While a number of recent studies have focused on the role of stromal cells in advanced carcinomas, the stromal changes contributing to carcinogenesis have received considerably less attention. Gastric and hepatocellular cancer are two of the leading causes of cancer mortality worldwide, and are strongly linked to chronic infection (H. pylori versus HBV/HCV, respectively) and the consequent state of sustained inflammation. This application is submitted by the Tumor Microenvironment Program at the Columbia University Cancer Center, bringing together leading investigators in the areas of gastric carcinogenesis and liver fibrosis with experts in other areas to examine the role of stromal cells in liver and gastric carcinogenesis. This highly collaborative and multidisciplinary group encompasses experts in stromal cells, chronic inflammation/NF-kB, angiogenesis, epigenetics, optical imaging, and bioinformatics. It also includes a clinical arm that will conduct parallel studies on stromal cells from primary gastric and liver tumors, and a translational component (effects of COX-2 inhibition on tumor vascular stromal cells). Our proposal is based heavily on novel observations by this team of researchers regarding the bone marrow origin of cancer and stromal cells, the mechanism of activation of myofibroblasts (e.g. stellate cells), and on the link between chronic inflammation, angiogenesis, and the development of cancer. The program includes 4 projects and 2 cores. Project 1. Stromal myofibroblasts in gastric carcinogenesis (PI - Timothy C. Wang). Project 2. Stromal myofibroblasts in hepatic carcinogenesis (PI - David A. Brenner) Project 3. Interactions between digestive cancers and the vascular stroma (PI - Jan Kitajewski) Project 4. Epigenetics and genetics of stromal cells in liver and gastric cancer (PI - Benjamin Tycko) The Cores, which include an Imaging Core led by Andreas Hielscher, and an Administrative/Bioinformatics Core led by Timothy C. Wang and Andrea Califano, will be utilized by most of the projects and will provide additional focus and unity to the Project as a whole. In addition, most of the projects will utilize unique transgenic models of cancer (e.g. INS-GAS), reporter gene mice (ASMA-RFP/COLL-EGFP/Luc) targeting myofibroblasts, and a new method of methylation-sensitive SNP chip analysis (MSNP) to profile the myofibroblasts. Taken together, the data from these murine and human studies should lead to new insights regarding tumor-stroma interactions and their origins in early cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA126513-05
Application #
7911806
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Mohla, Suresh
Project Start
2006-09-30
Project End
2011-09-21
Budget Start
2010-09-01
Budget End
2011-09-21
Support Year
5
Fiscal Year
2010
Total Cost
$848,610
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: Lessons 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
Worthley, Daniel L; Churchill, Michael; Compton, Jocelyn T et al. (2015) Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160:269-84
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
Zhao, Chun-Mei; Hayakawa, Yoku; Kodama, Yosuke et al. (2014) Denervation suppresses gastric tumorigenesis. Sci Transl Med 6:250ra115
Balabanova, Silvia; Holmberg, Chris; Steele, Islay et al. (2014) The neuroendocrine phenotype of gastric myofibroblasts and its loss with cancer progression. Carcinogenesis 35:1798-806
Kumar, J Dinesh; Holmberg, Chris; Kandola, Sandhir et al. (2014) Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells. PLoS One 9:e104877
Holmberg, Christopher; Ghesquière, Bart; Impens, Francis et al. (2013) Mapping proteolytic processing in the secretome of gastric cancer-associated myofibroblasts reveals activation of MMP-1, MMP-2, and MMP-3. J Proteome Res 12:3413-22

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