|
||||||||
|
PATHOLOGY Cancer Cells' Immortality May Depend on Longevity ProteinOne of the hallmarks of a cancer cell is its ability to relentlessly divide without regard for the laws of mortality that govern nearly every other cell in the body. But in their early stages, even tumor cells obey—they undergo a limited number of cell divisions and then die. Eventually, a handful of cells, or possibly only one, finds a way to break through this barrier and give rise to a malignant mass.
David Sinclair (left) and Haim Cohen have identified a gene that some cancer cells may use to retain telomeres, and thus become immortal. People with a defective copy of the gene age prematurely, presumably due to a lack of telomeres. Photo by Pam Murray A team of HMS researchers has identified a protein that 10 percent of tumor cells use to attain this immortal state. By blocking the molecule, it may be possible to stop these cancer cells from proliferating. The approach might also be used as part of a two-pronged strategy to combat the remaining 90 percent of tumors, the researchers say. "This gives us a new drug target for cancer," said David Sinclair, HMS assistant professor of pathology. He and Haim Cohen, HMS research fellow in pathology, published their findings in the March 6 Proceedings of the National Academy of Sciences Early Edition. Immortality SwitchMost tumor cells become cancerous by turning on a gene for telomerase, a protein that makes the protective caps at each end of a chromosome. In normal cells, these nubs, or telomeres, erode every time cell division occurs, and it is their steady unraveling that causes a cell to age and die. "The malignant cancer is generally the one that gains the ability to lengthen its telomeres," said Sinclair.But a minority of cancer cells—about 10 percent—manage to rebuild their telomeres without turning on the telomerase gene. Sinclair and his colleagues have evidence that they may be doing this by coopting the WRN protein, which is thought to build telomeres. The researchers found that "humanized" yeast cells—whose telomerase gene is turned off—did not survive beyond the normal number of cell divisions when deprived of SGS1, their version of WRN. Yeast cell colonies endowed with the homologue were able to proliferate endlessly. "We can think of SGS1 and the WRN proteins as longevity molecules," Sinclair said. "Cancer cells may use the WRN protein to become im-mortal and get around the barrier to tumorigenesis and cancer formation." If WRN plays the same role in the minority of human cancer cells that multiply without turning on telomerase, the discovery could lead to a new tumor-fighting strategy. "If we could block or inhibit the WRN protein in these 10 percent of cancers, we'd have a good chance of preventing proliferation," said Sinclair. Two FrontsIndeed, the approach might even be applied to the 90 percent that attain their immortality by switching on the telomerase gene. Researchers have found that when they block the telomerase gene in those cancer cells, they still make telomeres, presumably by switching to the WRN path."If you tackle the other 90 percent by blocking them, they'll jump into the other pathway," Sinclair said. "We have to use a double-pronged attack." Nature may have conducted a kind of clinical trial of the anti-WRN strategy. People with a rare disease, Werner's syndrome, are born without the WRN gene. Though they age much faster than other people, they do not develop the usual type of cancers. Instead, they are more vulnerable to rarer cancers such as sarcomas and meningiomas. "It is possible that the absence of WRN may give them partial protection, which is why these patients don't develop these other more common cancers. This is pure speculation at the moment," he said. Sinclair first suspected WRN's role in human cancers while unraveling the mystery of Werner's syndrome. Researchers had shown that the premature aging displayed by Werner's patients was due to a defect in their telomeres. To pinpoint the defect, Sinclair and Cohen created the special breed of humanized yeast. Normally, yeast cells make telomerase their whole life, while human cells stop making it soon after conception. The researchers turned off the telomerase gene using the recently developed Cre-lox P method. They turned off the gene in wild type yeast cells and those in which the SGS1 gene had been knocked out. Though the wild type cells appeared unaffected, the SGS1 knockouts, deprived of telomerase, aged faster and died earlier. In fact, the reduction in overall lifespan was about that of Werner's patients—30 percent. Cell SurvivorAs both sets of cultured cells began dying out, the researchers looked for survivors. "Typically, when we let cultured cells senesce, survivors come through—cells just pop up," said Sinclair. But only the yeast cultures with the SGS1 intact yielded survivors, and they kept on dividing.It is not yet clear how the SGS1 protein—and by implication, WRN —confers immortality on the cells. Previous work by Sinclair showed that SGS1 helps maintain the stability of the chromosome, especially its telomeres. Because this stability is crucial to the integrity of a cell, the optimal cancer-fighting therapy might be to block WRN only in cancer cells. On the other hand, said Sinclair, Werner's patients don't begin developing aging symptoms until they reach their mid- to late teens, which means systemic delivery for short periods—a month or two—may not have deleterious effects. "What I foresee is either having a short-term dose of this drug or targeting it to cells that are cancerous," said Sinclair. "Of course, getting this drug to cancer cells is the challenge." —Misia Landau |
