Effects of calcium and vitamin D₃ on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: A randomized controlled trial

Transforming growth factor alpha (TGFα) and TGFβ₁ are growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti-proliferative exposures. The effects of supplemental calcium and vitamin D₃ on these two markers in the normal-appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double-blind, placebo-controlled, 2×2 factorial clinical trial (n=92; 23/treatment group) of calcium 2g and/or vitamin D₃ 800IU/d versus placebo over 6mo. TGFα and TGFβ₁ expression was measured in biopsies of normal-appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-mo follow-up. In the calcium, vitamin D₃, and calcium plus vitamin D₃ groups relative to the placebo group (1) the mean overall expression of TGFβ₁ increased by 14% (P=0.25), 19% (P=0.17), and 22% (P=0.09); (2) the ratio of TGFα expression in the upper 40% (differentiation zone) to that in the lower 60% (proliferation zone) of the crypts decreased by 34% (P=0.11), 31% (P=0.22), and 26% (P=0.33); and (3) the TGFα/TGFβ₁ ratio in the upper 40% of the crypts decreased by 28% (P=0.09), 14% (P=0.41), and 22% (P=0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D₃ may increase TGFβ₁ expression and shift TGFα expression downward from the differentiation to the proliferation zone in the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial.