Gastric cancer - Molecular and clinical dimensions

Nature Reviews Clinical Oncology

Volumn 10, Issue 11, 2013, Pages 643-655

  Wadhwa, Roopma ^a   Song, Shumei ^a   Lee, Ju Seog ^a   Yao, Yixin ^a   Wei, Qingyi ^a   Ajani, Jaffer A ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BEVACIZUMAB; CAPECITABINE; CISPLATIN; DOCETAXEL; EPIRUBICIN; EVEROLIMUS; FLUOROPYRIMIDINE; FLUOROURACIL; FOLINIC ACID; GIMERACIL PLUS OTERACIL POTASSIUM PLUS TEGAFUR; IRINOTECAN; LAPATINIB; MICRORNA; MICRORNA 101; MICRORNA 10B; MICRORNA 145; MICRORNA 146A; MICRORNA 200C; MICRORNA 20A; MICRORNA 221; MICRORNA 296 5P; OXALIPLATIN; PACLITAXEL; PANITUMUMAB; PLACEBO; RAMUCIRUMAB; SCATTER FACTOR RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TRASTUZUMAB; UNCLASSIFIED DRUG;

ADJUVANT CHEMORADIOTHERAPY; ADVANCED CANCER; CAGA GENE; CANCER CHEMOTHERAPY; CANCER LOCALIZATION; CANCER RESISTANCE; CANCER RISK; CANCER STEM CELL; CARCINOGENESIS; CELL RENEWAL; DIGESTIVE SYSTEM TUMOR; EPITHELIAL MESENCHYMAL TRANSITION; GASTRECTOMY; GASTROESOPHAGEAL CANCER; GENE FUNCTION; GENETIC ASSOCIATION; HELICOBACTER INFECTION; HUMAN; ONCOGENE; PERIOPERATIVE PERIOD; PLCE1 GENE; POSTOPERATIVE CARE; PREOPERATIVE CARE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; RISK FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM; STOMACH CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; STOMACH NEOPLASMS;

EID: 84887405673     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2013.170     Document Type: Review

References (222)

1. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69-90 (2011
2. National Cancer Institute at the National Institutes of Health. Cellular Classification of Gastric Cancer[online], http://www.cancer.gov/cancertopics/ pdq/treatment/gastric/HealthProfessional/page2 (2013
3. Bertuccio, P. et al. Recent patterns in gastric cancer: A global overview. Int. J. Cancer 125, 666-673 (2009
4. Chen, J., Bu, X. L., Wang, Q. Y., Hu, P. J. & Chen, M. H. Decreasing seroprevalence of Helicobacter pylori infection during 1993-2003 in Guangzhou, southern China. Helicobacter 12, 164-169 (2007
5. Kawakami, E., Machado, R. S., Ogata, S. K. & Langner, M. Decrease in prevalence of Helicobacter pylori infection during a 10-year period in Brazilian children. Arq. Gastroenterol. 45, 147-151 (2008
6. Tkachenko, M. A. et al. Dramatic changes in the prevalence of Helicobacter pylori infection during childhood: A 10-year follow-up study in Russia. J. Pediatr. Gastroenterol. Nutr. 45, 428-432 (2007
7. Lee, K. J. et al. Gastric cancer screening and subsequent risk of gastric cancer: A large-scale population-based cohort study, with a 13-year follow-up in Japan. Int. J. Cancer 118, 2315-2321 (2006
8. Parkin, D. M. The global health burden of infection associated cancers in the year 2002. Int. J. Cancer 118, 3030-3044 (2006
9. Axon, A. Review article: Gastric cancer and Helicobacter pylori. Aliment. Pharmacol. Ther. 16 (Suppl4), 83-88 (2002
10. Kim, S. S., Ruiz, V. E., Carroll, J. D. & Moss, S. F. Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Lett. 305, 228-238 (2011
11. Conteduca, V. et al. H. pylori infection and gastric cancer: State of the art (review). Int. J. Oncol. 42, 5-18 (2013
12. Rizzato, C. et al. Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status. Int. J. Cancer 133, 315-322 (2013
13. Correa, P. & Houghton, J. Carcinogenesis of Helicobacter pylori. Gastroenterology 133, 659-672 (2007
14. Tsugawa, H. et al. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 12, 764-777 (2012
15. Pimentel-Nunes, P. et al. Helicobacter pylori induces increased expression of Toll-like receptors and decreased toll-interacting protein in gastric mucosa that persists throughout gastric carcinogenesis. Helicobacter 18, 22-32 (2013
16. Peek, R. M. Jr et al. Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. J. Natl Cancer Inst. 89, 863-868 (1997
17. Graham, D. Y. & Yamaoka, Y. H. pylori and cagA: Relationships with gastric cancer, duodenal ulcer, and reflux esophagitis and its complications. Helicobacter 3, 145-151 (1998
