Researchers have found the protein that makes some tumors unresponsive to radiation.

Radiation damages the chromosomes inside cells (lower panel), normally causing the cells to die.

Almost half of all cancer patients receive radiation treatment. When it works, the high-energy rays damage genetic material inside tumor cells, causing them to self-destruct. But some tumors are resistant to the radiation. HHMI investigator M. Celeste Simon at the University of Pennsylvania School of Medicine has uncovered one protein responsible for radiation resistance in some renal cancers and likely implicated in other cancers as well.

Simon's lab studies proteins involved in maintaining normal oxygen levels throughout the body. Called hypoxia inducible factors (HIFs), these proteins usually signal cells to conserve energy when oxygen is depleted, promoting survival. But some types of cells, like those that form new blood vessels, need to grow more aggressively when they sense an oxygen shortage. This is the job, Simon's lab has shown, of HIF2—it encourages oxygen-depleted cells to grow by activating growth factors and inhibiting p53, a protein that normally induces cell death in the presence of DNA damage.

It has long been known that p53 is a tumor suppressor. When it's turned off, tumors can grow more aggressively. p53 inhibition also leads to radiation resistance as it is responsible for telling cells with radiation damage to die.

Knowing this, as well as the fact that radiation-resistant tumors often show signs of oxygen depletion, Simon hypothesized that HIF2 was inhibiting p53 in these cancers. So she tested cell lines from renal cancers for HIF2 and p53 activity. She showed that when a tumor cell has increased HIF2, it has low p53 activity and is therefore resistant to radiation. Moreover, when the lab decreased the amount of HIF2 in a cell, it had increased p53 activity and increased response to radiation. The results appear in the August 25, 2009, issue of Proceedings of the National Academy of Sciences.

If researchers can find a way to block HIF2, Simon says, p53 would once more do its job of directing radiation-damaged cells to die. HIF2 is not the only protein that inhibits p53 in cancers, so while Simon's approach would work for renal cancers with active HIF2, there are likely multiple forms of radiation resistance. Simon does, however, have evidence that HIF2 is linked to some forms of radiation-resistant lung cancer.

Illustration: Omikron / Photo Researchers, Inc.