Elucidating the molecular mechanism(s) by which aspirin use reduces the risk and mortality of colorectal cancer (CRC) could lead to major breakthroughs in the field of cancer chemoprevention and treatment. The most compelling evidence to date indicates that the anti-tumor effects of aspirin and other NSAIDs are due to reduction of pro-inflammatory prostaglandin E2 (PGE2) production via inhibiting cyclooxygenase enzymatic activity. Our preliminary data supports this hypothesis by showing that aspirin reduced polyp numbers along with a decrease of prostaglandin production in tumors. However, no direct evidence has been developed that aspirin inhibits CRC initiation, progression, and metastasis by reduction of PGE2 production via targeting COX enzymes. In addition, previous studies have focused on the roles of NSAIDs in eliminating tumor epithelial cells and suppressing tumor-associated angiogenesis. Little is known about the impact of aspirin on CRC immune evasion. Our observations, never before reported, indicate that aspirin restores host immunosurveillance by inhibition of myeloid-derived suppressor cells (MDSCs) and PGE2 induces an infiltration of MDSCs into the intestinal tumor and mucosa via induction of CXCR2 ligand expression prompted us to postulate that aspirin might inhibit tumor initiation, progression, and metastasis by suppressing recruitment of MDSCs via targeting a novel COX-PGE2-CXCR2 pathway.
Aim 1 is designed to test this hypothesis. The results from this aim could not only identify key mechanisms responsible for anti-tumor effects of aspirin, but also may provide a rationale for development of new therapeutic approaches to subvert APC mutation- and tumor-induced immunosuppression by using CXCR2 antagonists and/or CXCR2 neutralizing antibodies. Moreover, our preliminary studies revealed for the first time that primary tumor induced immunosuppression in pre-metastatic organs, whereas treatment with a COXIB attenuated the effects of the primary tumor on pre-metastatic niche formation in the liver. Thus, it is conceivable to hypothesize that aspirin inhibits metastasis by blocking the formation of pre-metastatic niches via targeting the COX-PGE2-CXCR2 pathway.
Aim 2 is designed to examine this postulation. The results from this aim should provide a rationale for developing novel therapeutic approaches to inhibit CRC metastasis by blocking the pre-metastatic niche formation. Finally, one potential explanation for the cancer-preventive effects of aspirin could be due to inhibition of COX-1 activity in platelets. However, there is no clear evidence supporting this idea. We will test this role of platelet COX-1 in Aim 3. The results from this aim will provid a rationale for development of new therapeutic approaches to target platelet COX-1 in future cancer prevention and treatment efforts. Collectively, the mechanisms we identify in this proposal might be applicable for other solid cancers in general and can certainly be tested in other systems. In addition, targeting host immunosurveillance or platelets may also represent a novel therapeutic approach for CRC patients.

Public Health Relevance

The significance and novelty in this proposal is to determine whether 1) aspirin inhibits tumor formation, growth, progression, and metastasis by restoring host immunosurveillance via inhibition of a COX-PGE2- CXCR2 pathway, 2) aspirin inhibits metastasis by suppressing MDSC recruitment in pre-metastatic niches via targeting the same pathway, and 3) COX-1 in platelets is the direct target of aspirin that results in lower risk for CRC. We will test our hypotheses in a newly developed genetic model that recapitulates human CRC progression as compared to previous models. Our findings elucidating molecular mechanisms underlying the anti-tumor effects of aspirin on CRC have the potential to directly impact the clinical care of patients with CRC in a relatively short period of time.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA184820-01
Application #
8685705
Study Section
Special Emphasis Panel (ZCA1-SRLB-2 (J1))
Program Officer
Umar, Asad
Project Start
2014-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$399,474
Indirect Cost
$140,845
Name
Arizona State University-Tempe Campus
Department
Miscellaneous
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Wang, Dingzhi; DuBois, Raymond N (2018) Role of prostanoids in gastrointestinal cancer. J Clin Invest 128:2732-2742
Wang, Dingzhi; Sun, Haiyan; Wei, Jie et al. (2017) CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer. Cancer Res 77:3655-3665
Kim, Sun-Hee; Park, Yun-Yong; Cho, Sung-Nam et al. (2016) Krüppel-Like Factor 12 Promotes Colorectal Cancer Growth through Early Growth Response Protein 1. PLoS One 11:e0159899
Wang, Dingzhi; DuBois, Raymond N (2016) The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression. Trends Mol Med 22:1-3
Wang, Dingzhi; Fu, Lingchen; Sun, Haiyan et al. (2015) Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice. Gastroenterology 149:1884-1895.e4
Wang, Dingzhi; DuBois, Raymond N (2015) Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis 36:1085-93
Wang, Dingzhi; DuBois, Raymond N (2014) PPAR? and PGE2 signaling pathways communicate and connect inflammation to colorectal cancer. Inflamm Cell Signal 1:
Wang, Dingzhi; DuBois, Raymond N (2014) Myeloid-derived suppressor cells link inflammation to cancer. Oncoimmunology 3:e28581
Kim, Sun-Hee; Margalit, Ofer; Katoh, Hiroshi et al. (2014) CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models. Invest New Drugs 32:1105-1112
Dubois, Raymond N (2014) Role of inflammation and inflammatory mediators in colorectal cancer. Trans Am Clin Climatol Assoc 125:358-72; discussion 372-3

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