18. Hatakeyama, M. Helicobacter pylori cagA - A potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes Infect. 5, 143-150 (2003
19. Mueller, D. et al. c Src and c Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J. Clin. Invest. 122, 1553-1566 (2012
20. Müller, A. Multistep activation of the Helicobacter pylori effector CagA. J. Clin. Invest. 122, 1192-1195 (2012
21. Higashi, H. et al. SHP 2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295, 683-686 (2002
22. Meyer ter Vehn, T., Covacci, A., Kist, M. & Pahl, H. L. Helicobacter pylori activates mitogen-activated protein kinase cascades and induces expression of the proto-oncogenes c fos and c jun. J. Biol. Chem. 275, 16064-16072 (2000
23. Schirrmeister, W. et al. Ectodomain shedding of E cadherin and c Met is induced by Helicobacter pylori infection. Exp. Cell Res. 315, 3500-3508 (2009
24. Murata-Kamiya, N. et al. Helicobacter pylori cagA interacts with E cadherin and deregulates the β catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene 26, 4617-4626 (2007
25. Suzuki, M. et al. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J. Exp. Med. 202, 1235-1247 (2005
26. Hatakeyama, M. Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor cagA. Oncogene 27, 7047-7054 (2008
27. Bartchewsky, W. Jr et al. Effect of Helicobacter pylori infection on IL 8, IL 1β and COX 2 expression in patients with chronic gastritis and gastric cancer. Scand. J. Gastroenterol. 44, 153-161 (2009
28. Li, C. Q., Pignatelli, B. & Ohshima, H. Coexpression of interleukin 8 and inducible nitric oxide synthase in gastric mucosa infected with cagA+ Helicobacter pylori. Dig. Dis. Sci. 45, 55-62 (2000
29. Suganuma, M. et al. TNF α inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells. Int. J. Cancer 123, 117-122 (2008
30. Brandt, S., Kwok, T., Hartig, R., Konig, W. & Backert, S. NF κB activation and potentiation of proinflammatory responses by the Helicobacter pylori cagA protein. Proc. Natl Acad. Sci. USA 102, 9300-9305 (2005
31. Rad, R. et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin 1 polymorphisms for the development of severe histological changes in the gastric mucosa. J. Infect. Dis. 188, 272-281 (2003
32. Zambon, C. F. et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: Interactions influence outcome. Cytokine 29, 141-152 (2005
33. Chang, Y. J. et al. Induction of cyclooxygenase 2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c Src dependent nuclear factor-κB activation. Mol. Pharmacol. 66, 1465-1477 (2004
34. Walduck, A. K. et al. Identification of novel cyclooxygenase 2 dependent genes in Helicobacter pylori infection in vivo. Mol. Cancer 8, 22 (2009
35. Seo, J. H., Kim, H. & Kim, K. H. Cyclooxygenase 2 expression by transcription factors in Helicobacter pylori-infected gastric epithelial cells: Comparison between HP 99 and NCTC 11637. Ann. NY Acad. Sci. 973, 477-480 (2002
36. Liu, A. Q., Ge, L. Y., Ye, X. Q., Luo, X. L. & Luo, Y. Reduced FAF1 expression and Helicobacter infection: Correlations with clinicopathological features in gastric cancer. Gastroenterol. Res. Pract. 2012, 153219 (2012
37. Wang, G. et al. Involvement of aquaporin 3 in Helicobacter pylori-related gastric diseases. PLoS ONE 7, e49104 (2012
38. Tamura, G. et al. E cadherin gene promoter hypermethylation in primary human gastric carcinomas. J. Natl Cancer Inst. 92, 569-573 (2000
39. Becker, K. F. & Höfler, H. Frequent somatic allelic inactivation of the E cadherin gene in gastric carcinomas. J. Natl Cancer Inst. 87, 1082-1084 (1995
40. Peterson, A. J. et al. Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans. Gastroenterology 139, 2005-2017 (2010
41. Katayama, Y., Takahashi, M. & Kuwayama, H. Helicobacter pylori causes RUNX3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem. Biophys. Res. Commun. 388, 496-500 (2009
42. Yoshida, T. et al. Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis. Gastric Cancer http://dx.doi.org/10.1007/s10120 012 0230 x.
