Examining signaling mechanisms by which colonic pro-inflammatory cytokines modulate obesity-promoted colonic carcinogenesis.
cancer (CRC) is the third most common cancer and third most common cause of cancer
deaths in the United States. Amongst the many risk factors for this disease is obesity:
those with a BMI of 25-29.9 have a relative risk of 1.2 and 1.5 for developing CRC,
while those with a BMI of 30 have a relative risk of 1.5 and 2.0 for females and males,
respectively. Recent evidence ... read moresuggests that the low-grade chronic inflammatory state
that accompanies obesity can have multiple promotional effects on pro-carcinogenic cell
signaling cascades, and thus may be an important avenue by which excess adiposity
promotes the risk of CRC. The intent of the project described in this thesis was to
define some of the mechanistic links between inflammation and colon carcinogenesis in
obese rodent models as well as in humans. I aimed to: 1) elucidate the associations
between pro-inflammatory cytokines in the colon and pro-carcinogenic signaling pathways
in obese individuals; 2) delineate the mechanistic roles of colonic pro-inflammatory
IL-1β on the activation of Akt, NFkB and Wnt; and 3) define differences in colonic
pro-inflammatory cytokines and gene expression signatures in the colonic epithelium in
diet-induced (DIO) and genetically-induced (GIO) obese mouse models. To demonstrate the
clinical relevance of these principles, and to begin understanding how obesity might
generate biochemical inflammation in the human colon, we compared the concentrations of
TNF-α, IL-1β, IL-6 and IFNγ in the colonic mucosa of 16 lean and 26
obese individuals. In a general linear model, colonic TNF-α (r=0.41; p=0.01) and
IL-6 (r=0.41; p=0.01) concentrations increased incrementally with BMI. Among individuals
with a BMI of >34 the mean colonic concentrations of TNF-α and IL-6 were
two-fold greater than in lean subjects (p<0.03); those with milder obesity
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Joel Mason.
Committee: Rachel Buchsbaum, Xiang-Dong Wang, and Andrew Greenberg.
Keywords: Oncology, and Molecular biology.read less