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Sci. Aging Knowl. Environ., 14 August 2002
Vol. 2002, Issue 32, p. nw114
[DOI: 10.1126/sageke.2002.32.nw114]

NOTEWORTHY ARTICLES

No Supermodel

Cancer pathway might differ in mice and humans

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/32/nw114

Key Words: oncogenesis • MAP kinase • NIH 3T3

Abstract: We don't scuttle along baseboards or spritz our homes with urine; they don't drive air-fouling SUVs or lose their hide in the stock market. But deep down, mice and people are much alike, especially in the molecular events that trigger cancer--or so many scientists thought. A new study challenges that view, implying that a mutated gene that crops up in almost one-third of human cancers stimulates different biochemical pathways in mice and people. The finding, which some scientists question, suggests a new way to correct the gene's misbehavior.

Patients with pancreatic, thyroid, or colon cancer frequently carry a fault in the gene Ras, which helps govern cell growth. Studies of mice have revealed some of Ras's machinations: It activates three biochemical pathways, those involving the Raf kinase, PI3 kinase, and RalGEF proteins, respectively. The Raf kinase pathway--but not either of the other two pathways alone--makes a cell grow uncontrollably. New work, however, hints that Ras might function differently in people. Identical mutations in the gene don't trigger the same cancers in mice and humans, for instance.

Hamad and colleagues investigated further by using three mutated versions of Ras, each of which activates only one of the pathways. They commandeered a virus to haul DNA snippets containing the different forms of the gene into human and mouse cells. To determine whether the added DNA sparked cancer, the team gauged how well the cells grew on soft agar, a talent that characterizes cancerous cells. Only two kinds of cells flourished in culture: mouse cells that received the Raf kinase-prodding version and human cells with the RalGEF-activating insert. The disparity suggests that different pathways incite cancer in the two species and raises new questions about relying on mouse models to understand human cancer, says molecular biologist and co-author Christopher Counter of Duke University in Durham, North Carolina. "We're not saying that the mouse model is invalid, but it has limitations." For instance, drawing on rodent results, scientists searching for ways to stymie cancer have focused on severing the PI3 and Raf kinase pathways. Counter recommends targeting RalGEF.

The finding is "provocative," says cancer biologist Frank McCormick of the University of California, San Francisco, because it highlights our ignorance of Ras's role in cancer. Further investigation of human tumors might reveal differences not just between the two species, he says, but between types of human cells. "Every cell type may have its own repertoire of effectors." However, molecular biologist Geoffrey Clark of the National Cancer Institute's branch in Rockville, Maryland, sees another possible explanation for the discrepancy. A study published last September showed that although mouse cells with the RalGEF-activating mutation wouldn't grow on agar, they could seed tumors if injected into a rodent's bloodstream. In the latest experiments, the mutation might have turned the mouse cells cancerous, but they didn't multiply because of their aversion to agar. "Questions remain as to the relationship between growth in soft agar and tumor formation in animals," Clark says. Clearly, the study gives cancer researchers plenty to gnaw on.

--Mitch Leslie

N. M. Hamad, J. H. Elconin, A. E. Karnoub, W. Bai, J. N. Rich, R. T. Abraham, C. J. Der, C. M. Counter, Distinct requirements for Ras oncogonesis in human versus mouse cells. Genes Dev. 16, 2045-2057 (2002). [Abstract/Full Text] [Link is expected to work by 16 August 2002.]

Further Reading

Y. Ward, W. Wang, E. Woodhouse, I. Linnoila, L. Liotta, K. Kelly, Signal pathways which promote invasion and metastasis: Critical and distinct contributions of extra-cellular signal-regulated kinase and Ral-specific guanine exchange factor pathways, Mol. Cell. Biol. 21, 5958-5969 (2001). [Abstract] [Full Text]

Citation: M. Leslie, No Supermodel. Science's SAGE KE (14 August 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/32/nw114







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