In melanoma patients, elevated serum levels of vitamin D appear to be helpful. Tumors are thinner. Outcomes are improved. But how, exactly, are these benefits realized? To answer this question, researchers at the University of Leeds scrutinized the interaction between vitamin D and the vitamin D receptor (VDR) on melanoma cells. The researchers, fully aware that vitamin D on its own won’t treat cancer, hoped to identify cell signaling pathways that could lead to new therapeutic strategies.
Led by professor of dermatology Julia Newton-Bishop, the Leeds team decided to assess the activity of the gene that makes VDR. They interrogated the transcriptomes of 703 human melanoma tumors and 353 human melanoma tumors that had spread from the initial site. Then the investigators cross-referenced the activity of the VDR gene with patient characteristics such as tumor thickness and growth rate.
Basically, Newton-Bishop and colleagues wanted to see if the amounts of VDR in human melanoma cells were associated with genetic changes that happen when tumors become more aggressive. VDR expression, the scientists found, could be linked to specific cell pathways. Detailed results appeared November 5 in the journal Cancer Research, in an article titled, “Vitamin D-VDR signaling inhibits Wnt/beta-catenin-mediated melanoma progression and promotes anti-tumor immunity.”
“High tumor VDR expression was associated with upregulation of pathways mediating antitumor immunity and correspondingly with higher imputed immune cell scores and histologically detected tumor infiltrating lymphocytes,” the article’s authors wrote. “High VDR expressing tumors had downregulation of proliferative pathways, notably Wnt/beta-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases.”
These findings, which implicate vitamin D-VDR signaling in the control of downstream signals that help tame melanoma, were validated in additional in vitro tests as well as in mouse models.
“In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/beta-catenin signaling genes,” the scientists indicated. “Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail vein metastasis assays.”
In summary, human tumors with low levels of the VDR gene grew faster and had a lower activity of genes that control pathways that help the immune system fight cancer cells. Human tumors with lower VDR levels also had a higher activity of genes linked to cancer growth and spread, especially those controlling the Wnt/beta-catenin signaling pathway, which helps to modulate a variety of biological processes within the cell, such as its growth.
“After years of research, we finally know how vitamin D works with VDR to influence the behavior of melanoma cells by reducing activity of the Wnt/beta-catenin pathway,” said Newton-Bishop. “This new puzzle piece will help us better understand how melanoma grows and spreads, and hopefully find new targets to control it.
“But what’s really intriguing is that we can now see how vitamin D might help the immune system fight cancer. We know when the Wnt/beta-catenin pathway is active in melanoma, it can dampen down the immune response causing fewer immune cells to reach the inside of the tumor, where they could potentially fight the cancer better.
“Although vitamin D on its own won’t treat cancer, we could take insights from the way it works to boost the effects of immunotherapy, which uses the immune system to find and attack cancer cells.”