Sci. Aging Knowl. Environ., 8 January 2003
Vol. 2003, Issue 1, p. nw3
[DOI: 10.1126/sageke.2003.1.nw3]

NOTEWORTHY ARTICLES

No ALTernative

For hard-core cancer cells, only telomerase will do

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/1/nw3

Key Words: APB • ARF • crisis • Ink4a • PML • senescence • mTERC

Mountaineers deprived of oxygen can't recognize when it's time to head back to camp. Similarly, cancer cells keep growing when normal cells have the good sense to call it quits. Cancer cells commonly persist by activating an enzyme that maintains protective caps, known as telomeres, on chromosome ends. A new study suggests that the enzyme also enables cancer to grow in new tissues, an ability that alternative mechanisms of telomere maintenance don't have. The results should encourage researchers who hope to block cancer's treks by inhibiting the enzyme.

Paradoxically, to become cancerous, a cell must first shorten its telomeres, which generates mutations, and then activate a mechanism that maintains what's left, which confers immortality. Telomeres shrink with each successive cell division, and cancer-causing genetic glitches can arise when unprotected chromosomes fuse and break apart repeatedly, a process that transfers DNA chunks to new locations. Most cells balk at this point, and molecular safeguards stop cell division. Mutations can override this feature and allow cells to reproduce, but they usually die when DNA shuffles too extensively (see "Dangerous Liaisons"). However, a minority of mutated cells begins to produce the enzyme telomerase, which replenishes telomeres, enabling them to divide indefinitely--a hallmark of cancer. Although most normal human cells don't manufacture telomerase, cells from nearly all human tumors do.

Chang and colleagues wondered whether telomerase helps cancer cells spread as well as form. To address the question, the researchers isolated cells from cancer-prone mice that also lack the telomerase gene. They grew the cells in culture to force the telomeres to shorten, injected them into mice that produce telomerase normally, and looked for cancer. The cells readily formed tumors under the skin; they also traveled to the lungs but did not grow there. By contrast, when the team added telomerase to the cells before injecting them into animals, they spawned tumors under the skin and in the lungs. The result suggests that cancers need telomerase to metastasize.



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Have telomerase, will travel. Telomerase lets cancer cells spread to mouse lungs and form tumors there (purple). [Credit: S. Chang and R. DePinho/Harvard University]

 
Cells can rebuild telomeres without telomerase by enlisting the so-called ALT pathway--for "alternative lengthening of telomeres"--that seems to work by swapping material from long telomeres onto shorter ones. To test whether ALT, like telomerase, could promote metastasis, the team screened the cancer-prone, telomerase-deficient cells for ones that use ALT--identifiable by several molecular features. Then they injected the ALT-positive cells into mice. Like cells without telomerase, ALT cells grew tumors in skin but not in lung. Together, the results suggest that pumping up telomerase allows cancer cells to spread, but activating the ALT pathway doesn't suffice.

"It's [a] beautiful [discovery]," says oncologist Ned Sharpless of the University of North Carolina, Chapel Hill, adding that "it's clearly telomerase" that's responsible for the aggressiveness of a tumor. Many scientists hope that thwarting telomerase will quash cancer, but researchers worry that ALT could substitute for the enzyme and nullify the drug. "This work suggests that ALT isn't likely to be much of a problem," says cancer researcher Paul Yaswen of Lawrence Berkeley National Laboratory in California. With no alternative route, tumor-prone cells might turn back before they pass cancer's point of no return.

--R. John Davenport

S. Chang, C. M. Khoo, M. L. Naylor, R. S. Maser, R. A. DePinho, Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes Dev. 17, 88-100 (2003). [Abstract] [Full Text]


January 8, 2003 Citation: R. J. Davenport, No ALTernative. Science's SAGE KE (8 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/1/nw3








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