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Work offers new insight into cancer metastasis

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Scientists know a great deal about how tumors originate and develop, but relatively little about how cancer manages to metastasize and invade distant tissues and organs. Now, a team of researchers led by biology professor Robert Weinberg of MIT and the Whitehead Institute has discovered that tumors spread by reactivating and commandeering a "sleeper" protein that should have been shut off permanently in early embryo development.

"As a result, cancer cells acquire in one fell swoop many of the abilities they need to execute the complex stages of metastasis," Weinberg said.

Metastasis is a highly inefficient, multistep process. The cancer cells first must invade a nearby tissue and 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.

The entire operation involves so many steps that it raises an obvious question: How do cancer cells cobble these behaviors together and acquire the ability to do all this? According to the new study, they don't. Rather, they hijack an existing cellular process and use it to disperse throughout the body.

Reporting in the June 25 issue of the journal Cell, the researchers described how a breast carcinoma in mice misappropriates a protein called Twist. Twist is a gene regulator, meaning it tells genes when to turn on and when to turn off.

But Twist is mainly active in early embryonic development, where it enables cells to move from one part of an embryo to another and allocate these cells to different tissues. As an embryo develops, Twist's functions no longer are necessary, and it soon becomes dormant in most tissues throughout the rest of an organism's life.

Through a process that still is somewhat unclear to researchers, tumor cells reactivate this long-dormant protein and thereby acquire the ability to move throughout the body.

The research was conducted in two phases. First, Whitehead postdoctoral fellows Jing Yang and Sendurai Mani compared metastatic and nonmetastatic cancer cells taken from mouse tumors. Using microarray technology to determine levels of gene expression, they found certain genes that were active only in the metastatic cells. The gene that stood out among all the others was one coding for the protein Twist.

Next, Yang isolated highly metastatic cancer cells and disabled the Twist gene. When she injected these cells into mammary glands of mice, the mice developed primary, localized breast tumors, but the tumors were unable to metastasize. Furthermore, their study showed that Twist caused breast cells to separate from one another, losing their cell-cell adhesion and then scattering, thereby allowing these cells to travel to distant organ sites, like dandelion seeds dispersed by the wind.

"Twist is probably the first gene regulator that has been tied so definitively to human cancer metastasis," says Yang.

Andrea Richardson, a pathologist at Brigham and Women's Hospital and Harvard Medical School and coauthor on the paper, correlated these findings with her lab's data taken from human breast cancer studies, essentially reanalyzing her lab's data in light of Yang's. She found that Twist is highly expressed in invasive lobular carcinoma, a unique type of breast cancer where breast tumor cells completely lose their cell-cell adhesion and infiltrate other tissues.

"In many mouse studies, you have great models and come up with something and it cures the mice, but then it never seems to work in people," Richardson said. "In this case we were seeing the exact same phenotype and gene expression correlation in human breast tumors."

Although clinical applications of this research are still unclear, Richardson can see the potential for developing a Twist inhibitor--a drug that wouldn't kill a tumor but rather stop its metastatic capabilities. "Something like that would turn cancer into a chronic disease rather than a deadly one," she suggested.

Yang also can see potential to apply these findings diagnostically. "With breast cancer patients diagnosed with a primary tumor, it's hard to tell whether or not that tumor will generate metastases," she says. "Some small tumors will metastasize, some large ones won't. Here we might be able to discover if a tumor is ready to invade and metastasize or not by finding out if the Twist gene is on or off."

For now, the discovery of Twist is only the beginning. "There are a number of other regulatory proteins that have been studied in other labs and have properties very similar to those of Twist. The other regulators undoubtedly will play important roles in other types of human metastatic cancer," Weinberg said.

Additional authors of the Cell paper are from the Broad Institute of MIT and Harvard; the 3MGH Center for Cancer Research in Charlestown, Mass., the Ecole Normale Superieure in Paris; INSERM CRLC in Montpellier, France; and Ben Gurion University in Beer Sheva, Israel.

Funding is from the National Institutes of Health, the MIT/Ludwig Fund for Cancer Research, and Harvard SPORE in Breast Cancer.

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