Researchers discover why melanoma is so malignant
CAMBRIDGE, Mass. (September 4, 2005) — About
60,000 Americans will be diagnosed with melanoma this
year, says the American Cancer Society, and 10,000 of
those cases will be fatal. If not caught in the early
stages, melanoma can be a particularly virulent form
of cancer, spreading through the body with an efficiency
that few tumors possess. Now, researchers at Whitehead
Institute for Biomedical Research have discovered one
of the reasons why this particular skin tumor is so
ruthless. Unlike other cancers, melanoma is born with
its metastatic engines fully revved.
This new study shows that as melanocytes—cells
that protect the skin from sun damage by producing
pigmentation—morph into cancer cells, they
immediately reawaken a dormant cellular process
that lets them travel swiftly throughout the body. |
“Other cancers need to learn how to spread, but
not melanoma,” says Whitehead Member Robert
Weinberg, senior author of the paper that will be
published September 4 in the early online edition of
the journal Nature Genetics. “Now, for the first
time, we understand the genetic mechanism responsible
for this.”
Metastasis (the spread of disease to an unconnected
body part) is a highly inefficient, multi-step process
that requires cancer cells to jump through many hoops.
The cells first must invade a nearby tissue, then make
their way into the blood or lymphatic vessels. Next
they must migrate through the bloodstream to a distant
site, exit the bloodstream, and establish new colonies.
Researchers have wondered why melanoma in particular
is able to do this not only more efficiently than other
cancers, but at a far earlier stage. This new study
shows that as melanocytes—cells that protect the
skin from sun damage by producing pigmentation—morph
into cancer cells, they immediately reawaken a dormant
cellular process that lets them travel swiftly throughout
the body.
Central to this reawakened process is a gene called
Slug (named after the bizarre embryo shape that its
mutated form can cause in fruit flies). Slug is active
in the neural crest, an early embryonic cluster of cells
that eventually gives rise to a variety of cell types
in the adult, including dermal melanocytes. In this
early embryonic stage, Slug enables the neural crest
cells to travel, and then settle, throughout the developing
embryo.
“Slug is a key component of the neural crest’s
ability to migrate,” says Piyush Gupta, a MIT
graduate student in Weinberg’s lab and first author
on the paper. “Following its activation during
embryonic development, Slug is shut off in adult tissues.”
But when skin cells in, say, an individual’s mole,
become malignant, they readily reactivate Slug and gain
the ability to spread—something that other cancers
can spend decades trying to do.
Weinberg’s team demonstrated this through a number
of experiments. In the first, they created models of
various cancer types by introducing cancer causing genes
into normal human cells and then injecting the tumor
cells underneath the skin of mice. Mice injected with
breast cancer cells or with fibroblast (connective tissue)
cancer cells developed tumors, but the tumors didn’t
spread. Those injected with melanoma cells immediately
developed invasive tumors throughout their body, spreading
everywhere from the lungs to the spleen. This strongly
supported the suspicion that melanoma is so metastatic
in part due to properties intrinsic to melanocytes themselves,
and not simply because it is external and thus uniquely
exposed to environmental stresses.
For the second experiment, the team used microarray
technology (chips covered with fragments of DNA that
can measure gene levels) and found that Slug was expressed
in human melanoma. “Really, this isn’t that
surprising,” says Gupta, “when you consider
that melanocytes in the skin are direct descendants
of the neural crest.” In fact, Gupta points out
that occasionally physicians discover that perfectly
benign melanocytes will sometimes manage to migrate
through a patient’s body into, say, the lymph
nodes. This phenomenon isn’t related to cancer,
but rather demonstrates the latent ability of melanocytes
to travel.
Finally, the research team found that when Slug was
knocked out in melanoma cells, the cancer was unable
to metastasize when placed into a mouse.
“This work is yet another demonstration of the
notion that certain embryonic genes normally involved
in transferring cells from one part of the body to another
are also involved in enabling cancer cells to spread,”
says Weinberg, who is also a professor of biology at
MIT.
An earlier demonstration of this notion was reported
in a June 2004 paper in the journal Cell (http://www.wi.mit.edu/news/archives/2004/rw_0624.html).
Here, Weinberg and colleagues described how a similar
embryonic gene called Twist becomes active in certain
forms of breast cancer, thereby aiding metastasis. However,
there are two important distinctions: First, Twist isn’t
reactivated until later in the tumor’s life. And
second, while breast cancer cells appear to hijack Twist,
melanoma tumors kick-start a process that was once natural
to their cellular ancestors.
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