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Stanford Report, February 12, 2003

Cancer research uncovers protein’s double identity

By AMY ADAMS

Cancer cells are a wily foe. Just when researchers find the proteins that cause cancer cells to run rampant and develop new therapies to block their action, evidence shows that these same proteins serve a different role in other types of cancer. In essence, what cures one problem may trigger another.

In most cancers, a protein called NF-kB acts as a cellular accelerator, pushing the cell to continue dividing. With that in mind, researchers have begun generating drugs to disarm this accelerator and prevent cancer cells from dividing. But a paper in the Feb. 6 issue of Nature reported that in cancers of a group of cells called the epithelia, NF-kB actually slows division. Blocking NF-kB may fuel cancers in epithelial tissues — which include the skin, colon and breast — rather cure them.

"The tissue type is critical in determining the outcome of a cancer therapy," said Paul Khavari, MD, PhD, professor of dermatology who led the study. "We’ve been swimming against the current with this research, showing that epithelial cells may differ from commonly studied cell lines."

Khavari and his lab members used a novel approach for studying the function of NF-kB. Most studies of proteins involved in controlling cell division are done in cancerous cells in a lab dish. But these cells are abnormal in many ways — some of which contribute to the cancer, while others are mere side effects.

Rather than studying these mixed-up cells, Khavari created cancerous cells by inserting two genes into normal skin cells. One of these genes makes a protein that binds NF-kB and prevents it from functioning, basically eliminating the effect of NF-kB.

The other gene makes a highly active version of a protein called RAS, which is commonly mutated in cancer cells. Where NF-kB was thought to be the accelerator in epithelial cells, RAS is thought to be the brake.

Khavari then placed these altered skin cells on mice. Conventional wisdom holds that blocking the accelerator (NF-kB) and boosting the brakes (RAS) should slow down the cycle. Instead, Khavari’s cells became cancerous.

"We can’t extrapolate that therapies targeting NF-kB and RAS won’t be useful," Khavari said. However, he expects his results will apply to cancers of the skin, breast and colon — three of the most common cancers in the United States.

This study was particularly surprising given that researchers once thought many cell changes were needed to induce cancer. "It was a surprise that these cells became cancerous with just two genetic changes," Khavari said.

This work makes clear that not all cells use proteins the same way, Khavari noted. Cancer treatments that go to every cell in the body may have unintended consequences.

Instead of body-wide treatment, Khavari believes that treatments targeting just the cancer cells in question may be a more effective approach to fighting the disease, and with fewer side effects. "Such a step may be important in developing systematic approaches to treatment that are very precise," he said.

Co-first authors on the paper were postdoctoral fellows in the Khavari lab Maya Dajee, PhD, and Mirella Lazarov, PhD.

Other Stanford researchers who contributed to this work are postdoctoral fellows Jennifer Zhang, PhD, Cheryl Green, PhD, Alan Russell, PhD, and Yoshiaki Kubo, MD, PhD; Ti Cai, PhD, research associate; Peter Marinkovich, MD, assistant professor of dermatology; Shiying Tao, technician; and Qun Lin, PhD, research associate.




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