Cancer and fate swapping cells

Fate-swapping cells drive deadly tumor
Posted by Edyta Zielinska

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The reason melanoma is the deadliest form of skin cancer stems from the curious ability of all of its cells to swap fates, according to a study publishing in Cell this week. “This is an important study,” David Fisher, a researcher and dermatologist at Massachusetts General Hospital and Harvard Medical School, said in an email. “The work [helps] to explain several key features of melanoma — which may well occur in other cancers as well.”

One of the defining characteristics of tumor cells is that they divide more rapidly than most tissues in the body. Chemotherapy and radiation are effective treatments for some cancers for that very reason: they target rapidly dividing cells. But recently researchers have found a second population of cells in the tumor, called cancer stem cells, which divide more slowly, are resistant to treatment, and quickly replenish the tumor mass after therapy — causing the cancer to recur in patients.

Meenhard Herlyn from the Wistar Institute and colleagues found that melanoma doesn’t necessarily harbor stem cells, per se. Rather, in this cancer, every tumor cell carries the potential to be both stem-like (slowly dividing) and cancerous (rapidly dividing). This is not the case in other types of cancer, Herlyn explained, since other cancers contain cells that are not tumorigenic — in other words, when those cells are removed from a tumor, they do not have the potential to initiate tumor growth in a new context. In contrast, every cell in a melanoma tumor has that potential, possibly explaining the aggressiveness of this cancer, which is the cause of 75 percent of all deaths from skin cancer.

The researchers were able to distinguish the slowly dividing cells from quickly dividing cells using a marker for the enzyme JARID1B, only expressed by slow growing melanoma cells.

Finding JARID1B was a stroke of luck, said Herlyn. When Alexander Roesch, a visiting clinician from the Regensburg University Medical Center in Germany, told Herlyn that he had a tumor-suppressor gene he wanted to work on named JARID1B, Herlyn told Roesch that the gene was outside the scope of the laboratory. “We told him ‘you have to give up your project,'” Herlyn recalled. But when Roesch found a paper that indicated the JARID1B enzyme was expressed in stem cells, Herlyn agreed to work on it. His laboratory had been focused on trying to characterize melanoma stem cells, so this protein fit the bill. It was a fortuitous decision. “Two and a half years later, we came to the conclusion that there are no stem cells in melanoma,” said Herlyn.

When they took these JARID1B cells out of the tumor environment, these slow-growing cells “literally explode,” said Herlyn. “They have an incredibly high proliferation potential.” But the same fast-growing cells can return to a slow-growing state when re-implanted into an animal.

Not much is know about how JARID1B functions in the cell. It is clearly linked to the cell’s metabolism, and responsible for slowing growth, said Herlyn, “but how it is being turned on,” and its other functions in the cell, “we do not know,” said Herlyn.

The results suggest that therapies for melanoma will have to target both the slow and fast growing populations in order to be effective, the researchers said. To test the therapeutic potential of JARID1B as a target for anti-tumor therapy, Herlyn’s group used a short hairpin RNA to temporarily knock down the JARID1B enzyme. Although they observed an initial increase in tumor growth, over time, the tumor growth slowed. “The tumor cannot be maintained if this gene is knocked down,” said Herlyn.

“The work identifies a potentially important new drug target worthy of clinical investigation,” agreed Fisher.

A. Roesch, et al., “A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth,” Cell, 141:583-94, 2010.

Read more: Fate-swapping cells drive deadly tumor – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57402/#ixzz0p43hKPvM

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