Transformation of the gastric epithelium occurs in the setting of Helicobacter infection and chronic inflammation, and is mediated in part by epigenetic changes, but the role of nerves has not been studied. Preliminary data from our group has revealed that denervation of the stomach by truncal vagotomy markedly inhibits cancer of the gastric corpus in the INS-GAS mouse model. However, in contrast to the proximal INS-GAS tumors, classical intestinal-type gastric cancer in humans is largely a distal gastric neoplasm. Hence, we have phenocopied antral gastric cancer using a protocol (H. felis infection + MNU) that induces epigenetic alterations. In addition, we have shown that doublecortin-like kinase 1 (Dclk1) marks tuft cells, some long-lived that contribute to the niche, and also progenitor cells for the enteric nervous system (ENS). Our hypothesis, then, is that a close interaction between neural innervation and epigenetic modulation is necessary for initiation of gastric carcinogenesis. We propose three specific aims. (1). Can surgical or chemical denervation of the stomach inhibit antral gastric carcinogenesis? We will study the effects of vagotomy and chemical denervation in the H. felis/MNU model of antral gastric carcinogenesis using both prevention and treatment strategies. Moreover, we will examine the effects of truncal vagotomy on selected biomarkers in an ongoing phase I study of gastrectomy in human patients with gastric cancer. (2). What is the role of Dclk1+ progenitors in antral gastric carcinogenesis? Using Dclk1-CreERT mice, we will perform Dclk1 lineage tracing in mouse models of antral cancer. A diptheria toxin (conditional DTR/DT) strategy of cell ablation will be used to study the role of the Dclk1 tuft cells in antral gastric cancer. (3). What is the relationship between epigenetic modulation, neurogenesis, and genetic alterations in gastric cancer? We will use epigenetic modifiers (decitabine +/- gastrin) to study the impact on neurogenesis in the MNU/H. felis/GAS-KO model of gastric cancer. We will also examine the effects of denervation on epigenetic modulation. Finally, we will carry out exomic sequencing of tumors with and without vagotomy to determine the effects of denervation on carcinogen-dependent genetic alterations.

Public Health Relevance

Gastric cancer is the 2nd most common cause of cancer mortality in the world, and survival is better in countries where truncal vagotomy is routinely performed. Our data suggest that nerves and neural progenitors play a key role in the initiation and progress of tumors, and thus the current proposal has the potential to alter surgical approaches and provide new strategies for the treatment of stomach cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093405-14
Application #
8971999
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Daschner, Phillip J
Project Start
2001-05-01
Project End
2016-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
14
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus. Cell Mol Gastroenterol Hepatol 4:89-94
Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) The Origins of Gastric Cancer From Gastric Stem Cells: LessonsĀ From Mouse Models. Cell Mol Gastroenterol Hepatol 3:331-338
Feng, Yan; Mannion, Anthony; Madden, Carolyn M et al. (2017) Cytotoxic Escherichia coli strains encoding colibactin and cytotoxic necrotizing factor (CNF) colonize laboratory macaques. Gut Pathog 9:71
Hayakawa, Yoku; Sakitani, Kosuke; Konishi, Mitsuru et al. (2017) Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell 31:21-34
Sakitani, Kosuke; Hayakawa, Yoku; Deng, Huan et al. (2017) CXCR4-expressing Mist1+ progenitors in the gastric antrum contribute to gastric cancer development. Oncotarget 8:111012-111025
Hayakawa, Yoku; Chang, Wenju; Jin, Guangchun et al. (2016) Gastrin and upper GI cancers. Curr Opin Pharmacol 31:31-37
Esmail, Michael Y; Bacon, Rebecca; Swennes, Alton G et al. (2016) Helicobacter Species Identified in Captive Sooty Mangabeys (Cercocebus atys) with Metastatic Gastric Adenocarcinoma. Helicobacter 21:175-85
Burns, Monika; Muthupalani, Sureshkumar; Ge, Zhongming et al. (2015) Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice. PLoS One 10:e0142630
Hayakawa, Yoku; Ariyama, Hiroshi; Stancikova, Jitka et al. (2015) Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche. Cancer Cell 28:800-814
Wymore Brand, Meghan; Wannemuehler, Michael J; Phillips, Gregory J et al. (2015) The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community. ILAR J 56:169-78

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