As the first independent application led by an NCI K career development award recipient, this proposal will address central hypotheses in inflammation, a NIH Major Roadmap Initiative for 2008. Considerable experimental, epidemiological, and clinical data strongly support a causative link between inflammation and colorectal cancer (CRC). A compelling proof of this principle is six randomized trials that demonstrate that anti- inflammatory drugs such as aspirin and cyclooxygenase-2 (COX-2) selective inhibitors reduce the risk of colorectal adenoma among patients with a prior history of colorectal neoplasia. The pro-inflammatory COX-2 enzyme appears to be a central mediator of this relationship. Recently, in two large prospective cohorts, the Nurses'Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we observed that aspirin reduces risk of COX-2 positive CRC but not risk of COX-2 negative CRC. This work has raised """"""""...important questions about the biological basis and clinical implications of discovering differences between colon cancers that express high or low levels of COX-2."""""""" This statement, especially considered within the context of uncertainty regarding the optimal use of aspirin and non-steroidal anti-inflammatory drugs in light of their associated toxicities, highlights the critical need to further elucidate 1) lifestyle, dietary, and biochemical markers of susceptibility to COX-2 positive CRCs;2) underlying inflammatory and related prostaglandin pathways in aspirin-mediated inhibition of colorectal carcinogenesis. We will address these aims through studies which utilize the extensive questionnaire data, archived plasma and urine specimens, and tumor blocks already established for the NHS and HPFS cohorts and where needed, expand and collect more data to support our aims. Beyond our specific hypotheses, the resources generated in this proposal will allow for the rapid examination of future hypotheses as they emerge. As such, this application is a cost-efficient investment in improving our understanding of the key role of inflammation in colorectal neoplasia. Ultimately, the findings of this proposal may lead to improved risk stratification for tailoring preventative strategies utilizing lifestyle modification or chemopreventative agents that maximize efficacy but minimize toxicity.
Although aspirin can prevent colorectal cancer, a leading cause of death in the U.S., its optimal use in light of its toxicities remains uncertain. We will investigate the role of inflammation in colorectal carcinogenesis to define predictors of susceptibility for tailored preventative strategies.
|Zhang, Xuehong; Keum, NaNa; Wu, Kana et al. (2016) Calcium intake and colorectal cancer risk: Results from the nurses' health study and health professionals follow-up study. Int J Cancer 139:2232-42|
|Song, Mingyang; Nishihara, Reiko; Wang, Molin et al. (2016) Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status. Gut 65:296-304|
|Dou, Ruoxu; Nishihara, Reiko; Cao, Yin et al. (2016) MicroRNA let-7, T Cells, and Patient Survival in Colorectal Cancer. Cancer Immunol Res 4:927-935|
|Kantor, Elizabeth D; Zhang, Xuehong; Wu, Kana et al. (2016) Use of glucosamine and chondroitin supplements in relation to risk of colorectal cancer: Results from the Nurses' Health Study and Health Professionals follow-up study. Int J Cancer 139:1949-57|
|Phipps, Amanda I; Passarelli, Michael N; Chan, Andrew T et al. (2016) Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis. Carcinogenesis 37:87-95|
|Karami, Sara; Han, Younghun; Pande, Mala et al. (2016) Telomere structure and maintenance gene variants and risk of five cancer types. Int J Cancer 139:2655-2670|
|Song, Mingyang; Zhang, Xuehong; Meyerhardt, Jeffrey A et al. (2016) Marine Ï‰-3 polyunsaturated fatty acid intake and survival after colorectal cancer diagnosis. Gut :|
|Nimptsch, Katharina; Zhang, Xuehong; Cassidy, AedÃn et al. (2016) Habitual intake of flavonoid subclasses and risk of colorectal cancer in 2 large prospective cohorts. Am J Clin Nutr 103:184-91|
|Inamura, Kentaro; Song, Mingyang; Jung, Seungyoun et al. (2016) Prediagnosis Plasma Adiponectin in Relation to Colorectal Cancer Risk According to KRAS Mutation Status. J Natl Cancer Inst 108:|
|Mima, Kosuke; Nowak, Jonathan A; Qian, Zhi Rong et al. (2016) Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival. Oncotarget :|
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