Epidemiologic and clinical evidence has demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, protects against colorectal cancer (CRC) incidence and mortality. Elucidating the mechanism(s) responsible for the protective effect of NSAIDs could lead to major breakthroughs in the field of cancer chemoprevention and treatment. The most compelling evidence to date indicates that reduction of pro- inflammatory prostaglandin E2 (PGE2) production via inhibition of the cyclooxygenase pathway is responsible for part of this protective effect. Given that PGE2 can mediate the tumor-promoting effects of COX-1 and COX- 2, more selective pharmacological inhibition of PGE2 signaling may be efficacious in preventing CRC with avoiding the cardiovascular and other side effects associated with NSAID use. Although our group and others have extensively investigated the mechanisms by which PGE2 promotes CRC progression, it is still not fully understood how PGE2 accelerates CRC formation and progression. During the current funding period, our progress has led to many milestones in understanding the central role of PGE2 signaling in CRC and also provides the foundation for future investigation. Our preliminary data shows that PGE2 stimulates the expansion of colonic cancer stem cell (tumor-initiating cell) in vitro and in vivo. However, it is unclear whether PGE2 promotes CRC initiation and progression through enhancing cancer stem cell growth, maturation, and survival. We will address these questions in the Aim 1. Moreover, our preliminary results indicate that the CXCR2, one of downstream targets of PGE2, promotes chronic intestinal inflammation and colitis-associated tumorigenesis. We further provide the first evidence showing that CXCR2 is required to recruit myeloid-derived suppressor cells (MDSCs) to the colonic mucosal tissue. Previously, this receptor was thought to only mediate neutrophil migration to inflammatory sites. Although evidence for MDSC promotion of immunosuppression is accumulating, it remains unclear whether CXCR2-expressing MDSCs play a key role in connecting colonic chronic inflammation to colitis-associated carcinogenesis.
Aim 2 is designed to address these questions. Finally, our preliminary data revealed that adoptive transfer of human natural killer (NK) cells significantly inhibited liver metastases in a mouse model of CRC metastasis. However, the role of NK cells in inhibiting metastatic CRC and preventing tumor recurrence after surgery remains unclear. In addition, we will evaluate whether inhibition of MDSC recruitment by CXCR2 antagonists and reduction of MDSC numbers in tumor by aspirin enhance the ability of NK cells to eliminate CRC liver metastases. We will address these issue in Aim 3. Collectively, the results from our renewal proposal will not only reveal comprehensive insights of how PGE2, CXCR2, MDSCs, and NK cells coordinately contribute to CRC initiation, progression, and metastasis, but also provide a rational for applying adoptive transfer of allogeneic NK cells with subverting tumor-induced immunosuppression as novel therapeutic approaches in metastatic and adjuvant therapies.

Public Health Relevance

The significance and novelty in this renewal proposal is to investigate whether 1) chronic inflammation and inflammatory mediators such as PGE2 contribute to CRC initiation, growth, and metastasis via enhancing CSC expansion, 2) the CXCL1-CXCR2 signaling contributes to colonic chronic inflammation and colitis- associated carcinogenesis via MDSCs, 3) infused NK cells regress metastatic CRC and prevent recurrence in adjuvant setting, and 4) inhibition of MDSCs enhances the ability of NK cells to eliminate CRC liver metastases. Our results from this proposal have the potential to directly impact the clinical care of patients with CRC.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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Arizona State University-Tempe Campus
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United States
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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) Kr├╝ppel-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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