A new study published in Cancer Research on November 6, 2019, from Cancer Research UK suggests that vitamin D may reduce the aggressive nature of melanoma cells, and improve survival rates.
Melanoma is a type of skin cancer that is deadly but relatively rare in the population. This aggressive disease accounts for the majority of deaths due to skin cancer. Each year 16,000 patients are newly diagnosed with melanoma each year in the UK, with about 300 of these being advanced-stage cancer.
With the advancement of treatment methods, the survival rate has doubled over the past 40 years. Despite this, advanced stage melanoma has a 1-year survival rate of just 55%, compared to almost 100% for those whose cancer is picked up very early.
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Vitamin D (or properly, 1α,25-dihydroxyvitamin D3) is a fat-soluble vitamin with important physiological functions in the body. Prior research has shown that vitamin D deficiency in the blood is associated with poorer outcomes in melanoma.
Melanoma patients often avoid sunlight, to prevent exposing their skin to solar ultraviolet rays, and are therefore at a higher risk of being vitamin D-deficient. Conversely, a higher level of vitamin D in the blood is linked to smaller tumors and better outcomes. However, the mechanism responsible for this finding is unknown.
Investigating the link between vitamin D levels and melanoma
To investigate this phenomenon, the current University of Leeds study looked at how vitamin D interacts with melanoma cells through the vitamin D receptor (VDR) on the cell surface.
First, the scientists examined the VDR gene in 703 melanomas from human patients and 353 other melanoma tumors which had gone beyond their site of origin. They wanted to find out how actively this gene was producing the VDR protein in these tumors. To do this, they measured the amount of VDR in cells collected from each of these tumors.
They also indexed the thickness of each tumor and its rate of growth. The researchers then compared the level of VDR gene activity (or expression, as it is called) with the clinical characteristics of the melanoma in each patient.
The data suggested a link between the expression of the VDR (or the amount of VDR protein) found in each cell, which indicates gene activity, and the aggressiveness of the tumor.
The pathway responsible for the link
The researchers found that low levels of VDR gene expression occurred in tumors with higher growth rates, whether primary or metastatic melanomas. In addition, low levels of vitamin D also seemed to be linked to the inhibition of genes that regulate cancer-fighting immune responses in the body. In turn, such tumors showed lower numbers of immune cells, particularly of tumor-infiltrating lymphocytes (TILs) on microscopic examination.
Low VDR expression was also associated with a higher expression of genes that were associated with faster growth and spread of the tumors, or in other words, with genes that promote tumor aggressiveness. Reduced VDR expression was especially linked to genes that regulate the Wnt/β catenin pathway, a cellular signaling pathway that influences multiple processes within the cell including cell growth.
The scientists also found certain gene mutations in metastatic tumors, such as the deletion of the VDR gene or methyl group addition on the promoter region of the gene. This prevents the activation of the gene and thus results in an unduly low level of VDR on these tumor cells.
To confirm their results, they repeated the assays on mouse melanoma cells. These experiments also showed that increasing VDR expression in melanoma cells inhibited the Wnt/β catenin pathway, and reduced cancer cell growth rates as well as their rate of spread. Finally, they found that the presence of vitamin D deficiency was associated with shorter survival in primary melanoma tumors.
Thus, the study confirms that when the Wnt/β-catenin pathway is active within these tumor cells, it suppresses the immune response that normally fights cancerous cells and eliminates them before they can form tumors.
This pathway also encourages cell proliferation and tumor growth. Suppression of the pathway by increasing vitamin D-VDR binding improves host immunity and reduces the rate of tumor growth and metastasis.
Implications of the research
The excited researchers say this has given them the knowledge of how vitamin D affects melanoma cells via the VDR to increase Wnt/β catenin signaling and in turn encourage tumor growth and spread. Senior researcher Julia Newton-Bishop says,
This will help us better understand how melanoma grows and spreads, and hopefully find new targets to control it. We can now see how vitamin D might help the immune system fight cancer.”
Drawing encouragement from the way vitamin D suppresses the Wnt/β-catenin pathway, she further says, “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.”
Martin Ledwick from Cancer Research UK pointed out that the National Health Service (NHS) already advises that people take 10 micrograms of vitamin D every day to maintain good muscle and bone health, more particularly during winter when sunlight exposure is low.
Ledwick says that if melanoma has been recently diagnosed, the patient should have a serum Vitamin D measurement done to guide management. If the level of this vitamin is low, a medical consultation should be done to prevent ill-effects due to this deficiency, as vitamin D levels can be increased by diet or supplements.
Muralidhar, S., et al. (2019). Vitamin D-VDR signaling inhibits Wnt/beta-catenin-mediated melanoma progression and promotes anti-tumor immunity. Cancer Research. DOI: 10.1158/0008-5472.CAN-18-3927.