Dietary Calcium and Cholecalciferol Modulate Cyclin D1 Expression, Apoptosis, and Tumorigenesis in Intestine of adenomatous polyposis coli1638N/+ Mice1,

Abstract

Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)(1638N/+) mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc(1638N/+) mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 +/- 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc(1638N/+) mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.

Meta-Analyses of Vitamin D Intake, 25-Hydroxyvitamin D Status, Vitamin D Receptor Polymorphisms, and Colorectal Cancer Risk

“…Some animal studies indicated that vitamin D status may influence the growth of intestinal tumors (76)(77)(78)(79). Vitamin D status modulates various genes in the colorectal mucosa that may influence the cancer risk (71,80).…”

Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial

“…Both in vitro and animal studies show that calcium (11)(12)(13) and vitamin D (14) exert an impact on pathways involved in colonic neoplasia. However, these studies do not determine the direct effects of these compounds on the colon of subjects at risk of developing CRC.…”

Extracellular calcium-sensing receptor/PTH knockout mice colons have increased Wnt/β-catenin signaling, reduced non-canonical Wnt signaling, and increased susceptibility to azoxymethane-induced aberrant crypt foci

“…[1][2][3] The mechanism by which this chemoprevention occurs is not understood. 4 Although increased dietary calcium could chelate and reduce bile acid concentration in the lumen, a different target of increased luminal calcium is the extracellular calcium-sensing receptor or CaSR.…”