Gastric cancer is the second leading cause of cancer-related death worldwide and is strongly linked to chronic inflammation. It has been demonstrated that the polymorphisms of IL-1 are associated with the risk for gastric cancer;however, effective means for the prevention of related gastric cancer remains to be investigated. We have previously generated a HK-ATPase-human IL-1 (hIL-1) transgenic mouse model. The hIL-1 mice developed spontaneous gastric inflammation and progress to gastric cancer. We have also demonstrated that the accumulation and activation of myeloid-derived suppressor cells (MDSCs) are early events for the development of gastric cancer in the hIL-1 mice and MDSCs may be a new target for early prevention of gastric cancer. Curcumin, a bioactive food component with inhibition of NF-kB activation, has been shown to have the potential effects on cancer chemoprevention. However, the preventive effect of curcumin on gastric carcinogenesis and its molecular targets remain to be explored. The objective of this project is to study the preventive effect of curcumin on gastric carcinogenesis in this new hIL-1 mouse model by combination of celecoxib (a COX-2 inhibitor). We hypothesize that curcumin inhibits gastric carcinogenesis through by targeting inhibition of the activation of NF-kB in MDSCs and that celecoxib inhibits COX-2 and PGE2, resulting in inhibition of mobilization of MDSCs. Because the two agents act through different mechanisms, their actions may be synergistic. The hypothesis will be tested through three specific aims. (1) To determine the inhibitory effects of curcumin, celecoxib, and their combination on gastric inflammation and carcinogenesis in the hIL-1 mice. (2) To characterize the effects of curcumin and celecoxib on MDSCs mobilization and activation and elucidate the mechanisms of inhibition of gastric carcinogenesis by these agents in the hIL-1 mice. (3) To investigate the effect of targeting inhibition of MDSCs by curcumin and celecoxib on gastric epithelial cells and epithelium-stroma MDSCs interactions in gastric carcinogenesis. This project may provide direct evidence to suggest MDSCs as new target of curcumin for cancer prevention. The results of the study will provide useful information that will facilitate to develop more effective chemoprevention approaches for human gastric cancer.

Public Health Relevance

This project is to investigate the preventive effects of curcumin, celecoxib and their combination on gastric cancer in a newly developed model (hIL-1 transgenic mice). This study may provide strong evidence to support MDSCs as new target for cancer prevention. The results that curcumin combination of low dose of celecoxib synergistically prevent gastric cancer will encourage the development of these agents for the prevention of gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA149865-01
Application #
7872505
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Kim, Young S
Project Start
2010-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$201,188
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Tu, Shui Ping; Jin, Huanyu; Shi, Jin Dong et al. (2012) Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev Res (Phila) 5:205-15
Quante, Michael; Tu, Shui Ping; Tomita, Hiroyuki et al. (2011) Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19:257-72
Tu, Shui Ping; Quante, Michael; Bhagat, Govind et al. (2011) IFN-? inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis. Cancer Res 71:4247-59