43. Matsumoto, Y. et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat. Med. 13, 470-476 (2007
44. Holcombe, C. Helicobacter pylori: The African enigma. Gut 33, 429-431 (1992
45. Guilford, P. et al. E cadherin germline mutations in familial gastric cancer. Nature 392, 402-405 (1998
46. Huntsman, D. G. et al. Early gastric cancer in young, asymptomatic carriers of germ-line E cadherin mutations. N. Engl. J. Med. 344, 1904-1909 (2001
47. Hu, Z., Ajani, J. A. & Wei, Q. Molecular epidemiology of gastric cancer: Current status and future prospects. Gastrointest. Cancer Res. 1, 12-19 (2007
48. Wang, L. D. et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat. Genet. 42, 759-763 (2010
49. Study Group of Millennium Genome Project for Cancer. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat. Genet. 40, 730-740 (2008
50. Wang, T., Zhang, L., Li, H., Wang, B. & Chen, K. Prostate stem cell antigen polymorphisms and susceptibility to gastric cancer: A systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 21, 843-850 (2012
51. Saeki, N., Gu, J., Yoshida, T. & Wu, X. Prostate stem cell antigen: A Jekyll and Hyde molecule? Clin. Cancer Res. 16, 3533-3538 (2010
52. Abnet, C. C. et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat. Genet. 42, 764-767 (2010
53. Zhang, H. et al. Genetic variants at 1q22 and 10q23 reproducibly associated with gastric cancer susceptibility in a Chinese population. Carcinogenesis 32, 848-852 (2011
54. Wang, M. et al. Potentially functional variants of PLCE1 identified by GWASs contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population. PLoS ONE 7, e31932 (2012
55. Luo, D. et al. Genetic variation in PLCE1 is associated with gastric cancer survival in a Chinese population. J. Gastroenterol. 46, 1260-1266 (2011
56. Palmer, A. J. et al. Genetic variation in C20orf54, PLCE1 and MUC1 and the risk of upper gastrointestinal cancers in Caucasian populations. Eur. J. Cancer Prev. 21, 541-544 (2012
57. Shi, Y. et al. A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1. Nat. Genet. 43, 1215-1218 (2011
58. Wu, K. C. et al. Molecular basis of therapeutic approaches to gastric cancer. J. Gastroenterol. Hepatol. 24, 37-41 (2009
59. Wong, H & Yau, T. Targeted therapy in the management of advanced gastric cancer: Are we making progress in the era of personalized medicine? Oncologist 17, 346-358 (2012
60. Schneider, B. G. et al. Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Int. J. Cancer 127, 2588-2597 (2010
61. Markman, B., Dienstmann, R. & Tabernero, J. Targeting the PI3K/Akt/mTOR pathway - Beyond rapalogs. Oncotarget 1, 530-543 (2010
62. Chalhoub, N. & Baker, S. J. PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol. 4, 127-150 (2009
63. Bergfeld, S. A. & DeClerck, Y. A. Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Rev. 29, 249-261 (2010
64. Takaishi, S., Okumura, T. & Wang, T. C. Gastric cancer stem cells. J. Clin. Oncol. 26, 2876-2882 (2008
65. Chen, C. N. et al. Gene expression profile predicts patient survival of gastric cancer after surgical resection. J. Clin. Oncol. 23, 7286-7295 (2005
66. Cho, J. Y. et al. Gene expression signature-based prognostic risk score in gastric cancer. Clin. Cancer Res. 17, 1850-1857 (2011
67. Deng, N. et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61, 673-684 (2012
68. Ivanova, T. et al. Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut 62, 22-33 (2013
69. Kim, H. K. et al. A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients. PLoS ONE 6, e16694 (2011
70. Kim, H. K. et al. Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy. Pharmacogenomics J. 12, 119-127 (2012
71. Ooi, C. H. et al. Oncogenic pathway combinations predict clinical prognosis in gastric cancer. PLoS Genet. 5, e1000676 (2009
72. Takeno, A. et al. Gene expression profile prospectively predicts peritoneal relapse after curative surgery of gastric cancer. Ann. Surg. Oncol. 17, 1033-1042 (2010
73. Tan, I. B. et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 141, 476-485 (2011
74. Wu, Y. et al. Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer. Gut 26, 1100-1111 (2013
