Summary

Researchers have shown that radiation-resistance among tumor stem cells can be dramatically lowered by heating them up.

Sometimes zapping a tumor with ionizing radiation doesn’t work out as planned. The tumor shrinks at first, but stem cells within the tumor survive and eventually seed the growth of new, more aggressive tumors.

Now researchers have shown that this extraordinary radiation-resistance among tumor stem cells can be dramatically lowered by heating them up. The results were obtained in highly aggressive mouse and human breast cancer tumors, but the technique could possibly be used against many types of cancer. The paper is the cover story in the October 27, 2010 issue of Science Translational Medicine.

We hypothesized that the heat was sensitizing tumors mainly by disrupting their stem cells’ DNA-repair capacity.

Rachel Atkinson

The study’s lead author, Rachel L. Atkinson, is a graduate student in Baylor College of Medicine’s Med into Grad program, an HHMI-funded initiative that gives graduate schools funding to integrate medicine and translational research into their graduate training programs. The work was done in the labs of Baylor molecular biologist Jeffrey M. Rosen and oncologist Jenny Chang.

The tumor-heating technique that Atkinson and her colleagues investigated was a high-tech version of an ancient strategy. A 5,000-year old Egyptian papyrus depicts the use of heat against breast cancer. Heat treatment—formally called hyperthermia—hasn’t proven effective when used alone, but researchers noted its apparent ability to make tumor cells more susceptible to radiation therapy.

Initial clinical tests of hyperthermia plus radiation in the 1970s and 1980s didn’t fare well—likely because the heating wasn’t accurate or consistent, says Atkinson, who is in Baylor’s Translational Biology and Molecular Medicine program. But recent improvements in the ability to precisely heat tumors have led to a revival of interest in using it to make tumor cells more sensitive to radiation. Researchers are also eager to learn how this potential treatment strategy might work.

“We hypothesized that the heat was sensitizing tumors mainly by disrupting their stem cells’ DNA-repair capacity,” Atkinson says. To find out, she and her colleagues used a cutting-edge hyperthermia technique that involves tiny gold-coated spheres called nanoshells. Nanoshells are designed to absorb certain near-infrared frequencies of light, and they gravitate toward the blood vessels that feed tumors. After they have infiltrated a tumor, the nanoshells can be heated by a skin-penetrating near-infrared laser, with minimal effect on the surrounding healthy tissue. “The technology offers a very quick and precise way of rapidly raising the temperature of a tumor,” Rosen says.

Atkinson tried out the technique in human breast tumors that had been transplanted into mice and in mice with aggressive breast tumors. With radiation alone, cancer stem cells in both types of tumors rapidly repaired their DNA damage. In fact, the proportion of cancer stem cells in the tumors sharply increased—presumably due to their greater radiation resistance—and grew even faster than non-irradiated tumors.

But when Atkinson followed the radiation treatment with 20 minutes of hyperthermia at 108 degrees Fahrenheit, the results were dramatically different. The proportion of cancer stem cells in these tumors stayed the same and in most cases actually fell, suggesting that the stem cells had lost their ability to repair damage.

When surviving tumor cells were transplanted back into mice, the resulting tumors grew more slowly than before, had a much lower percentage of stem cells, and had a physical appearance consistent with a less aggressive tumor. “Looking at the histology of what grew back after those transplants really gave us the most dramatic results,” Rosen says. “It underscores the importance of examining not only the reduction in the size of the tumor, but also the change in the cell heterogeneity within the tumor.”

Ionizing radiation kills cells in part by repeatedly blasting through both strands of the molecular spine of their DNA. These double-strand breaks are difficult to repair and, if they aren’t repaired, can trigger cell suicide (apoptosis). Atkinson found that after radiation treatment alone, tumor stem cells mobilized their repair-related proteins with unusual swiftness compared to ordinary tumor cells. But after radiation-plus-hyperthermia treatment, this process was greatly delayed, and proteins that normally help damaged stem cells avoid apoptosis also failed to be mobilized. “The combination of the radiation plus hyperthermia seriously disrupted what is normally a highly efficient radiation-damage repair,” Atkinson says.

Atkinson, Rosen, and Chang now hope to set up clinical trials of the combined technique in breast cancers at multiple institutions in the Texas Medical Center. Clinical trials using a similar technique are already underway at the Michael E. DeBakey V.A Medical Center in Houston. “In principle this approach isn’t limited to breast cancers but could be applied to other cancers too, provided that they can be precisely targeted with the heat treatment,” Chang says.

Rosen adds that hyperthermia isn’t necessarily the only enhancement for radiation therapy. “The data suggest that it could augment any therapy that causes DNA breaks in tumor cells, including some chemotherapies,” he says. “This field is developing rapidly.”

The Translational Biology and Molecular Medicine began in 2005, and Atkinson was in its first group of students. “She’s very oriented towards translational science,” says Chang, who is currently director of The Methodist Hospital Cancer Center. “Unfortunately many students in biology Ph.D. programs spend their time examining a molecular pathway and never really understand how it can impact health and disease in people.”

Atkinson says she might not have been involved in this research if not for the Med into Grad initiative. “I’ve been fortunate to be in this program,” she says.

For More Information

Jim Keeley 301.215.8858 keeleyj@hhmi.org