||5R21CA223686-02 Interpret this number
||Understanding Sex Differences in Colon Cancer Metabolism
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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