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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."
Prof. Julia Newton-Bishop
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