Grant Number:	5R21CA223686-02 Interpret this number
Primary Investigator:	Johnson, Caroline
Organization:	Yale University
Project Title:	Understanding Sex Differences in Colon Cancer Metabolism
Fiscal Year:	2019

Abstract Colon cancer is the second most common cancer to affect women worldwide. While women have a 30-40% lower incidence of colon cancer than men, they have a higher likelihood of cancer presentation on the right- side of the colon, i.e., the area between the cecum and proximal transverse colon. This is of concern because patients with right-sided colon cancer (RCC) have poorer clinical outcomes than those with left-sided colon cancers (LCCs), i.e., the area between the distal transverse colon to sigmoid colon. The reasons for this difference in outcome are not known; however, it has been proposed that hormones influence colonic metabolism and affect cancer growth but this has not yet been investigated. The hormone estradiol, is 10-fold higher in the blood of premenopausal women than age-matched men. It is thought to protect against colon cancer through activation of the estrogen receptor . Such activation causes pro-apoptotic signaling, activation of the vitamin D receptor and inhibition of activator protein 1 (AP-1) expression, changes which together decrease colon cancer. Estradiol has an additional protective effect through regulation of cholesterol and bile acid (BA) metabolism. Estradiol increases biliary cholesterol saturation and decreases BA secretion, ultimately lowering levels of carcinogenic secondary BAs in the colon; secondary BAs are involved in multiple signaling processes which promote the production of reactive oxygen species, oxidative stress and DNA damage, including AP-1 activation. Notably BAs on the right side of the colon are at 10-fold higher concentrations compared to left. After menopause, estradiol levels decrease, and these protective mechanisms are reversed. In addition, cholesterol increases to levels that exceed those seen in men of comparable age, increasing the likelihood for increased BA secretion and secondary BA production in the colon. It is also possible that the farnesoid X receptor, androgen receptor, and indirect actions of the androgen testosterone are linked to colon cancer metabolism; however, their roles are not clear. We hypothesize that women have a greater propensity to develop RCC than men due to postmenopausal changes in key metabolic pathways that are regulated by sex hormones. Consequently, procarcinogenic metabolites are increased in the right-side of the colon promoting colon cancer. Therefore, we aim to examine the differences in metabolism between colon tumor tissues obtained from men and women with LCC and RCC. We will also determine the relationship between metabolites, proteins and overall survival. This proposal will reveal potential biomarkers that could aid in earlier diagnosis of RCC, and establish a rationale for performing a larger study to assess cause-and-effect through examination of diet, microbiome and lifestyle. Importantly, this represents the first comprehensive analysis of metabolic differences between women and men linked to patient outcomes in colon cancer. We anticipate the results will improve RCC clinical outcomes by enhancing our understanding of the mechanisms contributing to RCC, and provide a rational basis for the development of more specific, effective treatments of RCC.





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