Tumor, oxygen link provides clues for new cancer therapies

"The ways cells sense changes in oxygen have only recently become clear," says Dr. Simon, investigator, Howard Hughes Medical Institute, and professor, cell and molecular biology at the University of Pennsylvania School of Medicine.

Pathologic conditions, such as the development of a tumor, reduce the amount of oxygen delivered to the cells. To survive, cells adapt by expressing fewer genes and proteins, and protein synthesis slows to conserve adenosine triphosphate (ATP), the major energy source for cellular reactions. This allows the cells to survive until oxygen and ATP levels return to normal.

Angiogenesis and erythropoietin production levels rise to boost oxygen delivery by the bloodstream.

"The whole point of HIF is to alleviate the consequences of oxygen deprivation," Dr. Simon says.

Hypoxia drives cycle

"Hypoxia is an important reality for all tumors," Dr. Simon says. "Solid tumors with hypoxic areas, such as epidermal tumors, are the most aggressive and difficult to treat, and a major reason for treatment failure.

"As a tumor grows, it becomes oxygen starved," she says. "Once a tumor gets beyond about 2 to 3 cubic millimeters in size, the availability of oxygen via diffusion is severely limited. If the tumor doesn't find a way to obtain more oxygen, it won't continue growing. So HIF activates a long list of angiogenic factors like vascular endothelial growth factor (VEGF), which recruit vessels into the tumor, usually by coopting nearby blood vessels or causing nearby vascular beds to grow into the tumor. If you recruit vessels into the tumor, you're going to increase the delivery of oxygen and nutrients to the tumor. This will promote continued tumor growth and ultimately metastasis, because the cells in the tumor can slough off into the vasculature and migrate to distinct anatomic sites."

Once the tumor is receiving more oxygen and nutrients, it proliferates, and is likely to outstrip the ability of the existing vasculature to provide growth factors and nutrients. At this point, cellular oxygen levels drop again.

"And so the whole process starts over. It's a cyclical, fluctuating pattern," Dr. Simon says.

Hypoxia boosts potency

Now that hypoxia regulation by HIF and other transcription factors is better understood, some investigations are focusing on exploiting hypoxia to boost the potency of cancer therapies. Certain cytotoxic drugs become more toxic in regions where oxygen is reduced. One animal study found that the vasodilator hydralazine induced reduction in blood flow (and thus oxygen delivery) to tumors, which increased the tumor cytotoxicity of several chemotherapy agents.¹

Another group enlisted hyperbaric oxygen breathing, administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers to increase the delivery of oxygen to hypoxic areas, which reduced their resistance to radiation and chemotherapy. ²

Recently, investigators combined hypoxia gene therapy with ionizing radiation to overcome resistant hypoxic tumor cells. This method activates radiation-responsive gene promoters to direct a suicide gene to irradiated tissue only, which triggers targeted cell killing. ³ Another group genetically engineered bacterial spores to express multiple therapeutic transgenes. ²

However, every study has to contend with the radio resistance and genomic instability of hypoxic tumors, Dr. Simon says, adding, "Tumors that exhibit HIF accumulation correlate with a very poor prognosis for a broad spectrum of human cancers."

Targeting the process

Researchers are also developing chemotherapeutic agents that target the processes HIF initiates to slow tumor growth. In animal studies, HIF inhibition has delayed the growth of tumors, decreased angiogenesis, and increased responsiveness to radiotherapy.