75. Zang, Z. J. et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat. Genet. 44, 570-574 (2012
76. Zouridis, H. et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci. Transl. Med. 4, 156ra140 (2012
77. Tan, D. S., Gerlinger, M., Teh, B. T. & Swanton, C. Anti-cancer drug resistance: Understanding the mechanisms through the use of integrative genomics and functional RNA interference. Eur. J. Cancer 46, 2166-2177 (2010
78. Subramaniam, D., Ramalingam, S., Houchen, C. W. & Anant, S. Cancer stem cells: A novel paradigm for cancer prevention and treatment. Mini Rev. Med. Chem. 10, 359-371 (2010
79. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008
80. Peacock, C. D. & Watkins, D. N. Cancer stem cells and the ontogeny of lung cancer. J. Clin. Oncol. 26, 2883-2889 (2008
81. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415-428 (2007
82. Voutsadakis, I. A. The ubiquitin-proteasome system and signal transduction pathways regulating epithelial mesenchymal transition of cancer. J. Biomed. Sci. 19, 67 (2012
83. Li, Y. Q. et al. c Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc. Natl Acad. Sci. USA 108, 9951-9956 (2011
84. Roberts, A. B. & Wakefield, L. M. The two faces of transforming growth factor β in carcinogenesis. Proc. Natl Acad. Sci. USA 100, 8621-8623 (2003
85. Bierie, B. & Moses, H. L. TGFβ: The molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506-520 (2006
86. Watabe, T. & Miyazono, K. Roles of TGF β family signaling in stem cell renewal and differentiation. Cell Res. 19, 103-115 (2009
87. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 29, 4741-4751 (2010
88. Zhou, J. B. et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc. Natl Acad. Sci. USA 104, 16158-16163 (2007
89. Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507-7511 (2009
90. Singh, B. N., Fu, J., Srivastava, R. K. & Shankar, S. Hedgehog signaling antagonist GDC 0449 (vismodegib) inhibits pancreatic cancer stem cell characteristics: Molecular mechanisms. PLoS ONE 6, e27306 (2011
91. Heindl, S. et al. Relevance of MET activation and genetic alterations of KRAS and E cadherin for cetuximab sensitivity of gastric cancer cell lines. J. Cancer Res. Clin. Oncol. 138, 843-858 (2012
92. Komuro, A. et al. Diffuse-type gastric carcinoma: Progression, angiogenesis, and transforming growth factor β signaling. J. Natl Cancer Inst. 101, 592-604 (2009
93. Ebi, M., Kataoka, H., Higashiyama, S. & Joh, T. TGFβ induces EGFR transactivation and HB EGF C terminal fragment nuclear translocation through ADAM17 activation in gastric cancer cells. Gastroenterology 140 (Suppl1), S629 (2011
94. Kang, M. H. et al. Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion. Oncol. Rep. 22, 525-534 (2009
95. Takahashi, Y. et al. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin. Cancer Res. 2, 1679-1684 (1996
96. Sharma, V. K., Vasudeva, R. & Howden, C. W. Changing demographics of gastric cancer: 15 year experience. Gastroenterology 114 (Suppl1), A40 (1998
97. Takaishi, S. et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27, 1006-1020 (2009
98. Ishimoto, T. et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc () and thereby promotes tumor growth. Cancer Cell 19, 387-400 (2011
99. Fornaro, L. et al. Anti-HER agents in gastric cancer: From bench to bedside. Nat. Rev. Gastroenterol. Hepatol. 8, 369-383 (2011
100. Schlessinger, J. Common and distinct elements in cellular signaling via EGF and FGF receptors. Science 306, 1506-1507 (2004
101. Dhanasekaran, D. N. & Johnson, G. L. MAPKs: Function, regulation, role in cancer and therapeutic targeting. Oncogene 26, 3097-3099 (2007
102. Lordick, F. et al. HER2 status of advanced gastric cancer is similar in Europe and Asia[abstract 253]. Ann. Oncol. 18 (Suppl7), vii95-vii96 (2007
103. Zhang, X. L. et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J. Surg. 33, 2112-2118 (2009
104. Terashima, M. et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin. Cancer Res. 18, 5992-6000 (2012
105. Browne, B. C. et al. Inhibition of IGF1R activity enhances response to trastuzumab in HER 2 positive breast cancer cells. Ann. Oncol. 22, 68-73 (2011
