metaplasia and gastric carcinogenesis. Biomed. Res. Int. 2015, 2015, 737621.
102. Amieva, M.; Peek, R.M., Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology 2016, 150, 64-78.
103. Bartfeld, S.; Bayram, T.; van de Wetering, M.; Huch, M.; Begthel, H.; Kujala, P.; Vries, R.; Peters, P.J.; Clevers, H. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 2015, 148, 126-136.
104. Blaser, M.J.; Perez-Perez, G.I.; Kleanthous, H.; Cover, T.L.; Peek, R.M.; Chyou, P.H.; Stemmermann, G.N.; Nomura, A. Infection with Helicobacter pylori strains possessing CagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995, 55, 2111-2115.
105. Ogura, K.; Maeda, S.; Nakao, M.;Watanabe, T.; Tada, M.; Kyutoku, T.; Yoshida, H.; Shiratori, Y.; Omata, M. Virulence factors of Helicobacter pylori responsible for gastric diseases in mongolian gerbil. J. Exp. Med. 2000, 192, 1601-1610.
106. Censini, S.; Lange, C.; Xiang, Z.; Crabtree, J.E.; Ghiara, P.; Borodovsky, M.; Rappuoli, R.; Covacci, A. cag, A pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA 1996, 93, 14648-14653.
107. Backert, S.; Ziska, E.; Brinkmann, V.; Zimny-Arndt, U.; Fauconnier, A.; Jungblut, P.R.; Naumann, M.; Meyer, T.F. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type iv secretion apparatus. Cell. Microbiol 2000, 2, 155-164.
108. Odenbreit, S.; Puls, J.; Sedlmaier, B.; Gerland, E.; Fischer, W.; Haas, R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 2000, 287, 1497-1500.
109. Hirata, Y.; Maeda, S.; Mitsuno, Y.; Tateishi, K.; Yanai, A.; Akanuma, M.; Yoshida, H.; Kawabe, T.; Shiratori, Y.; Omata, M. Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation. Gastroenterology 2002, 123, 1962-1971.
110. Mitsuno, Y.; Yoshida, H.; Maeda, S.; Ogura, K.; Hirata, Y.; Kawabe, T.; Shiratori, Y.; Omata, M. Helicobacter pylori induced transactivation of SRE and AP-1 through the ERK signalling pathway in gastric cancer cells. Gut 2001, 49, 18-22.
111. Higashi, H.; Tsutsumi, R.; Muto, S.; Sugiyama, T.; Azuma, T.; Asaka, M.; Hatakeyama, M. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 2002, 295, 683-686.
112. Saito, Y.; Murata-Kamiya, N.; Hirayama, T.; Ohba, Y.; Hatakeyama, M. Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21. J. Exp. Med. 2010, 207, 2157-2174.
113. Hirata, Y.; Maeda, S.; Mitsuno, Y.; Akanuma, M.; Yamaji, Y.; Ogura, K.; Yoshida, H.; Shiratori, Y.; Omata, M. Helicobacter pylori activates the cyclin D1 gene through mitogen-activated protein kinase pathway in gastric cancer cells. Infect. Immun. 2001, 69, 3965-3971.
114. Ohnishi, N.; Yuasa, H.; Tanaka, S.; Sawa, H.; Miura, M.; Matsui, A.; Higashi, H.; Musashi, M.; Iwabuchi, K.; Suzuki, M.; et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc. Natl. Acad. Sci. USA 2008, 105, 1003-1008.
115. Basu, S.; Pathak, S.K.; Chatterjee, G.; Pathak, S.; Basu, J.; Kundu, M. Helicobacter pylori protein HP0175 transactivates epidermal growth factor receptor through TLR4 in gastric epithelial cells. J. Biol. Chem. 2008, 283, 32369-32376.
116. Sierra, J.C.; Asim, M.; Verriere, T.G.; Piazuelo, M.B.; Suarez, G.; Romero-Gallo, J.; Delgado, A.G.; Wroblewski, L.E.; Barry, D.P.; Peek, R.M., Jr.; et al. Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 2017.
