Circulating Biomarkers of Inflammation and Oxidative Stress: Associations with Risk Factors for Colorectal Neoplasms and Response to Micronutrient-Based Chemopreventive Interventions Open Access

Hopkins, Myfanwy Heather (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/s4655h612?locale=en
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Abstract

Colorectal cancer (CRC), the second leading cause of cancer deaths in the U.S., is a disease highly correlated with excess adiposity, smoking, and a Western-style diet. Twenty-fold variations in international CRC rates and migration studies showing high acquired risk within one generation, emphasize the importance of environmental exposures in the etiology of CRC, and thus its preventability. It is now clear that increased inflammation and oxidative stress play a major role in colon carcinogenesis, basic science indicates antioxidants may reduce oxidative stress, and dietary antioxidants, calcium and vitamin D may play important roles in reducing inflammation in the colon. In addition to preventative strategies, treatable biomarkers of risk analogous to cholesterol in relation to hearth disease are needed to quickly and accurately assess the effectiveness of preventative strategies. This dissertation investigates associations of biomarkers of inflammation and oxidative stress with risk factors for CRC, and modulation of the markers by micronutrient-based chemopreventive interventions in patients at higher risk for developing CRC.

In a randomized, double-blind, placebo-controlled clinical trial of antioxidant micronutrient supplementation in colorectal adenoma patients, significant reductions in oxidative stress and inflammation biomarkers were found in non-smokers, but were found to increase in smokers. In a randomized, double-blind, placebo-controlled trial investigating the effects of calcium and/or vitamin D3 on biomarkers of inflammation in colorectal adenoma patients, a combined inflammation z-score was reduced with vitamin D3 or calcium supplementation. In addition, significant associations were found between several biomarkers of inflammation and increased levels of adiposity in colorectal adenoma patients.

The results of this dissertation indicate that in those at risk for developing CRC, 1) an antioxidant micronutrient cocktail can reduce biomarkers of inflammation and oxidative stress in non-smokers, 2) vitamin D or calcium can modulate biomarkers of inflammation, and 3) these biomarkers of inflammation are associated with increased general and central adiposity. The results of this dissertation warrant further investigation of these circulating inflammation and oxidative stress biomarkers for use as pre-neoplastic biomarkers of risk for CRC, and for use in assessing the efficacy, safety, and optimum dose range for chemopreventive interventions.

Table of Contents

TABLE OF CONTENTS

ILLUSTRATIONS AND TABLES
CHAPTER 1. BACKGROUND…………………………........................................1
Background...........................................................................................................1
Colorectal Cancer Epidemiology... ................................................................1
Colon Morphology..........................................................................................3
Molecular Mechanisms of Colon Carcinogenesis..........................................4


Inflammation, Oxidative Stress, and Colorectal Cancer................................7
Antioxidants and Colon Cancer....................................................................10
Vitamin D and Colorectal Adenomas...........................................................12
Calcium and Colorectal Adenomas ..............................................................15
Hypotheses .........................................................................................................17
Specific Aims .....................................................................................................18
Methods ..............................................................................................................20

CHAPTER 2. ANTIOXIDANT MICRONUTRIENTS AND BIOMARKERS OF
OXIDATIVE STRESS AND INFLAMMATION IN COLORECTAL ADENOMA
PATIENTS: RESULTS FROM A RANDOMIZED, CONTROLLED CLINICAL
TRIAL......................................................................................................................23
Abstract .......................................................................................................24
Introduction .................................................................................................25
Materials and Methods.................................................................................27
Results .........................................................................................................32
Discussion ...................................................................................................34
Tables and Figures ......................................................................................40

CHAPTER 3. ASSOCIATIONS OF CIRCULATING INFLAMMATORY
BIOMARKERS WITH RISK FACTORS FOR COLORECTAL CANCER IN
COLORECTAL ADENOMA PATIENT...............................................................45
Abstract ......................................................................................................46
Introduction ................................................................................................47

Materials and Methods................................................................................48
Results ........................................................................................................50
Discussion ..................................................................................................52
Tables and Figures .....................................................................................56

CHAPTER 4. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION
ON MARKERS OF APOPTOSIS IN NORMAL COLON MUCOSA: A
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL
…..............................................................................................................................60
Abstract ........................................................................................................61
Introduction .................................................................................................62
Materials and Methods.................................................................................63
Results ..........................................................................................................68
Discussion ....................................................................................................70
Tables and Figures .......................................................................................78
CHAPTER 5. CONCLUSIONS AND FUTURE DIRECTIONS
CONCLUSIONS AND FUTURE DIRECTIONS………......................................84
REFERENCES..........................................................................................................90
APPENDIX. Laboratory Procedures
Measurement of CySS ………......................................................................118

ILLUSTRATIONS AND TABLES

Figure 1. Colon polyp Morphology………………………………………..…….....3
Table 1.1 Selected baseline characteristics of participants (n=47)……….……….40
Table 1.2 Effects of antioxidant micronutrients on inflammatory cytokines and
oxidative stress markers in plasma………………………………………….……...42

Table 1.3 Effects of antioxidant micronutrients on inflammatory cytokines and
oxidative stress markers in plasma by current smoking status………………….…43
Table 2.1 Selected baseline characteristics of the clinical trial participants……....56
Table 2.2 Biomarkers of inflammation according to possible colorectal
cancer risk factors in colon adenoma patients……………………………………..57
Table 3.1 Selected baseline characteristics of the clinical trial participants..……..78
Table 3.2 Changes in biomarkers of inflammation in plasma of
colorectal adenoma patients ………………………………………………………79
Table 3.3 Changes in inflammation Z-score in plasma of
colorectal adenoma patients……………………………………………………….81
Table 3.4 Changes in plasma CRP and inflammation z-score levels
stratified by sex and NSAID use in colorectal adenoma patients …………….…..82










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