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.
|Yuan, Chen; Bao, Ying; Sato, Kaori et al. (2017) Influence of dietary insulin scores on survival in colorectal cancer patients. Br J Cancer 117:1079-1087|
|Hanyuda, Akiko; Cao, Yin; Hamada, Tsuyoshi et al. (2017) Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status. Eur J Epidemiol 32:393-407|
|Nimptsch, Katharina; Song, Mingyang; Aleksandrova, Krasimira et al. (2017) Genetic variation in the ADIPOQ gene, adiponectin concentrations and risk of colorectal cancer: a Mendelian Randomization analysis using data from three large cohort studies. Eur J Epidemiol 32:419-430|
|Song, Mingyang; Chan, Andrew T (2017) Diet, Gut Microbiota, and Colorectal Cancer Prevention: A Review of Potential Mechanisms and Promising Targets for Future Research. Curr Colorectal Cancer Rep 13:429-439|
|Lindström, Sara; Finucane, Hilary; Bulik-Sullivan, Brendan et al. (2017) Quantifying the Genetic Correlation between Multiple Cancer Types. Cancer Epidemiol Biomarkers Prev 26:1427-1435|
|Masugi, Yohei; Nishihara, Reiko; Hamada, Tsuyoshi et al. (2017) Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer. Cancer Immunol Res 5:1046-1055|
|Cao, Yin; Wu, Kana; Mehta, Raaj et al. (2017) Long-term use of antibiotics and risk of colorectal adenoma. Gut :|
|Liu, Li; Nishihara, Reiko; Qian, Zhi Rong et al. (2017) Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor. Gastroenterology 153:1517-1530.e14|
|Mehta, Raaj S; Song, Mingyang; Nishihara, Reiko et al. (2017) Dietary Patterns and Risk of Colorectal Cancer: Analysis by Tumor Location and Molecular Subtypes. Gastroenterology 152:1944-1953.e1|
|Hamada, Tsuyoshi; Cao, Yin; Qian, Zhi Rong et al. (2017) Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status. J Clin Oncol 35:1836-1844|
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