117. Franco, A.T.; Israel, D.A.; Washington, M.K.; Krishna, U.; Fox, J.G.; Rogers, A.B.; Neish, A.S.; Collier-Hyams, L.; Perez-Perez, G.I.; Hatakeyama, M.; et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc. Natl. Acad. Sci. USA 2005, 102, 10646-10651.
118. Murata-Kamiya, N.; Kurashima, Y.; Teishikata, Y.; Yamahashi, Y.; Saito, Y.; Higashi, H.; Aburatani, H.; Akiyama, T.; Peek, R.M., Jr.; Azuma, T.; et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the _-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene 2007, 26, 4617-4626.
119. Bronte-Tinkew, D.M.; Terebiznik, M.; Franco, A.; Ang, M.; Ahn, D.; Mimuro, H.; Sasakawa, C.; Ropeleski, M.J.; Peek, R.M., Jr.; Jones, N.L. Helicobacter pylori cytotoxin-associated gene a activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo. Cancer Res. 2009, 69, 632-639.
120. Lee, I.O.; Kim, J.H.; Choi, Y.J.; Pillinger, M.H.; Kim, S.Y.; Blaser, M.J.; Lee, Y.C. Helicobacter pylori CagA phosphorylation status determines the GP130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. J. Biol. Chem. 2010, 285, 16042-16050.
121. Hayakawa, Y.; Hirata, Y.; Kinoshita, H.; Sakitani, K.; Nakagawa, H.; Nakata, W.; Takahashi, R.; Sakamoto, K.; Maeda, S.; Koike, K. Differential roles of ASK1 and TAK1 in Helicobacter pylori-induced cellular responses. Infect. Immun. 2013, 81, 4551-4560.
122. Segal, E.D.; Cha, J.; Lo, J.; Falkow, S.; Tompkins, L.S. Altered states: Involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc. Natl. Acad. Sci. USA 1999, 96, 14559-14564.
123. Amieva, M.R.; Vogelmann, R.; Covacci, A.; Tompkins, L.S.; Nelson, W.J.; Falkow, S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 2003, 300, 1430-1434.
124. Saadat, I.; Higashi, H.; Obuse, C.; Umeda, M.; Murata-Kamiya, N.; Saito, Y.; Lu, H.; Ohnishi, N.; Azuma, T.; Suzuki, A.; et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 2007, 447, 330-333.
125. Hirata, Y.; Ohmae, T.; Shibata, W.; Maeda, S.; Ogura, K.; Yoshida, H.; Kawabe, T.; Omata, M. MyD88 and tnf receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. J. Immunol 2006, 176, 3796-3803.
126. Hayakawa, Y.; Hirata, Y.; Nakagawa, H.; Sakamoto, K.; Hikiba, Y.; Kinoshita, H.; Nakata, W.; Takahashi, R.; Tateishi, K.; Tada, M.; et al. Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer. Proc. Natl. Acad. Sci. USA 2011, 108, 780-785.
127. Hayakawa, Y.; Hirata, Y.; Sakitani, K.; Nakagawa, H.; Nakata,W.; Kinoshita, H.; Takahashi, R.; Takeda, K.; Ichijo, H.; Maeda, S.; et al. Apoptosis signal-regulating kinase-1 inhibitor as a potent therapeutic drug for the treatment of gastric cancer. Cancer Sci 2012, 103, 2181-2185.
128. Shibata,W.; Maeda, S.; Hikiba, Y.; Yanai, A.; Sakamoto, K.; Nakagawa, H.; Ogura, K.; Karin, M.; Omata, M. C-Jun NH2-terminal kinase 1 is a critical regulator for the development of gastric cancer in mice. Cancer Res. 2008, 68, 5031-5039.
129. Kawahara, T.; Teshima, S.; Kuwano, Y.; Oka, A.; Kishi, K.; Rokutan, K. Helicobacter pylori lipopolysaccharide induces apoptosis of cultured guinea pig gastric mucosal cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 281, G726-734.
