The Principal Investigator

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]

More than a decade after a University of Wisconsin-Madison lab first showed the therapeutic viability of human embryonic stem cells, the U.S. Food and Drug Administration (FDA) today (Jan. 23) approved the world’s first study using embryonic stem cells in humans.

Geron, the California-based biotech company who financed the original 1998 UW-Madison studies leading to the breakthrough, will now begin to test stem cells in people with severe spinal cord injuries. The announcement sent Geron’s company shares up over 40 percent during the trading day , which MarketWatch reported was the company’s biggest percentage surge since January 1998.

With the proper chemical nudging embryonic stem cells can become any cell type in the body, offering a potential therapeutic goldmine as a replacement for dying cells caused by disease, injury or old age.

Only a few years after scientists determined a way to isolate and maintain human embryonic stem cells, scientists found themselves pulled into a heated ethical battle. In 2001, former President George W. Bush created an Executive Order banning the use of federal money for any newly generated lines of stem cells due to his opposition to the destruction of viable embryos. This ruling essentially handcuffed stem cell researchers across the country.

Scientists from Geron and the University of California at Irvine coaxed stem cells from the lines created before the ban went into effect to become supporting neural cells called oligodendrocytes. The researchers found that paralyzed rats receiving injections of the newly generated cells seven days post-injury showed improve locomotor activity.

The FDA-approved study, a Phase I clinical trial that will measure the safety of embryonic stem cell treatment in humans, will be a small trial of a maximum of 10 patients with severe spinal injuries. Doctors will treat patients with injections of oligodendrocytes at the site of injury within seven to 14 days post-injury, the narrow window of time where the stem cell therapy showed the highest efficacy in rodents.

Geron originally requested FDA approval to test the therapy in clinical trials back in March 2008. According to The New York Times, the FDA first declined Geron, saying more data was needed. But now, just days after the inauguration of President Barack Obama, Geron received the FDA’s nod to proceed. Today’s announcement fueled speculation among scientists that political oversight by the Bush administration was to blame for the delay, and the swift approval may be a sign that Obama will soon move to relax federal restrictions on stem cell research.

Though many see the federal approval of the Geron trial as a huge step for stem cell research, scientists stress even if all goes well and the treatment proves to be safe, years of hurdles exist ahead before stem cell therapy would be available to all patients with spinal cord injuries.