The Principal Investigator

A recent paper published in Nature proposes a critical role for autophagy in the beneficial effects of exercise. The article shows that exercise (treadmill running) in mice stimulates the process of autophagy. Interestingly, the induction of autophagy is required for some of the positive metabolic effects of exercise (increased sensitivity to insulin, etc.).  Mice with mutations in the autophagy pathway show impaired exercise endurance and do not receive any of the metabolic benefits of exercise.

Autophagy is a critical function for cells. Not only is it an efficient mechanism for clearing debris, but it also facilitates the dynamic regulation of cellular activity. Cells use autophagy to allocate resources toward critical activities at times when these resources are scarce. Additionally, autophagy, through mechanisms that are not entirely clear, is thought to be involved in the pathology of many diseases from cancer to neurodegeneration.

This paper gives us some insight into why exercise is appears to help prevent many seemingly disparate diseases.

To emerge unscathed after being blasted with radiation, cancer stem cells take advantage of a molecular pathway used to protect normal adult stem cells, according to a report published Wednesday (2.4.09) in Nature.

Scientists at Stanford University and the City of Hope National Medical Center used a combination of information collected from human and mouse breast cancer cells to help them solve the mystery of how cancer stem cells survive the radiation therapy that kills off non-stem cells present in a tumor. The radiation resistance of cancer stem cells allows a tumor to grow back and patients to relapse months to years after therapy.

“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,” said Stanford radiation oncologist Maximilian Diehn in a press release. “Ultimately, we hope to improve patient outcomes by developing therapeutic approaches that directly target stem cells or that overcome resistance mechanisms.”

Compared to non-stem cells, previous studies found blood and central nervous system stem cells have lower numbers of reactive oxygen species (ROS) that are critical to cell function. Although ROS are naturally produced free radicals, the body has a system in place to keep the chemicals in check throughout the lifetime. Like bouncers at a club, antioxidants help prevent cellular destruction and clean up the messes made by ROS. The breakdown of the antioxidant defense system and subsequent rise of free radicals causes DNA damage and gives rise to a host of diseases, including heart and neurodegenerative disorders.

Radiation therapy tries to take advantage of the wrath free radicals play on a cell by directly ionizing the DNA and intracellular chemicals of cancer cells. Grasping for stability, the reactive intracellular chemicals can tear a cell apart.

To find out what causes cancer stem cells to be more resistant to radiation than other cancer cells, the Stanford team analyzed breast cancer stem cells plucked from human and mouse breast tumors and discoverer the cells had lower levels of pro-oxidant, or free-radical-promoting chemicals compared to normal breast cancer cells.

The scientists then exposed breast cancer stem cells to ionizing radiation and found they underwent less DNA strand breaks compared to the mature breast cells, and populations of breast cancer stem cells were twice as likely to survive in comparison to mature breast cells after exposure to radiation, suggestive of resistance to radiotherapy.

Lastly, when comparing the gene expression in cancer stem cells versus non-stem cells the group uncovered the answer they were looking for: cancer stem cells displayed higher expression levels in genes involved in the production of glutathione (GSH), an antioxidant that deactivates ROS. By blocking GSH, the scientists were able to increase the vulnerability of breast cancer stem cells to radiation.

“Although your body would normally eliminate cells with chromosomal damage, it also needs to spares those cells responsible for regenerating and maintaining the surrounding tissue – the stem cells,” Stanford cancer biologist Michael Clarke said in a press release. “It’s protective.”

Scientists hope to use the information gained from their recent studies can be used to determine ways to “inactive [the] protective mechanism in cancer cells while sparing normal cells,” Clarke said.

Source of cancer stem cells’ resistance to radiation discovered at Stanford [press release]