130. Keates, S.; Hitti, Y.S.; Upton, M.; Kelly, C.P. Helicobacter pylori infection activates NF-_ B in gastric epithelial cells. Gastroenterology 1997, 113, 1099-1109.
131. Maeda, S.; Akanuma, M.; Mitsuno, Y.; Hirata, Y.; Ogura, K.; Yoshida, H.; Shiratori, Y.; Omata, M. Distinct mechanism of Helicobacter pylori-mediated NF-_ B activation between gastric cancer cells and monocytic cells. J. Biol. Chem. 2001, 276, 44856-44864.
132. Brandt, S.; Kwok, T.; Hartig, R.; Konig, W.; Backert, S. Nf-kappab activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc. Natl. Acad. Sci. USA 2005, 102, 9300-9305.
133. Lamb, A.; Yang, X.D.; Tsang, Y.H.; Li, J.D.; Higashi, H.; Hatakeyama, M.; Peek, R.M.; Blanke, S.R.; Chen, L.F. Helicobacter pylori CagA activates NF-_B by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination. EMBO Rep. 2009, 10, 1242-1249.
134. Nakata,W.; Hayakawa, Y.; Nakagawa, H.; Sakamoto, K.; Kinoshita, H.; Takahashi, R.; Hirata, Y.; Maeda, S.; Koike, K. Anti-tumor activity of the proteasome inhibitor bortezomib in gastric cancer. Int. J. Oncol. 2011, 39, 1529-1536.
135. Sakitani, K.; Hirata, Y.; Hayakawa, Y.; Serizawa, T.; Nakata,W.; Takahashi, R.; Kinoshita, H.; Sakamoto, K.; Nakagawa, H.; Akanuma, M.; et al. Role of interleukin-32 in Helicobacter pylori-induced gastric inflammation. Infect. Immun. 2012, 80, 3795-3803.
136. Varro, A.; Noble, P.J.; Pritchard, D.M.; Kennedy, S.; Hart, C.A.; Dimaline, R.; Dockray, G.J. Helicobacter pylori induces plasminogen activator inhibitor 2 in gastric epithelial cells through nuclear factor-_B and RhoA:Implications for invasion and apoptosis. Cancer Res. 2004, 64, 1695-1702.
137. Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015, 517, 576-582.
138. Zhou, J.; Hayakawa, Y.;Wang, T.C.; Bass, A.J. RhoA mutations identified in diffuse gastric cancer. Cancer Cell 2014, 26, 9-11.
139. Wang, K.; Yuen, S.T.; Xu, J.; Lee, S.P.; Yan, H.H.; Shi, S.T.; Siu, H.C.; Deng, S.; Chu, K.M.; Law, S.; et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 2014, 46, 573-582.
140. Kakiuchi, M.; Nishizawa, T.; Ueda, H.; Gotoh, K.; Tanaka, A.; Hayashi, A.; Yamamoto, S.; Tatsuno, K.; Katoh, H.; Watanabe, Y.; et al. Recurrent gain-of-function mutations of RhoA in diffuse-type gastric carcinoma. Nat. Genet. 2014, 46, 583-587.
141. Hirata, Y.; Maeda, S.; Ohmae, T.; Shibata, W.; Yanai, A.; Ogura, K.; Yoshida, H.; Kawabe, T.; Omata, M. Helicobacter pylori induces I_B kinase _ nuclear translocation and chemokine production in gastric epithelial cells. Infect. Immun. 2006, 74, 1452-1461.
142. Maeda, S.; Yoshida, H.; Ogura, K.; Mitsuno, Y.; Hirata, Y.; Yamaji, Y.; Akanuma, M.; Shiratori, Y.; Omata, M. H. Pylori activates through a signaling pathway involving ikappab kinases, NF-kB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology 2000, 119, 97-108.
