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cientists have uncovered a biological mechanism through
which vitamin D can change the course of melanoma. They found that vitamin D
influences a signaling pathway inside melanoma cells that helps them to thrive.
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research finds a novel mechanism that could explain melanoma.
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."
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