Scientists Unlock the Mystery Behind Cancer Stem Cell Radiation Resistance

Nature, February 4, 2009

It has long been well known that ordinary cells throughout the body are easily damaged by radiation, while cancer cells are not. For this reason, cancer patients who undergo radiation therapy often suffer from the destruction of their healthy tissue, whether or not the radiation is also successful in destroying the cancer cells. Radiation is not always successful in destroying cancer cells, however, and the reasons behind this fact have remained elusive, until now.

In collaboration with the City of Hope National Medical Center, researchers at the Stanford University School of Medicine have found a possible solution to this problem. Studying breast epithelial stem cells from humans and mice, the scientists discovered a "protective pathway" that shields normal stem cells from DNA damage. Unfortunately, this molecular defense mechanism is also a characteristic of some types of cancer stem cells; fortunately, however, when this pathway is blocked, the cells become more susceptible to radiation.

The protective pathway consists of the increased expression of proteins that bind and deactivate the various types of reactive oxygen species (ROS) which damage DNA. The scientists found that normal stem cells, such as stem cells of blood and breast epithelial origin, have lower levels of ROS than do regular cells which are not stem cells. Similarly, cancer stem cells also have lower levels of ROS since the cancer stem cells produce a higher level of the antioxidant proteins than do non-stem-cell cells. The antioxidant proteins in turn intercept and deactivate the ROS before cellular damage has been incurred. In non-stem-cell cells, this protective mechanism poses a distinct advantage, while in cancer stem cells it is a distinct disadvantage. Cancer stem cells with low ROS levels were found to be twice as likely to survive a course of ionizing radiation than were other tumorous cells that had higher levels of ROS.

The discovery of the protective protein expression now offers a new approach to cancer treatment: the scientists found that blocking the generation and activation of the protective proteins makes the cancer stem cells more susceptible to radiation, especially when glutathione is blocked, as this is one of the strongest of all antioxidants. Of course, it is important to block the protective protein expression only in the cancer stem cells, and not also in the normal, noncancerous and non-stem-cell cells.

According to Dr. Michael Clark, associate director of the Stanford Institute for Stem Cell and Regenerative Medicine and the original discoverer of the first cancer stem cell in a solid tumor, "The resistance observed in the breast cancer stem cells seems to be a similar if not identical mechanism to that used by normal stem cells. Although your body would normally eliminate cells with chromosomal damage, it also needs to spare those cells responsible for regenerating and maintaining the surrounding tissue - the stem cells. It's protective. Basically, we need to figure out a way to inactivate that protective mechanism in cancer cells while sparing normal cells."

As Dr. Robert Cho adds, "Our ultimate goal is to come up with a therapy that knocks out the cancer stem cells. If you irradiate a tumor and kill a lot of it but leave the cancer stem cells behind, the tumor has the ability to grow back," which in fact is exactly what often happens, thereby leading to relapses in patients months or even years after a seemingly successful treatment. Although the debate over the exact origin of cancer stem cells has not yet been put to rest, there is no debate over the fact that cancer stem cells, even in very small quantities, can reconstitute an entire tumor cell population, and the natural resistance of these cells to conventional medical therapies such as radiation has continued to pose a major dilemma to oncologists and their patients. Now, there may be at least a partial solution.

According to radiation oncologist and post-doctoral fellow Maximilian Diehn, M.D., Ph.D., "Since cancer stem cells appear to be responsible for driving and maintaining tumor growth in many tumors, it is critical to understand the mechanisms by which these cells resist commonly used therapies such as chemotherapy and radiotherapy. Ultimately, we hope to improve patient outcomes by developing therapeutic approaches that directly target cancer stem cells or that overcome their resistance mechanisms."