The researchers suggest that reducing the activity of the pathway could be a way to help the immune system fight this most dangerous of skin cancers.
While scientists have observed that people with melanoma fare less well if they have low levels of vitamin D, they have not known the reason.
The new Cancer Research study provides a molecular explanation.
“This new puzzle piece will help us better understand how melanoma grows and spreads, and hopefully find new targets to control it,” says Julia Newton-Bishop, a professor of dermatology at the University of Leeds in the United Kingdom.
“But what’s really intriguing,” she adds, “is that we can now see how vitamin D might help the immune system fight cancer.”
Melanoma starts in melanocytes
Cancer arises when cells grow out of control and proliferate. In the case of melanoma, cancer starts in melanocytes, which are the cells that make the pigment that gives color to skin, hair, and eyes.
Although it is the least common of the skin cancers, melanoma is the most dangerous.
This is because, without early diagnosis and treatment, there is a much higher chance of cancer spreading to other parts of the body.
According to the National Cancer Institute (NCI), which is one of the National Institutes of Health (NIH), around 2.3% of people in the United States will receive a melanoma diagnosis at some point in their lives.
The NCI estimate that more than 92% of people with melanoma survive at least 5 years after diagnosis and that nearly 1,196,000 were living with melanoma in the U.S. in 2016.
Vitamin D and its receptor
For the new study, Prof. Newton-Bishop and colleagues investigated the cell biology of vitamin D in melanoma. They began by looking at what happens when cells lack a protein known as a vitamin D receptor (VDR).
Vitamin D cannot send signals into cells unless the cells have VDRs on their surfaces.
It is the binding of the vitamin D molecule to its matching receptor that releases the signal into the cell.
So, to examine what happens in cells that lack VDR, the team studied the VDR gene that has the instructions for making the protein.
They investigated VDR in samples from 703 human melanoma tumors and in another 353 melanoma tumors that had spread from the original site.
They also looked for links between the gene’s activity and other features, including the thickness of the melanoma tumors and how fast they grew, together with any genetic alterations that might accompany faster tumor growth.
Tumors grew faster with low VDR
Following these investigations, the team then used mice to see how melanoma aggressiveness responded to changes in VDR levels.
The findings showed that human tumors grew more rapidly when their VDR gene expression was low. In addition, these tumors showed lower expression in genes that control pathways that promote immune activity against cancer cells.
The researchers also found that low VDR in tumors corresponded to higher expression of genes that promote cancer growth and spread.
One particularly noticeable gene cluster was the one that controls a signaling pathway called Wnt/β-catenin. This pathway has many cell functions, one of which is to promote growth.
In a further set of experiments on mice with melanoma, the researchers showed that they could reduce the activity of the Wnt/β-catenin pathway by raising VDR expression on the cancer cells. This manipulation also reduced the chances of the melanoma spreading to the animals’ lungs.
Helping the immune system fight cancer
The findings reveal a potential way of using vitamin D to reduce Wnt/β-catenin pathway activity, and thereby help the immune system to tackle the cancer.
“We know when the Wnt/β-catenin pathway is active in melanoma,” Prof. Newton-Bishop explains, “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,” she continues, “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.”
“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/β-catenin pathway.” — Prof. Julia Newton-Bishop
