The investigation and development of dietary and life‐style modifiable, pre‐neoplastic biomarkers of risk for colorectal neoplasms Open Access

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Despite advances in screening and treatment, mortality due to CRC has declined only modestly in recent years, highlighting the need for treatable, pre-neoplastic biomarkers of risk for the disease. The antineoplastic effects of calcium and vitamin D against CRC may, in part, depend on modifying markers of their metabolism and the APC/β-catenin pathway. In this dissertation I report the results of investigations of markers of these pathways (APC, β-catenin, and E-cadherin, calcium receptor (CaR), vitamin D receptor (VDR), CYP27B1, and CYP24A1) as treatable, pre-neoplastic biomarkers of risk for colorectal neoplasms.

In a pilot colonoscopy-based case-control study of incident, sporadic colorectal adenoma we found the ratio of the proportion of APC expression in the upper 40% of crypts (Φh APC) with total β-catenin expression (APC/β-catenin score) to be significantly greater in controls than in cases. The APC/β-catenin score was positively associated with protective risk factors against colorectal neoplasms. Controls had greater Φh APC and E-cadherin expression and lower β-catenin expression, but none of these differences were statistically significant.

In a randomized, double-blind, placebo-controlled clinical trial evaluating the effects of supplemental calcium and vitamin D3, alone and in combination, we found increased Φh APC and E-cadherin expression, an increased APC/β-catenin score, and decreased β-catenin expression in the active treatment groups. We also found that supplemental calcium and vitamin D3 modulated markers of their metabolism with increased CaR, VDR, and CYP27B1 expression in the active treatment groups, and increased CYP24A1 expression in the vitamin D3 treatment groups and decreased CYP24A1 expression in the calcium treatment group.

These results suggest that 1) APC, β-catenin, CaR, VDR, CYP27B1, and CYP24A1 expression may be treatable, pre-neoplastic biomarkers of risk for colorectal neoplasms; and 2) the antineoplastic effects of calcium and vitamin D may, in part, depend on modifying markers of the APC/β-catenin pathway and markers of calcium and vitamin D metabolism. The results of this dissertation support further investigation of these markers as potential treatable, pre-neoplastic biomarkers of risk for colorectal neoplasms.

Table of Contents

Chapter 1. Background and Significance. 1

Colorectal morphology. 3

Colorectal cancer pathogenesis. 3

APC, β-catenin, and E-cadherin. 5

Risk Factors for Colorectal Cancer. 9

Dietary Risk Factors. 14

Vitamin D and calcium.. 18

Gaps in the Literature Addressed by This Dissertation. 24

Specific Aims. 26

Hypotheses. 27

Chapter 2. Markers of the APC/β-catenin signaling pathway as potential treatable, pre-neoplastic biomarkers of risk for colorectal neoplasms. 28

Abstract. 29

Introduction. 30

Materials and Methods. 31

Results. 36

Discussion. 39

Chapter 3. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on APC, β-catenin, and E-cadherin expression in the normal mucosa of colorectal adenoma patients. 53

Abstract. 54

Introduction. 55

Study Participants and Methods. 56

Results. 62

Discussion. 64

Chapter 4. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients. 77

Abstract. 78

Introduction. 79

Study Participants and Methods. 80

Results. 86

Discussion. 88

Chapter 5. Summary and Public Health Implications. 103

Chapter 6. Future Directions. 106

References. 108

Appendix. 128

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition Health Sciences, Public Health Health Sciences, Epidemiology
Keyword	colonic neoplasms biomarkers life-style diet calcium vitamin D
Committee Chair / Thesis Advisor	Bostick, Roberd M, Emory University
Committee Members	McCullough, Marjorie, American Cancer Society / Nutrition and Health Sciences Goodman, Michael, Emory University Victoria, Stevens, American Cancer Society / Nutrition and Health Sciences Flanders, W Dana, Emory University

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	The investigation and development of dietary and life‐style modifiable, pre‐neoplastic biomarkers of risk for colorectal neoplasms ()	2018-08-28 16:27:01 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions