Sneaky cells


By Philip Cohen A PROMISING new approach to treating cancer could instead encourage tumours to grow in some cases. Researchers led by Ronald DePinho of the Dana-Farber Cancer Institute in Boston hoped to stop cancer by blocking an enzyme called telomerase which helps rebuild the ends of chromosomes, or telomeres. When cells divide, they lose DNA from their telomeres. Telomerase isn’t made in most of the body’s cells so they can only divide a limited number of times before their chromosomes become so frayed that they die. But when cells turn cancerous, they often switch telomerase back on, which helps explain why they can divide indefinitely. In theory, blocking telomerase should trigger the death of tumour cells. So DePinho and his colleagues created mice missing telomerase and one of two tumour suppressor genes, INK4a or p53, which produce proteins that protect against cancer. One or other of these genes are defective in more than half of all human tumours. Mice have such long telomeres that it takes several generations before losing DNA from their chromosome ends has any effect. In the mice lacking INK4a, 64 per cent of the first generation developed cancer. But as chromosomes dwindled in subsequent generations, so did the incidence of tumours. Only 50 per cent of third generation mice and 31 per cent of fifth-generation mice developed tumours (Cell, vol 97, p 515). That suggested that telomerase would indeed be a good target for anticancer drugs. But the results for the mice lacking both p53 and telomerase dampened this optimism. In a second paper in the same issue of Cell (p 527), DePinho and his colleagues say that cells from the mice are about twice as likely to turn cancerous as those lacking just p53. “It shows that cancer cells are pretty sneaky,” he says. A closer look at the cells suggested why. Cells lacking p53 and telomerase were three times as likely as those lacking p53 alone to suffer a severe genetic rearrangement, which can trigger cancer. Rearrangements may be more likely if telomeres become badly eroded and DePinho believes p53 normally triggers the suicide of cells before this happens. “It calls into question the wisdom of inhibiting telomerase in some tumours,” says Tyler Jacks, a cancer cell biologist at the Massachusetts Institute of Technology in Cambridge. “But it might be hard to figure out which ones.” Tumours sometimes contain a mixture of cells in which different tumour suppressors are defective. DePinho agrees that treating tumours with telomerase inhibitors alone now seems less attractive. “It complicates this approach for drug development,” he says. “You’ll need to hit the cells in other ways,
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