Colorectal Adenomas, Calcium and Vitamin D Public
Fedirko, Veronika (2009)
Abstract
Colorectal cancer is the second cause of cancer death in the US, and despite advances in treatment, screening, and prevention, its mortality has declined only modestly in recent years. Thus, there is need to develop new chemopreventive agents for colorectal neoplasms, and for new clinically accepted pre-neoplastic biomarkers of risk for colorectal neoplasms that may be used in colorectal cancer screening and in chemoprevention trials to assess the effectiveness of treatment. The goals for this dissertation are to investigate the roles of two evidentially well-supported chemopreventive agents, vitamin D3 and calcium, in colorectal carcinogenesis, and to develop modifiable biomarkers of risk for colorectal neoplasia.
In a pooled analysis of three colonoscopy based case-control studies, a substantial, statistically significant, lower risk for incident, sporadic colorectal adenomas was found with higher levels of circulating 25-(OH)-vitamin D3. This inverse association was stronger among those who took aspirin or other non-steroidal anti-inflammatory drugs. In a pilot randomized, double-blind, placebo-controlled clinical trial of calcium and vitamin D3 supplementation, modulation of expression of cell cycle biomarkers in the normal-appearing colorectal mucosa of patients with previously resected colorectal adenomas was found in the calcium and vitamin D3 groups. The strongest treatment effects were on the markers of cell differentiation and apoptosis, and vitamin D3 related. Findings from this clinical trial also support a new hypothesis that vitamin D3 and calcium reduce oxidative DNA damage in the colon, especially among those who have higher colorectal expression of the vitamin D receptor.
In conclusion, the results of my dissertation support hypotheses that higher intakes of vitamin D3 and calcium favorably modulate biomarkers of risk for colorectal neoplasms, and higher circulating 25-(OH)-vitamin D3 levels are associated with lower risk for incident, sporadic colorectal adenoma. The results of this dissertation warrant further investigation of the expression of cell cycle biomarkers in the normal-appearing colorectal mucosa as potential modifiable biomarkers of risk for colorectal neoplasms.
Table of Contents
TABLE OF CONTENTS
ILLUSTRATIONS LIST OF TABLES CHAPTER 1. INTRODUCTION AND BACKGROUND .................................................................. 1 Introduction ................................................................................................................ 1 Background ..................................................................................................................3 Overview of Colorectal Cancer Epidemiology .......................................................................3 Morphology of the Colon ................................................................................................ 6 Colon Carcinogenesis .................................................................................................... 7 Risk Factors for Colorectal Cancer ........................................................................... ......13 Calcium and Colorectal Adenomas .................................................................................. 29 Vitamin D and Colorectal Adenomas .................................................................................32 Calcium, Vitamin D and Colorectal Adenomas .....................................................................41 Modifiers of Calcium and Vitamin D Effects ........................................................................43 Effects of Calcium and/or Vitamin D on Cell Proliferation ..................................................... 44 Effects of Calcium and/or Vitamin D on Cell Apoptosis ........................................................ 47 Effects of Calcium and/or Vitamin D on Cell Differentiation .................................................. 49 Calcium, Vitamin D, and Oxidative Stress ......................................................................... 51 Hypotheses ................................................................................................................54 Objectives ..................................................................................................................55 Specific Aims .............................................................................................................. 55 Methods......................................................................................................................58 Data Analysis Plan ....................................................................................................... 60 Statistical Power Considerations ..................................................................................... 61 Student Contribution to Data Collection ........................................................................... 63 Study Strengths .......................................................................................................... 64
CHAPTER 2. BLOOD 25-HYDROXYVITAMIN D3 CONCENTRATIONS AND INCIDENT, SPORADIC COLORECTAL ADENOMA RISK: A POOLED CASE- CONTROL STUDY ......................................................................................................... 66 Abstract .................................................................................................................... 67 Introduction ............................................................................................................... 68 Materials and Methods ................................................................................................. 70 Results ..................................................................................................................... 79
Discussion ................................................................................................................. 82 Tables and Figures ...................................................................................................... 93
CHAPTER 3. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION ON MARKERS OF APOPTOSIS IN NORMAL COLON MUCOSA: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL ............................................................................................................................... 106 Abstract ................................................................................................................... 107 Introduction .............................................................................................................. 108 Patients and Methods ..................................................................................................110 Results .................................................................................................................... 119 Discussion ................................................................................................................ 121 Tables and Figures ..................................................................................................... 127
CHAPTER 4. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION ON MARKERS OF PROLIFERATION AND DIFFERENTIATION IN NORMAL COLON MUCOSA: A RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED CLINICAL TRIAL ........................................................................................ 136 Abstract ................................................................................................................... 137 Introduction .............................................................................................................. 138 Patients and Methods ................................................................................................. 140 Results .................................................................................................................... 146 Discussion ................................................................................................................ 149 Tables and Figures ..................................................................................................... 157
CHAPTER 5. EFFECTS OF VITAMIN D AND CALCIUM SUPPLEMENTATION ON MARKERS OF DNA DAMAGE IN NORMAL COLON MUCOSA: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL ............................................................................................................................... 165 Abstract ................................................................................................................... 166 Introduction .............................................................................................................. 167 Patients and Methods ................................................................................................. 168 Results .................................................................................................................... 176 Discussion ............................................................................................................... 179 Tables and Figures .................................................................................................... 187
CONCLUSIONS AND PUBLIC HEALTH IMPLICATIONS ......................................................... .196 FUTURE DIRECTIONS ................................................................................................ .199
REFERENCES..............................................................................................................204
APPENDIX. Laboratory Procedures ................................................................................. 240 Protocol for Biopsy Specimen Processing and Immunohistochemical Staining .......................... 240
Protocol for Quantifying Staining Density of Immunohistochemically Detected Biomarkers in Normal Colon Crypts ("Scoring").....242 Protocol for Measuring Plasma 25-(OH)- and 1,25-(OH)2 - Vitamin D Levels (CaDvMAP Study)....246 Protocol for Genotyping of the VDR BsmI Polymorphism (CaDvMAP Study) ....246 Protocol for 8-Hydroxy-2'-deoxyguanosine (8-OH-dG) Immunohistochemical (IHC) Staining ...248
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