106. Wilkinson, N. W. et al. Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adenocarcinoma. J. Gastrointest. Surg. 8, 448-453 (2004
107. Isinger-Ekstrand, A. et al. Genetic profiles of gastroesophageal cancer: Combined analysis using expression array and tiling array-comparative genomic hybridization. Cancer Genet. Cytogenet. 200, 120-126 (2010
108. Moutinho, C. et al. Epidermal growth factor receptor structural alterations in gastric cancer. BMC Cancer 8, 10 (2008
109. Liu, Z. M. et al. Epidermal growth factor receptor mutation in gastric cancer. Pathology 43, 234-238 (2011
110. Pinto, C. et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br. J. Cancer 101, 1261-1268 (2009
111. Jaiswal, B. S. et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23, 603-617 (2013
112. Migliore, C. & Giordano, S. Molecular cancer therapy: Can our expectation be MET? Eur. J. Cancer 44, 641-651 (2008
113. El-Rifai, W. & Powell, S. M. Molecular biology of gastric cancer. Semin. Radiat. Oncol. 12, 128-140 (2002
114. Smolen, G. A. et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA 665752. Proc. Natl Acad. Sci. USA 103, 2316-2321 (2006
115. Janjigian, Y. Y. et al. MET expression and amplification in patients with localized gastric cancer. Cancer Epidemiol. Biomarkers Prev. 20, 1021-1027 (2011
116. Lee, J. et al. Impact of MET amplification on gastric cancer: Possible roles as a novel prognostic marker and a potential therapeutic target. Oncol. Rep. 25, 1517-1524 (2011
117. Guo, A. et al. Signaling networks assembled by oncogenic EGFR and c Met. Proc. Natl Acad. Sci. USA 105, 692-697 (2008
118. Arteaga, C. L. HER3 and mutant EGFR meet MET. Nat. Med. 13, 675-677 (2007
119. Corso, S., Comoglio, P. M. & Giordano, S. Cancer therapy: Can the challenge be MET? Trends Mol. Med. 11, 284-292 (2005
120. Corso, S. et al. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol. Cancer 9, 121 (2010
121. Bachleitner-Hofmann, T. et al. HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells. Mol. Cancer Ther. 7, 3499-3508 (2008
122. Byun, D. S. et al. Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma. Int. J. Cancer 104, 318-327 (2003
123. Oki, E. et al. Impact of PTEN/AKT/PI3K signal pathway on the chemotherapy for gastric cancer[abstract 4034]. J. Clin. Oncol. 24 (Suppl18), 187s (2006
124. Garrett, J. T. et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc. Natl Acad. Sci. USA 108, 5021-5026 (2011
125. Shin, E. Y. et al. Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer. J. Cancer Res. Clin. Oncol. 126, 519-528 (2000
126. Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219-1223 (2011
127. Song, S. & Ajani, J. A. The role of microRNAs in cancers of the upper gastrointestinal tract. Nat. Rev. Gastroenterol. Hepatol. 10, 109-118 (2013
128. Li, T. et al. MicroRNA 296 5p increases proliferation in gastric cancer through repression of Caudal-related homeobox 1. Oncogene http://dx.doi.org/10. 1038/onc.2012.637
129. Wang, M. et al. Overexpressed miR 301a promotes cell proliferation and invasion by targeting RUNX3 in gastric cancer. J. Gastroenterol. http://dx.doi.org/10.1007/s00535 012 0733-6
130. Wang, M. et al. miR 17 5p/20a are important markers for gastric cancer and murine double minute 2 participates in their functional regulation. Eur. J. Cancer 49, 2010-2021 (2013
131. Wu, X. et al. MicroRNA expression signatures during malignant progression from Barrett's esophagus to esophageal adenocarcinoma. Cancer Prev. Res. (Phila.) 6, 196-205 (2013
132. Zhou, C. et al. microRNA 372 maintains oncogene characteristics by targeting TNFAIP1 and affects NFκB signaling in human gastric carcinoma cells. Int. J. Oncol. 42, 635-642 (2013
133. Zhi, Q. et al. Oncogenic miR 544 is an important molecular target in gastric cancer. Anticancer Agents Med. Chem. 13, 270-275 (2013
134. Wang, Y. Y. et al. Clinicopathologic significance of miR 10b expression in gastric carcinoma. Hum. Pathol. 44, 1278-1285 (2013
135. Deng, H. et al. MicroRNA 195 and microRNA 378 mediate tumor growth suppression by epigenetical regulation in gastric cancer. Gene 518, 351-359 (2013
