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
Chapter 2. Markers of the APC/β-catenin signaling pathway as potential treatable, pre-neoplastic biomarkers of risk for colorectal neoplasms. 28
Materials and Methods. 31
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
Study Participants and Methods. 56
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
Study Participants and Methods. 80
Chapter 5. Summary and Public Health Implications. 103
Chapter 6. Future Directions. 106
About this Dissertation
|Committee Chair / Thesis Advisor|
|The investigation and development of dietary and life‐style modifiable, pre‐neoplastic biomarkers of risk for colorectal neoplasms ()||2018-08-28||