'Knockout' ties cancer gene, kidney growth.

Current dogma in cancer biology holds that tumors can arise when certain "tumor-suppressor" genes malfunction and allow cells to grow and multiply rapidly, much the way cells do when an organ first forms.

"We always talk about cancer as abnormal development," says Jordan A. Kreidberg, a molecular geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Mass. In support of that idea, Kreidberg and his colleagues have demonstrated that one gene implicated in Wilms' tumor -- a type of kidney cancer that afflicts mainly infants -- plays an essential role in kidney development in the embryo.

For their experiments, Rudolf Jaenisch, Kreidberg, and their fellow Whitehead scientists created a special "knockout" mouse strain in which offspring carried one or two faulty copies of a gene that normally "suppresses" the development of Wilms' tumor. They did this by implanting the faulty gene into cells taken from very early mouse embryos, Kreidberg explains. As these cells divided, the inserted mutant gene sometimes "knocked out" the normal gene by switching places with it on the chromosome. Then the researchers placed these altered cells into other embryos. The cells became part of the resulting mice, which then transmitted the altered genes to some of their descendants.

Kidneys do not develop in mouse embryos containing two copies of this faulty suppressor gene, Kreidberg and his colleagues report in the Aug. 27 CELL. "You might think you'd get uncontrolled cell growth," Kreidberg told SCIENCE NEWS. "Instead, you get no kidney at all." Also, the heart, lungs, and gonads are abnormal, causing the embryos to die at about two weeks.

"This [work] has provided some very clear evidence that [the normal gene] is absolutely essential for early kidney development," comments Bryan R.G. Williams, a molecular biologist at the Cleveland Clinic Research Institute.

Typically, human kidneys begin to form when a knob of epithelial cells makes contact with a nearby patch of mesodermal cells and causes them to become epithelial cells. The knob develops into the urethra and the kidney's major collecting duct, while the newly induced epithelium becomes the organ's plumbing. In the knockout mice, this transformation did not occur, and the knob eventually shrank, Kreidberg says.

The Wilms' tumor-suppressor gene directs the production of a protein whose molecular structure suggests it binds to DNA, either activating or suppressing gene activity. "But how that contributes to kidney development is really unknown," says Kreidberg, who hopes the mouse strain will provide researchers a way to study this process.

"Now people can look at particular target genes for Wilms' tumor gene regulation, and it provides a model system for testing various mutants," Williams says.

The Whitehead group would also like to use the mouse as a model for studying how these faulty suppressor genes lead to Wilms' tumor. Children who inherit one good and one bad copy of the gene can develop kidney cancer if the good copy gets destroyed or misplaced somehow in one cell, which then multiplies out of control. That one bad gene can also lead to malformed genitals and urinary tracts, the scientists note.

But, unlike people, mice do not develop the tumor, even if they're born with just one copy of the suppressor gene, says Kreidberg. So the researchers hope to figure out a way to disable both copies of the normal gene after the kidneys form. Then perhaps these mice would get cancer.