136. Wen, D. et al. miR 133b acts as a tumor suppressor and negatively regulates FGFR1 in gastric cancer. Tumour Biol. 34, 793-803 (2013
137. Saito, Y. et al. The tumor suppressor microRNA 29c is downregulated and restored by celecoxib in human gastric cancer cells. Int. J. Cancer 132, 1751-1760 (2012
138. Cao, W. et al. Expression and regulatory function of miRNA 34a in targeting survivin in gastric cancer cells. Tumour Biol. 34, 963-971 (2012
139. Zheng, L. et al. miRNA 145 targets v ets erythroblastosis virus E26 oncogene homolog 1 to suppress the invasion, metastasis, and angiogenesis of gastric cancer cells. Mol. Cancer Res. 11, 182-193 (2013
140. Liu, K. et al. Decreased expression of microRNA let-7i and its association with chemotherapeutic response in human gastric cancer. World J. Surg. Oncol. 10, 225 (2012
141. Akiyoshi, S. et al. Clinical significance of miR 144 ZFX axis in disseminated tumour cells in bone marrow in gastric cancer cases. Br. J. Cancer 107, 1345-1353 (2012
142. He, X. P. et al. Downregulation of miR 101 in gastric cancer correlates with cyclooxygenase 2 overexpression and tumor growth. FEBS J. 279, 4201-4212 (2012
143. Crone, S. G. et al. microRNA 146a inhibits G. protein-coupled receptor-mediated activation of NF κB by targeting CARD10 and COPS8 in gastric cancer. Mol. Cancer 11, 71 (2012
144. Ichikawa, D., Komatsu, S., Konishi, H. & Otsuji, E. Circulating microRNA in digestive tract cancers. Gastroenterology 142, 1074-1078.e1 (2012
145. Cui, L. et al. Gastric juice microRNAs as potential biomarkers for the screening of gastric cancer. Cancer 119, 1618-1626 (2013
146. Zhang, X. et al. Gastric juice microRNA 421 is a new biomarker for screening gastric cancer. Tumour Biol. 33, 2349-2355 (2012
147. Cai, H. et al. Plasma microRNAs serve as novel potential biomarkers for early detection of gastric cancer. Med. Oncol. 30, 452 (2013
148. Li, C. et al. MiRNA 199a 3p in plasma as a potential diagnostic biomarker for gastric cancer. Ann. Surg. Oncol. http://dx.doi.org/10.1245/s10434 012 2600-3
149. Wang, M. et al. Circulating miR 17 5p and miR 20a: Molecular markers for gastric cancer. Mol. Med. Report 5, 1514-1520 (2012
150. Valladares-Ayerbes, M. et al. Circulating miR 200c as a diagnostic and prognostic biomarker for gastric cancer. J. Transl. Med. 10, 186 (2012
151. Stern, H. M. Improving treatment of HER2-positive cancers: Opportunities and challenges. Sci. Transl. Med. 4, 127rv2 (2012
152. Nahta, R. Molecular mechanisms of trastuzumab-based treatment in HER2-overexpressing breast cancer. ISRN Oncol. 2012, 428062 (2012
153. Kim, J. W. et al. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 272, 296-306 (2008
154. Lu, Y., Zi, X. & Pollak, M. Molecular mechanisms underlying IGF I induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int. J. Cancer 108, 334-341 (2004
155. Chen, C. T. et al. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol. Cancer Ther. 11, 660-669 (2012
156. Shattuck, D. L., Miller, J. K., Carraway, K. L. & Sweeney, C. Met receptor contributes to trastuzumab resistance of HER2-overexpressing breast cancer cells. Cancer Res. 68, 1471-1477 (2008
157. Molina, M. A. et al. Trastuzumab (herceptin), a humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744-4749 (2001
158. Nagy, P. et al. Decreased accessibility and lack of activation of ErbB2 in JIMT 1, a herceptin-resistant, MUC4-Expressing breast cancer cell line. Cancer Res. 65, 473-482 (2005
159. Gong, S. J., Jin, C. J., Rha, S. Y. & Chung, H. C. Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines. Cancer Lett. 214, 215-224 (2004
160. Arcaro, A. & Guerreiro, A. S. The phosphoinositide 3 kinase pathway in human cancer: Genetic alterations and therapeutic implications. Curr. Genomics 8, 271-306 (2007
161. Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351-1356 (2008
162. Eichhorn, P. J. et al. Phosphatidylinositol 3 kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/ phosphatidylinositol 3 kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221-9230 (2008
163. Korkaya, H. et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 47, 570-584 (2012
164. Shah, M. A. & Ajani, J. A. Gastric cancer - An enigmatic and heterogeneous disease. JAMA 303, 1753-1754 (2010
