One question about cancer frustrates and befuddles physicians and patients alike: Why does it often come back after patients go through aggressive chemotherapy and radiation?
City of Hope researchers have helped push science a step closer to an answer.
Scientists at Stanford University School of Medicine teamed up with City of Hope breast cancer researchers to study the power of cancer stem cells — cells that may be the sleeping giants of the cancer world. These cells appear to maintain tumor growth in many types of cancers and are relatively resistant to standard therapies. Part of the reason, say the researchers, is a protective pathway meant to shield normal stem cells from DNA damage.
When the researchers blocked this pathway, the cancer stem cells became more susceptible to radiation — a discovery that could lead to ways to finally knock down cancer stem cells’ defenses. The research team reported its findings in the Feb. 4 issue of Nature.
City of Hope’s George Somlo, M.D., co-director of the Breast Cancer Program and principal investigator of a City of Hope clinical trial allowing for the collaboration on the paper, said cancer stem cells may be critical to cancer recurrence months or even years after patients are treated.
“We believe a certain percentage of the cells in breast tumors, called cancer stem cells, may remain dormant and survive the insult inflicted by chemotherapy and radiation treatment,” said Somlo, professor and director of breast oncology in the Department of Medical Oncology & Therapeutics Research.
Robert Cho, M.D., clinical instructor of pediatrics at Stanford, and Stanford radiation oncologist and postdoctoral fellow Maximilian Diehn, M.D., Ph.D., shared lead authorship on the paper. Together with City of Hope researchers, they studied breast epithelial stem cells from humans and mice to unravel why cancer stem cells are more resistant to radiation than other cancer cells.
The key may lie in pesky molecules called reactive oxygen species. These unstable molecules can bounce around and damage a cell’s DNA and proteins.
Previous studies have shown that blood stem cells have less of these harmful molecules than non-stem cells do, so researchers in the current study looked to see if the same held true for breast stem cells. And it did — not only in normal mouse breast stem cells, but in mouse and human breast cancer stem cells.
The researchers found out why: Breast cancer stem cells were neutralizing the reactive oxygen species by churning out high levels of antioxidants. Antioxidants capture and disarm reactive oxygen species before they can cause much damage.
This protection might explain why mouse breast cancer stem cells were less likely than other cancer cells to experience DNA damage after ionizing radiation. (Radiation therapy and traditional chemotherapies do their cell-killing work primarily by damaging cancer cells’ DNA.)
The researchers also found that, in mice with breast tumors, cancer stem cells with low levels of reactive oxygen species were about twice as likely as other tumor cells to survive a course of ionizing radiation.
Scientists believe that stem cells may hold these superior powers of self-protection because stem cells are so critical to regenerating and maintaining tissue.
The findings could lead to a new approach to treating cancer. In the study, blocking the activity of an important antioxidant called glutathione made the cancer stem cells significantly more sensitive to radiation.
“Possible strategies for the future include breast cancer-targeted increase of reactive oxidants in combination with our current standard radiation and chemotherapy treatments, or alternatively, increased protection from oxidant damage of noncancerous cells (such as normal hematopoietic cells, skin or bowel tissue) while delivering targeted and higher doses of chemo- and radiotherapy,” Somlo said.
Stanford’s Michael Clarke, M.D., the Karel H. and Avice N. Beekhuis Professor in Cancer Biology, was senior author. Besides Somlo, City of Hope physicians on the project included Carlos Garberoglio, M.D., I. Benjamin Paz, M.D., Jeannie Shen, M.D., and Sean K. Lau, M.D.
Stanford University Medical Center’s Office of Communications & Public Affairs contributed to this story.
