Starve a Tumor, or Feed a Tumor?

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http://www.urmc.rochester.edu/pr/news/story.cfm?id=375

 

Starve a Tumor, or Feed a Tumor?

 

 

" The tumor is meaner if it’s hypoxic. "

 

 

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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