Researchers discover why melanoma is so malignant

September 04, 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.

"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.
-end-
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.

This research was supported by a grant from the U.S. National Institutes of Health and the National Cancer Institute.

Written by David Cameron

Whitehead Institute for Biomedical Research

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