Clone numbers decline (red) when UVB is withdrawn.

Brash/NAS

Acancer cell can spawn a tumor only if it begins to multiply, a process usually blamed on mutations in oncogenes or tumor-suppressor genes. Now, a new study suggests that carcinogens may promote the growth of cancer cells by altering the cell's surroundings instead of by causing genetic damage.

Clonal expansion, when a single cancer cell explodes into a multitude, is what makes cancers dangerous. “One cell never killed anybody,” says Douglas Brash of Yale Medical School in New Haven, CT. The widely accepted “multiple-hit hypothesis” attributes clonal expansion to a mutation that liberates the cell from normal growth controls.

Suspecting a different mechanism was involved, Brash and his coworkers exposed mice to enough UV light to cause a slight sunburn. After three to five weeks of continuous exposure, the skin of the mice was peppered with expanding clumps of cells that had mutations in the p53 tumor-suppressor gene. However, these clumps stopped growing once the UV lamps were shut off. Because growth required continued exposure to UV, Brash and colleagues concluded that clonal expansion did not involve additional mutations to tumor-suppressor genes. Instead, UV was somehow making the mutated cell's environment conducive to growth. “Mutations aren't the whole story,” Brash says. “There are nonmutational events needed to get a multiple-hit model to work.”

Brash thinks that UV exposure might promote clonal expansion by disrupting the skin. The epidermis is composed of many hexagonal compartments, each of which contains up to 20 cells, including a stem cell. In the irradiated mice, the size of a clump of mutant cells was usually a multiple of ∼20 cells, suggesting that UV irradiation enables a mutant stem cell to jump to an adjacent compartment. Brash speculates that UV may kill cells in neighboring compartments, thus giving the mutated cells room to grow.“This paper is going to generate a lot of thought and make people rethink their assumptions about tumorigenesis,” says Amato Giaccia of Stanford Medical Center in Palo Alto, CA. “People should think about further experiments to either disprove or substantiate it.” ▪

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