One key to eradicating an entire tumor lies within its stem cells, according to a recent study that identified a source of cancer stem cell resistance to radiation and chemotherapy.

Maximilian Diehn, M.D., Ph.D.
Stanford University

Bruce Haffty, M.D.
Robert Wood Johnson Medical School

Researchers at the Stanford University School of Medicine, in collaboration with scientists at the City of Hope National Medical Center in Duarte, Calif., discovered a protective pathway that shielded cancer stem cells from DNA damage. When that pathway was blocked, researchers found the cells became more susceptible to radiation.

"Normal stem cells need to be around for the life of an organism and therefore, teleologically, you want to protect those cells as much as possible," said Maximilian Diehn, M.D., Ph.D., a radiation oncologist in the Department of Radiation Oncology at Stanford and the Stanford Institute for Stem Cell Biology and Regenerative Medicine. Dr. Diehn and Robert Cho, M.D., were co-first authors of the study published online Feb. 4, 2009, in the journal Nature.

"Prior work indicated that some normal tissue stem cells display enhanced reactive oxygen species (ROS) defenses," said Dr. Diehn. "We wondered whether cancer stem cells, which share many similarities with normal stem cells, may also display these enhanced defenses against ROS."

ROS are highly reactive molecules that include oxygen ions, free radicals and peroxides. ROS form as a natural byproduct of the normal metabolism of oxygen and are also critical intermediaries in cell killing by ionizing radiation and some chemotherapy drugs.

Researchers studied breast cancer stem cells from humans and mice. They found that both normal breast stem cells and breast cancer stem cells contained lower levels of ROS than their progeny. This discovery suggests that cancer stem cells have enhanced free-radical scavenging systems—increased expression of molecules that bind and deactivate ROS—which could make them more resistant to radiation, said Dr. Diehn.

"If this turns out to be true in a significant fraction of human tumors, then this may be a reason why certain tumors are resistant or become resistant to chemotherapy or radiation," he said. "Now that we know about this mechanism, if one can come up with a way of abrogating those defenses in the cancer stem cells one might be able to sensitize them to currently available therapies."

Discovery is in Line with Previous Research

This recent discovery is also consistent with previous research demonstrating hypoxic cancer cell resistance to radiation and chemotherapy.

"What they've shown in this study is that some of these cancer stem cells are resistant to radiation and the whole hypoxia/oxygenation story may play into that as well," said Bruce Haffty, M.D., a professor in the Department of Radiation Oncology at the Robert Wood Johnson Medical School in New Jersey and co-chair of the radiation oncology-focused Bolstering Oncoradiologic and Oncoradiotherapeutic Skills for Tomorrow (BOOST) program at the RSNA annual meeting.

Dr. Haffty will present the Annual Oration in Radiation Oncology, "Genetic Factors in the Diagnostic Imaging and Radiotherapeutic Management of Breast Cancer," at RSNA 2009.

"I see this study as combining a theory and a story that has been around for many, many years—that hypoxia is a problem in general," said Dr. Haffty. "What's unclear to me is whether you would address the ROS problem in stem cells differently than just hypoxia in general and whether this will have a greater impact than hypoxia-directed therapy that has been around for some time."

Dr. Haffty added that he sees this latest study as another part of ongoing puzzle-solving as doctors and scientists work to understand hypoxia-related agents.

"In general, I'd have to say that although attacking hypoxia in cancer in combination with radiation has been a success, it certainly has not been a home run by any means," he said. "There have been small incremental gains in the studies that have looked at hypoxia-directed therapy. It's possible that this new knowledge will help promote and fine tune those studies and lead us into better anticancer drugs.

"I'm not sure this particular finding is going to have an immediate clinical impact," Dr. Haffty continued. "It's a unique finding, but still there is a lot of work to be done to capitalize on that in terms of clinical gain."

Dr. Diehn agreed that studies must continue.

More than One Answer to Stem Cell Resistance

"As with most things in cancer research, it's unlikely that there is going to be one answer explaining cancer stem cell resistance to standard therapies," he said. "The fact that we are discovering multiple ways that these cells might resist radiation and chemotherapy fits well with the history of cancer biology."

That history includes earlier research within the cancer stem cell field, which has gained momentum over the past decade or so. During that time, Dr. Diehn said, it has been proposed that the cells may be resistant to radiation and chemotherapy.

Implications of the cancer stem cell hypothesis for cancer treatment.

Conventional cytotoxic therapies can shrink tumors but may preferentially spare some cancer stem cells (CSCs). Because CSCs are left behind, tumors can eventually regrow. CSC-targeted therapies could remove the self-renewing tumor cells and thus lead to tumor stabilization and likely eventual regression.

"People have proposed a number of potential mechanisms," he said. "ROS defenses wasn't usually one of them, but the idea that cancer stem cells might be resistant has been around for a while. It's becoming apparent now, from studies such as ours and also from those of a number of other investigators, that cancer stem cells in many different tumors appear to be resistant to chemotherapy and radiation and that they use different mechanisms to accomplish this.

"In some tumors it appears to be these ROS defenses, in other tumors it appears to be enhanced DNA repair capabilities, and in still others it appears to be enhanced expression of drug transporters that can pump chemotherapy drugs out of the cells," Dr. Diehn continued. "It's my opinion that we're going to find out that cancer stem cells are resistant to standard therapies in many tumors and that they use a combination of resistance mechanisms that are likely to be unique to each tumor."

"The main hurdle to clinical application is that lowering ROS defenses is likely to sensitize all cells," he said. "But you'd like to do it in a way that doesn't also sensitize the normal tissues. That's always a problem in cancer therapy. Future work is going to focus on trying to come up with a way of sensitizing the cancer stem cells preferentially and not the relevant normal tissue stem cells.

"We're still in the early stages, but one potential way we might be able to do it is to try to attack the transcription factors, or let's say the gene expression programs, that are controlling the enhanced ROS defenses," Dr. Diehn concluded. "That's the next step."

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