143. Shibata, W.; Hirata, Y.; Maeda, S.; Ogura, K.; Ohmae, T.; Yanai, A.; Mitsuno, Y.; Yamaji, Y.; Okamoto, M.; Yoshida, H.; et al. Caga protein secreted by the intact type IV secretion system leads to gastric epithelial inflammation in the mongolian gerbil model. J. Pathol. 2006, 210, 306-314.
144. Torok, A.M.; Bouton, A.H.; Goldberg, J.B. Helicobacter pylori induces interleukin-8 secretion by toll-like receptor 2- and toll-like receptor 5-dependent and -independent pathways. Infect. Immun. 2005, 73, 1523-1531.
145. Smith, M.F., Jr.; Mitchell, A.; Li, G.; Ding, S.; Fitzmaurice, A.M.; Ryan, K.; Crowe, S.; Goldberg, J.B. Toll-like receptor (TLR) 2 and TLR 5, but not TLR 4, are required for Helicobacter pylori-induced NF-_B activation and chemokine expression by epithelial cells. J. Biol. Chem. 2003, 278, 32552-32560.
146. Viala, J.; Chaput, C.; Boneca, I.G.; Cardona, A.; Girardin, S.E.; Moran, A.P.; Athman, R.; Memet, S.; Huerre, M.R.; Coyle, A.J.; et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol 2004, 5, 1166-1174.
147. Shibata,W.; Takaishi, S.; Muthupalani, S.; Pritchard, D.M.; Whary, M.T.; Rogers, A.B.; Fox, J.G.; Betz, K.S.; Kaestner, K.H.; Karin, M.; et al. Conditional deletion of I_B-kinase-_ accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia. Gastroenterology 2010, 138, 1022-1034.
148. Sakamoto, K.; Hikiba, Y.; Nakagawa, H.; Hayakawa, Y.; Yanai, A.; Akanuma, M.; Ogura, K.; Hirata, Y.; Kaestner, K.H.; Omata, M.; et al. Inhibitor of kB kinase β regulates gastric carcinogenesis via interleukin-1α expression. Gastroenterology 2010, 139, 226-238 e226.
149. Niwa, T.; Tsukamoto, T.; Toyoda, T.; Mori, A.; Tanaka, H.; Maekita, T.; Ichinose, M.; Tatematsu, M.; Ushijima, T. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010, 70, 1430-1440.
150. O’Gorman, A.; Colleran, A.; Ryan, A.; Mann, J.; Egan, L.J. Regulation of NF-_B responses by epigenetic suppression of I expression in HCT116 intestinal epithelial cells. Am. J. Physiol Gastrointest Liver Physiol 2010, 299, G96-G105.
151. Houghton, J.; Stoicov, C.; Nomura, S.; Rogers, A.B.; Carlson, J.; Li, H.; Cai, X.; Fox, J.G.; Goldenring, J.R.; Wang, T.C. Gastric cancer originating from bone marrow-derived cells. Science 2004, 306, 1568-1571.
152. Hayakawa, Y.; Sakitani, K.; Konishi, M.; Asfaha, S.; Niikura, R.; Tomita, H.; Renz, B.W.; Tailor, Y.; Macchini, M.; Middelhoff, M.; et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 2017, 31, 21-34.
153. Zhao, C.M.; Hayakawa, Y.; Kodama, Y.; Muthupalani, S.; Westphalen, C.B.; Andersen, G.T.; Flatberg, A.; Johannessen, H.; Friedman, R.A.; Renz, B.W.; et al. Denervation suppresses gastric tumorigenesis. Sci. Transl. Med. 2014.
154. Rabben, H.L.; Zhao, C.M.; Hayakawa, Y.; Wang, T.C.; Chen, D. Vagotomy and gastric tumorigenesis. Curr. Neuropharmacol. 2016, 14, 967-972.
155. Quante, M.; Tu, S.P.; Tomita, H.; Gonda, T.; Wang, S.S.; Takashi, S.; Baik, G.H.; Shibata, W.; Diprete, B.; Betz, K.S.; et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011, 19, 257-272.