Vitamin D receptor expression tied to colorectal cancer outcomes

Last Updated: 2016-04-18

By Will Boggs MD

NEW YORK (Reuters Health) - Increased vitamin D receptor expression by tumor stromal fibroblasts is associated with better colorectal cancer outcomes, researchers from Spain report.

"Since the expression of the vitamin D receptor (VDR), the protein that mediates the action of vitamin D compounds, had been shown to decrease in colon carcinoma cells at advanced stages of the disease, it was thought that vitamin D and its derivatives could only be helpful for colon cancer prevention and for patients at early stages of colon cancer progression," said Dr. Alberto Munoz from Universidad Autonoma de Madrid.

"Our results show that these compounds may also exert a protective role in a proportion of colon cancer patients at advanced stages of the disease provided that their cancer-associated fibroblasts (CAFs) express VDR," he told Reuters Health by email.

Stromal fibroblasts increase the frequency of tumor-initiating cells and contribute to poor prognosis in colorectal cancer, and the potential effects of vitamin D on the stroma of patients with colorectal cancer are unknown.

Dr. Munoz's team explored VDR expression and vitamin D3 (calcitriol) action on colorectal stromal cells.

Median overall survival was significantly longer in patients whose CAFs expressed higher levels of VDR than in patients whose CAFs expressed lower levels of VDR (17.4 vs. 12.6 months; p=0.003), according to the study, online April 6 in Gut.

Calcitriol inhibited activation of patient-derived fibroblasts and their promigratory action on colon carcinoma cells, and VDR expression levels appeared to determine the extent of the inhibitory effects of calcitriol on fibroblast protumoral properties.

After calcitriol exposure, CAFs exhibited a gene signature associated with longer survival of patients with colorectal cancer.

Calcitriol also inhibited the protumoral properties of fibroblasts from lung, foreskin, and embryos, all of which expressed VDR.

"Up to now, a series of such protective effects (antiproliferative, prodifferentiation) of calcitriol against colon cancer had been reported on tumor (carcinoma) cells, but never on tumor fibroblasts that are accepted to be important players during the tumorigenic process contributing to tumor malignization," Dr. Munoz explained. "Thus, calcitriol has anticancer effects in colon cancer by acting at both levels/cell types: tumor cells and CAFs."

"It is important to maintain an adequate vitamin D status in colon cancer patients during their whole disease period (probably of all cancer patients and, moreover, of the whole population)," he concluded.

Dr. Elizabeth T. Jacobs from University of Arizona Cancer Center in Tucson told Reuters Health by email, "It is interesting that the authors found that higher VDR expression in tumor stromal fibroblasts was related to better survival in colorectal cancer (CRC) patients, in addition to the finding that the hormonal form of vitamin D inhibited two pathways in colon carcinoma cells. These findings tie together population-level observations with mechanisms of action."

"These findings lay the groundwork for precision medicine related to the vitamin D pathway via the assessment of whether a patient expresses the vitamin D receptor in either carcinoma cells or in tumor stromal fibroblasts," she said. "As the authors point out, these findings suggest that if the patient does express VDR, targeted drug treatment with VDR agonists may be a viable treatment strategy for CRC."

"However," Dr. Jacobs cautioned, "these findings do not necessarily indicate that increasing vitamin D intake would aid in improving survival in CRC patients."

SOURCE: http://bit.ly/1Wb0qRC

Gut 2016.