Sep. 12, 2003 Within a tumor, chaos reigns: Nutrients are scarce, and healthy tissue is muscled out by cancerous tissue so aggressive that the tumor even sacrifices parts of itself to continue its relentless expansion.
It's in this rough-and-tumble environment, controlled by a dizzying array of molecular signals, that researchers at the James P. Wilmot Cancer Center are grappling with a conundrum: Starve a tumor of oxygen, and the tumor should die – but without oxygen, pretty much all of today's anti-cancer weapons are useless. Feeding the tumor may actually be better for the patient.
"It's like a two-headed beast," says Edith Lord, Ph.D., professor of Oncology in Microbiology & Immunology at the University of Rochester's cancer center. "If you cut off the blood vessels, the tumor doesn't grow, but it's also harder to treat with current therapies."
Five years ago the dawn of a new era in cancer research – the pursuit of anti-angiogenesis, or the cutting off or prevention of blood vessel growth – was hailed as a new way to knock out tumors by starving them of oxygen. But progress has been slow and spotty, and scientific results inconsistent. There have been a few clinical trials of the new medicines, but none is yet approved for widespread use.
Now doctors are coming more to terms with the negative complications of starving tumors of oxygen.
"The crucial role that oxygen plays in killing tumors has been under appreciated," says Bruce Fenton, Ph.D., associate professor of radiation oncology at the Wilmot Cancer Center.
Radiation and other current therapies rely on the formation of harmful molecules known as free radicals to damage cells, but without oxygen their efforts fall short as cells can often repair themselves. Cancer cells that contain oxygen are about two to three times more vulnerable to radiation than cells without, says Fenton.
Colleague Paul Okunieff, M.D., head of Radiation Oncology at the Wilmot Cancer Center, is more blunt about the effects of low oxygen, known as hypoxia.
"The tumor is meaner if it's hypoxic," Okunieff says. "Oxygen is by far the most powerful molecule for making cells vulnerable to radiation. Tumor cells that survive hypoxic conditions are often the cells that are most aggressive, most hardy, and most likely to go out and start new cancer colonies," he says. They're also the tumor cells most likely to have mutations that make them prone to spreading.
For decades scientists have tried the opposite approach, by feeding oxygen to tumors to kill them more effectively. Doctors have asked patients to breathe extra oxygen during radiation treatments to make tumors more vulnerable to radiation; they've given patients transfusions so there would be more oxygen-carrying red blood cells in tumors; and they've tried other methods to take advantage of oxygen's killing abilities.
While some methods have had some success, none has worked well consistently, says Okunieff. Meanwhile, with a surge of anti-angiogenesis research, researchers continue to study the consequences of starving the tumor of oxygen.
"Those areas of low oxygen in tumors are more resistant to our treatments," says Lord, "for a number of reasons." Besides less oxygen to form free radicals, cells under low-oxygen conditions don't divide as much, so they have more time to repair themselves before being vulnerable to radiation and other measures that target dividing cells. It's also harder to get drugs to areas without blood vessels, and without those blood vessels even the body's natural cancer-fighting immune cells can't reach the tumor to attack it.
The blood vessels that a tumor creates, much like a new highway infrastructure built to serve a teeming suburban area, are vastly different from the network in the rest of the body. In healthy tissue, the layout is well planned and ordered, and the walls of small arteries contain elastic and muscular layers to fine-tune their diameter and closely control blood flow.
But in tumors, blood vessels are poorly laid out, and they lack the elasticity and muscle control vital for health. The vessels are like poorly planned, circuitous alleys that might pop up around a makeshift shantytown. In an article in the Sept. 20 issue of the International Journal of Cancer, Lord published some of the earliest images ever taken of a tumor spreading, showing the birth of a tumor and the genesis of its blood vessels – angiogenesis – even before the tumor itself is visible. And recently in the British Journal of Cancer, she showed how an immune factor, interleukin-12, prevents angiogenesis.
"There's no rhyme nor reason for how blood vessels grow in tumors," says Fenton. "It's like a race, where the tumor is expanding rapidly and the blood vessels are growing as fast as they can to keep up. Both are out of control. Oftentimes the tumor grows so fast that it crushes its own blood vessels, leading to cell death in some regions of the tumor because there is no oxygen."
As some parts of the tumor die from lack of oxygen, other sectors advance, resulting in a patchwork of thriving tumor tissue, hypoxic tissue barely limping along, and dead tissue. Some parts of a tumor have less than 5 percent of the oxygen levels in healthy tissue, and for limited times can survive with no oxygen at all, making these regions highly resistant to radiation treatment.
Lord's team is working on ways to customized treatment based on tumor oxygen levels in tumors. She has developed a fluorescent molecule that tags hypoxic regions within tumors, and she is working with doctors at the University of Pennsylvania to identify patients who have tumors that are hypoxic and may need different treatments than traditional radiation and chemotherapy.
Fenton's team is working on new ways to combine radiation and antiangiogenic drugs. Surprisingly, some antiangiogenic agents can increase blood flow to the tumor, possibly by pruning off superfluous, less efficient blood vessels. His lab is exploring ways to kill tumors more efficiently by adjusting the timing of the delivery of such drugs with radiation.
In addition to Lord, Fenton and Okunieff, other Rochester researchers working on hypoxia or the tumor micro-environment include John Frelinger, Ph.D., a molecular immunologist; Thomas Foster, Ph.D., an expert in photodynamic therapy; and hematologist Steven Bernstein, M.D. Funding for the work has come largely from the National Cancer Institute and the Sally Edelman and Harry Gardner Cancer Research Foundation of Hilton.
"This is a complex problem, and that's why we need a diverse group of investigators working together to solve it," Lord says.
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