Colorectal cancer (CRC) is common in the United States and other Western countries. Compelling evidence indicates that environmental factors increase the risk of CRC. It is generally accepted that colorectal adenomas are precursors to CRC. Defining environmental and lifestyle factors that favor adenoma formation is integral to improved surveillance and prevention. Our group found that lower levels of apoptosis in normal appearing rectal mucosa and increased BMI were strong predictors of adenoma risk. This competing renewal will test the central hypothesis that systemic cytokines and adipokines or local biomarkers of inflammation predict risk for colorectal adenomas and low apoptosis within the normal colonic epithelium.
The specific aims are: (1) To measure circulating biomarkers of inflammation, C- reactive protein, interleukin-6 (IL-6), and TNFa, and test for associations with adenomas and apoptosis. (2) To measure circulating adipokines leptin and adiponectin and test for associations with adenomas and apoptosis. (3) To assay local activation or expression of TNFa and IL6 to test the hypothesis that high levels these local biomarkers of inflammation correlate with increased adenoma risk or low apoptosis. (4) To assess activation of NFkB and STATS, anti-apoptotic transcription factors in colonic epithelial cells;these factors are activated by multiple cytokines, adipokines and insulin, and are linked to colorectal neoplasia. Study subjects will be 600 consenting male and female patients who meet eligibility criteria. Blood samples will be collected immediately before routine colonoscopy and pinch biopsies of normal rectal mucosa will be collected during colonoscopy. Apoptosis will be measured in biopsies using morphological light microscopy-based assays and caspase-3 immunohistochemistry. Plasma levels of cytokines and adipokines will be measured by ELISA. Local expression of TNFa and IL6 will be measured by real time PCR. Tissue levels of activated NFkB and STATS will be measured by electromobility shift assay. This study is a logical extension of previous research. The proposal has the potential to improve our understanding of the role of obesity and inflammation in the development of colorectal neoplasia and to predict mechanistic links between inflammation and adenoma risk. Ultimately the results may inform surveillance and prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044684-19
Application #
7837683
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Mahabir, Somdat
Project Start
1988-02-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
19
Fiscal Year
2010
Total Cost
$369,974
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Jackson, John W; VanderWeele, Tyler J; Blacker, Deborah et al. (2015) Mediators of First- Versus Second-generation Antipsychotic-related Mortality in Older Adults. Epidemiology 26:700-9
Keku, Temitope O; Dulal, Santosh; Deveaux, April et al. (2015) The gastrointestinal microbiota and colorectal cancer. Am J Physiol Gastrointest Liver Physiol 308:G351-63
Mack, Christina DeFilippo; Brookhart, M Alan; Glynn, Robert J et al. (2015) Comparative Effectiveness of Oxaliplatin Versus 5-flourouricil in Older Adults: An Instrumental Variable Analysis. Epidemiology 26:690-9
Murphy, Caitlin C; Martin, Christopher F; Sandler, Robert S (2015) Racial differences in obesity measures and risk of colorectal adenomas in a large screening population. Nutr Cancer 67:98-104
Nugent, Julia L; McCoy, Amber N; Addamo, Cassandra J et al. (2014) Altered tissue metabolites correlate with microbial dysbiosis in colorectal adenomas. J Proteome Res 13:1921-9
Dulal, Santosh; Keku, Temitope O (2014) Gut microbiome and colorectal adenomas. Cancer J 20:225-31
Santoro, M Agostina; Andres, Sarah F; Galanko, Joseph A et al. (2014) Reduced insulin-like growth factor I receptor and altered insulin receptor isoform mRNAs in normal mucosa predict colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 23:2093-100
Kang, Melissa; Peery, Anne F; Locklear, Cameron et al. (2013) Plasma insulin, glucose, IGF-I, IGF-II, and IGFBP-3 and risk of recurrent colorectal adenomas. J Gastroenterol Hepatol Res 2:531-535
Frantz, David J; Crockett, Seth D; Galanko, Joseph A et al. (2013) Percent Body Fat Measured by Bioelectrical Impedance is Not Associated with Colorectal Adenoma Status. J Gastroenterol Hepatol Res 2:445-448
Kang, Melissa; Edmundson, Patrick; Araujo-Perez, Felix et al. (2013) Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas. BMC Cancer 13:91

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