165. Bickenbach, K. & Strong, V. E. Comparisons of gastric cancer treatments: East vs West. J. Gastric Cancer 12, 55-62 (2012
166. Tamura, S., Takeno, A. & Miki, H. Lymph node dissection in curative gastrectomy for advanced gastric cancer. Int. J. Surg. Oncol. 2011, 748745 (2011
167. Macdonald, J. S. et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N. Engl. J. Med. 345, 725-730 (2001
168. Sakuramoto, S. et al. Adjuvant chemotherapy for gastric cancer with S 1, an oral fluoropyrimidine. N. Engl. J. Med. 357, 1810-1820 (2007
169. Bang, Y. J. et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): A phase 3 open-label, randomised controlled trial. Lancet 379, 315-321 (2012
170. Ajani, J. A. et al. Gastric cancer. J. Natl Compr. Canc. Netw. 8, 378-409 (2010
171. Lim, L., Michael, M., Mann, G. B. & Leong, T. Adjuvant therapy in gastric cancer. J. Clin. Oncol. 23, 6220-6232 (2005
172. Ychou, M. et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: An FNCLCC and FFCD multicenter phase III trial. J. Clin. Oncol. 29, 1715-1721 (2011
173. Paoletti, X. et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta-analysis. JAMA 303, 1729-1737 (2010
174. Cunningham, D. et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N. Engl. J. Med. 355, 11-20 (2006
175. Smalley, S. R. et al. Updated analysis of SWOG-directed intergroup study 0116: A phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J. Clin. Oncol. 30, 2327-2333 (2012
176. Fuchs, C. S. et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5 FU (ECF) before and after CI 5 FU and radiotherapy (CRT) compared with bolus 5 FU/LV before and after CRT: Intergroup trial CALGB 80101[abstract 4003]. J. Clin. Oncol. 29 (Suppl.), 4003 (2011
177. Lee, J. et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: The ARTIST trial. J. Clin. Oncol. 30, 268-273 (2012
178. Sasako, M. et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S 1 versus surgery alone in stage II or III gastric cancer. J. Clin. Oncol. 29, 4387-4393 (2011
179. Dikken, J. L. et al. Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS). BMC Cancer 11, 329 (2011
180. Van Cutsem, E. et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J. Clin. Oncol. 24, 4991-4997 (2006
181. Koizumi, W. et al. S 1 plus cisplatin versus S 1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): A phase III trial. Lancet Oncol. 9, 215-221 (2008
182. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376, 687-697 (2010
183. FDA. Trastuzumab. Office of Medical Products and Tobacco[online], http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ CDER/ucm230418.htm (2010
184. Lordick, F. et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol. 14, 490-499 (2013
185. Waddell, T. et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol. 14, 481-489 (2013
186. Ohtsu, A. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol. 29, 3968-3976 (2011
187. Van Cutsem, E. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A biomarker evaluation from the AVAGAST randomized phase III trial. J. Clin. Oncol. 30, 2119-2127 (2012
188. Ajani, J. A. et al. Multicenter phase III comparison of cisplatin/S 1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: The FLAGS trial. J. Clin. Oncol. 28, 1547-1553 (2010
189. Thuss-Patience, P. C. et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer- a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur. J. Cancer 47, 2306-2314 (2011
190. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT00879333 (2013
191. Everolimus for advanced gastric cancer: Results of the randomized,
192. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT00917384/ (2013
193. Fuchs, C. S. et al. REGARD: A phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy[abstract LBA5]. J. Clin. Oncol. 30 (Suppl34), LBA5 (2012
194. Ford, H. et al. Cougar 02: A randomized phase III study of docetaxel versus active symptom control in advanced esophagogastric adenocarcinoma[abstract LBA4]. J. Clin. Oncol. 30 (Suppl34), LBA4 (2012
195. Bang, Y. J. et al. A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study[abstract 11]. J. Clin. Oncol. 30 (Suppl34), 11 (2012
