By Duke Medicine News and Communications

DURHAM, N.C. -- Scientists from Duke University Medical Center have identified the "master switch" that cancer cells use to dispatch protective messages to nearby blood vessels, fortifying the vessels against deadly onslaughts of radiation.

The messages enable blood vessels to survive and ultimately nourish any remaining cancer cells that escape toxic radiation therapy.

Radiation biologists from the Duke Comprehensive Cancer Center identified the master switch as a protein called "Hypoxia Inducible Factor" (HIF-1) that turns on production of these protective messages.

They suppressed HIF-1 with experimental drugs given together with radiation therapy in animals with cancer. In doing so, they successfully inhibited blood vessel growth in tumors and, thereby, the growth of tumors themselves.

The Duke scientists hope to test this potential new therapy plus radiation in humans within the very near future. Results of their current findings are reported in the May, 2004, issue of Cancer Cell.

"HIF-1 is the switch inside cancer cells that gets turned on by radiation therapy," said Mark Dewhirst, Ph.D., DVM, professor of radiation oncology at Duke and principal investigator of the study. "Once it is activated, HIF-1 then triggers the production of well-known growth factors such as VEGF and bFGF, as well as more than forty different protein signals that regulate tumor metabolism, metastasis and angiogenesis." Angiogenesis is the process by which cancer cells grow new blood vessels to nourish and sustain themselves.

"By blocking the master switch, we effectively blocked many of the proteins which promote angiogenesis," said Dewhirst.

The Duke discovery follows dozens of recent developments in the field of anti-angiogenesis, in which scientists have attempted to block specific proteins that give rise to or protect tumor-feeding blood vessels.

The most noteworthy success has been Avastin, the first drug to be approved by the FDA to suppress angiogenesis in patients with spreading colorectal cancer. Avastin inhibits the protein VEGF and has been shown to extend patients' lives when taken together with chemotherapy.

Dewhirst and first author Benjamin Moeller said their technique of suppressing HIF-1 expression could, theoretically, be a more potent inhibitor of blood vessel survival than the current approach of just suppressing a single protein, such as VEGF.

"We're employing a treatment strategy where we accomplish two hits -- killing the cancer cells with radiation and blocking their blood vessel survival with an anti-HIF drug," said Moeller, a graduate student in the Duke M.D./Ph.D. program. "By pinpointing and blocking the source of all the signals, we have successfully halted the cancerous blood vessel growth in animals without harming normal blood vessels."

Approximately half of all cancer patients in the U.S. are treated with radiation therapy. However, the success of therapy depends largely on how sensitive a tumor's blood vessels are to radiation. If blood vessels in the tumor survive after radiation, they can provide nutrients to the surviving cancer cells to begin rebuilding the tumor.

Thus, knowing how HIF-1 works inside cancer cells is critical to manipulating its behavior and making its blood vessels more responsive to radiation, said Moeller.

It is already known that radiation boosts oxygen levels inside cancer cells. In the new study, Moeller demonstrated that the infusion of oxygen releases pent-up RNA, the genetic blueprint molecule, for HIF-1 protein which is bound up in tiny particles called stress granules. The oxygen disintegrates these stress granules and allows HIF-1 to be produced and to engage in production of growth factors.

Secondarily, the infusion of oxygen produces "reactive oxygen species" -- also known as oxygen free radicals -- inside cancer cells. Reactive oxygen species were also shown to boost HIF-1 production, the study showed.

"Tumors so desperately seek to protect themselves against radiation that they have two completely different mechanisms for boosting HIF-1 regulated gene production to protect their blood vessels," said Dewhirst. The team's unexpected findings shift the accepted paradigm of how HIF-1 works inside cancer cells and provides major insight into how HIF-1 regulates angiogenesis after radiation therapy, he said.

"We've known that oxygen levels and blood vessel growth inside tumors are two major influences on how a tumor responds to radiation and chemotherapy," said Dewhirst. "Now we've shown for the first time that HIF-1 is a major target we could block in combination with radiation therapy or any other therapies that causes oxygen levels to rise after treatment."