The overall goal of this application is to investigate the role of bone marrow-derived stem cells in the development and progression of gastric cancer. Epithelial cancers are believed to originate from transformation of a tissue stem cell, but a second possible source of cancer stem cells is the bone marrow derived cell (BMDC). Epithelial cancers often arise in the setting of tissue loss and inflammation, and are preceded by hyperproliferation and metaplasia. Our group utilized has developed the Helicobacter mouse model of gastric cancer to address the origins of epithelial cancers. These studies from our laboratory suggest that chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, leads to chronic inflammation and repopulation of the stomach with BMDCs that then progress to metaplasia, dysplasia to intraepithelial cancer [Science 2004;306:1568-1571]. These findings from our laboratory suggest that epithelial cancers may originate from marrow-derived sources and have broad implications for the multistep model of cancer progression. We propose to use this model system to investigate further the biology of bone marrow-derived stem cells in cancer.
Our aims i n this proposal will address the following questions: (1) What is the origin of the cancer stem cells and is there any correlation with number of circulating cells? (2) Are bone marrow stem cells inherently more susceptible to malignant progression than tissue stem cells, and can they differentiate into mature gastric cells? (3) Do IL-1 beta and other cytokines activate the immune system to result in cancer initiation? (4) Is bacterial overgrowth, a consequence of achlorhydria, necessary for progression of BMDCs to dysplasia and gastric cancer? (5) Do inherited (e.g. p53) genetic mutations in the bone marrow stem cell population lead to cancer irreversibility in the setting of histologic dysplasia? These collaborative studies between investigators at Columbia University and MIT will provide new insights into mechanisms of cancer initiation and progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120979-05
Application #
7877787
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2006-09-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$468,120
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
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; 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
Hayakawa, Yoku; Jin, Guangchun; Wang, Hongshan et al. (2015) CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. Gut 64:544-53
Zhao, Chun-Mei; Hayakawa, Yoku; Kodama, Yosuke et al. (2014) Denervation suppresses gastric tumorigenesis. Sci Transl Med 6:250ra115
Asfaha, Samuel; Dubeykovskiy, Alexander N; Tomita, Hiroyuki et al. (2013) Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis. Gastroenterology 144:155-66
Gonda, Tamas A; Kim, Young-In; Salas, Martha C et al. (2012) Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice. Gastroenterology 142:824-833.e7
Quante, Michael; Bhagat, Govind; Abrams, Julian A et al. (2012) Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21:36-51

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