196. Lennerz, J. K. et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J. Clin. Oncol. 29, 4803-4810 (2011
197. Oliner, K. S. et al. Evaluation of MET pathway biomarkers in a phase II study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or esophagogastric junction (EGJ) cancer[abstract 4005]. J. Clin. Oncol. 30 (Suppl.), 4005 (2012
198. Hwang, J. Y. et al. Recapitulation of previous genome-wide association studies with two distinct pathophysiological entities of gastric cancer in the Korean population. J. Hum. Genet. 58, 233-235 (2013
199. Saeki, N. et al. A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer. Gastroenterology 140, 892-902 (2011
200. Gu, H. et al. Replication study of PLCE1 and C20orf54 polymorphism and risk of esophageal cancer in a Chinese population. Mol. Biol. Rep. 39, 9105-9111 (2012
201. Mammano, E. et al. Epidermal growth factor receptor (EGFR): Mutational and protein expression analysis in gastric cancer. Anticancer Res. 26, 3547-3550 (2006
202. Hong, S. P. et al. Overexpression of Notch 1 signaling associates with the tumorigenesis of gastric adenorna and intestinal type of gastric cancer. Gastroenterology 132, A617 (2007
203. Yu, G. Z. et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer. Clin. Cancer Res. 15, 1821-1829 (2009
204. Lang, S. A. et al. Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int. J. Cancer 120, 1803-1810 (2007
205. Zhou, Y. N. et al. Clinicopathological significance of E cadherin, VEGF, and MMPs in gastric cancer. Tumor Biol. 31, 549-558 (2010
206. Kitoh, T. et al. Increased expression of matrix metalloproteinase 7 in invasive early gastric cancer. J. Gastroenterol. 39, 434-440 (2004
207. Fukaya, M. et al. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology 131, 14-29 (2006
208. Hattori, Y. et al. Immunohistochemical detection of K sam protein in stomach cancer. Clin. Cancer Res. 2, 1373-1381 (1996
209. Pereira, P. S. et al. E cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia. Hum. Mol. Genet. 15, 1704-1712 (2006
210. Kobayashi, M., Kawashima, A., Mai, M. & Ooi, A. Analysis of chromosome 17p13 (p53 locus) alterations in gastric carcinoma cells by dual-color fluorescence in situ hybridization. Am. J. Pathol. 149, 1575-1584 (1996
211. Guo, C. Y., Xu, X. F., Wu, L. Y. & Liu, S. F. PCR SSCP DNA sequencing method in detecting PTEN gene mutation and its significance in human gastric cancer. World J. Gastroenterol. 14, 3804-3811 (2008
212. Li, H. et al. Insulin-like growth factor-I receptor blockade reduces tumor angiogenesis and enhances the effects of bevacizumab for a human gastric cancer cell line, MKN45. Cancer 117, 3135-3147 (2011
213. Cepero, V. et al. MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res. 70, 7580-7590 (2010
214. Fuchs, C. et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5 FU (ECF) before and after CI 5 FU and radiotherapy (RT): Interim toxicity results from Intergroup trial CALGB 80101[abtract 4003]. J. Clin. Oncol. 29 (Suppl.), 4003 (2011
215. Tsuburaya, A. et al. SAMIT: Preliminary safety data from a 2 × 2 factorial randomized phase III trial to investigate weekly paclitaxel (PTX) followed by oral fluoropyrimidines (FPs) versus FPs alone as adjuvant chemotherapy in patients (pts) with gastric cancer[abstract 4017]. J. Clin. Oncol. 29 (Suppl.), 4017 (2011
216. Leong, T. L. et al. TOPGEAR: An international randomized phase III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG)[abstract TPS4141]. J. Clin. Oncol. 30 (Suppl.), TPS4141 (2012
217. Lordick, F. et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol. 14, 490-499 (2013
218. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT00450203 (2013
219. Waddell, T. S. et al. A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3)[abstract LBA4000]. J. Clin. Oncol. 30 (Suppl.), LBA4000 (2012
220. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT00680901 (2013
221. Kang, J. H. et al. Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol. 30, 1513-1518 (2012
222. US National Library of Medicine. ClinicalTrials.gov[online], http://clinicaltrials.gov/show/NCT00978549 (2009