AS208 - Pro and anti-inflammatory cytokines and colorectal cancer

Investigator Names and Contact Information

Gloria Ho (gho1@NSHS.edu)

Introduction/Intent

Introduction/Intent

Inflammation is implicated in the etiology of colorectal cancer -- inflammatory bowel disease increases the risk of colorectal cancer dramatically, and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colorectal cancer. Some proinflammatory cytokines, such as TNF-α and IL-6, have oncogenic effects as indicated in experimental studies. A prospective study recently reported that high plasma levels of C reactive protein (CRP), an inflammatory marker that is induced by IL-6, increases the risk of colon cancer.

This proposed study will further examine the role of proinflammatory cytokines in the etiology of colorectal cancer. It will be conducted in conjunction with an on-going NIH funded case-cohort study [AS129- Association of diabetes and insulin-like growth factor-I (IGF-I) with risks of colorectal, breast, and endometrial cancer, Strickler, PI], in which the risk for breast, endometrial, and colorectal cancers is examined for the associations with insulin, IGF-I, and estradiol assessed at the serologic and genetic levels. The 500 incident colorectal cancer cases and the 900 subcohort subjects in this case-cohort study will be the subjects of this proposed study. Plasma levels of TNF-α, and IL-6 will be assayed. Polymorphisms of genes involved in the signal transduction pathways of these cytokines will also be examined. The objectives are (1) to determine if plasma levels of these proinflammatory markers and the polymorphisms of their genes are associated with the risk of colorectal cancer, and (2) to identify genetic, physiological, and environmental factors (e.g., polymorphisms, serum levels of estradiol and insulin, obesity, etc.) that are associated with the levels of these proinflammatory markers.

The ongoing case-cohort study [AS129] is gathering data on the physiological and genetic markers of the insulin/IGF system in about 2,600 WHI OS subjects. The proposed study here will add data related to the inflammatory system to this existing database. These biological pathways intertwine; for examples, inflammatory cytokines can hinder insulin receptor signaling and contribute to hyperinsulinemia, and estradiol can inhibit the production of inflammatory cytokines, etc. By adding the data of inflammatory markers to the existing database, we will have the opportunity to examine the inter-relationships among these physiological and genetic markers and whether these biomarkers act independently to affect the risk of colorectal cancer.

If proinflammatory cytokines are indeed involved in the etiology of colorectal cancer, the results of this study will help to identify the postmenopausal women who are susceptible to proinflammatory responses and subclinical inflammation. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer.

Specific Aims

The proposed study will be conducted in conjunction with an on-going NIH funded case-cohort study [AS129] in 900 breast, 500 colorectal, and 300 endometrial cancer cases and 900 subcohort subjects; this case-cohort study aims to examine whether the risks for breast, colorectal, and endometrial cancers are associated with serum levels of insulin, glucose, IGF-I, IGFBP-3, and estradiol as well as the variations in genes involved in the insulin/IGF signaling pathways. The 500 colorectal cancer cases and 900 women in the subcohort will be included in this proposed study of inflammatory markers. The objectives are as follows:

1. To examine if the risk of colorectal cancer is associated with

   • increased plasma levels of proinflammatory markers measured at baseline: tumor necrosis factor receptors 1 and 2 and several IL-1 and IL-6.
   • polymorphisms of genes encoding these 3 inflammatory markers and the intracellular proteins involved in signal transduction of TNF-α and IL-6.

2. To investigate if plasma levels of these proinflammatory markers and variations of their genes are associated with characteristics of disease at diagnosis, e.g., cancer site (colon vs. rectum), stage, and histological type.

3. Among the women in the subcohort, to identify factors that are associated with the plasma levels of these proinflammatory markers. Factors of particular interest are polymorphisms of their genes, serum levels of estradiol, IGF-I, and insulin, insulin resistance, diabetes, obesity, hormone replacement therapy (HRT), and use of aspirin.