New research conducted at the University of Kansas Medical Center could make treatment for gastrointestinal cancers safer- while also helping to mitigate the dangers of nuclear accidents and terrorist attacks.
The research, led by Subhrajit Saha, Ph.D., assistant professor in the Department of Radiation Oncology at KU Medical Center, began more than five years ago when his team embarked on a quest to understand the biology behind radiation-induced gastrointestinal syndrome (RIGS)- a serious risk for people being treated for stomach, pancreatic, colorectal and other cancers in the abdominal area.
RIGS prevents the body from absorbing nutrients and often causes nausea, vomiting, and diarrhea. RIGS occurs primarily when radiation treatment for these abdominal cancers destroys healthy tissue in the GI tract, especially the outer layer of the intestines, known as the epithelium. And when the epithelium is lost, bacteria can spill into the body and cause sepsis, which can kill a patient. Because there is no drug treatment for RIGS, doctors must turn to radiation to treat their patients, which requires them to use extreme caution up to the point of compromising on the necessary treatment. This is of specific concern to cancer patients as more than half of patients treated with abdominal radiotherapy are affected by RIGS.
"That's why when the colon is involved, doctors don't want to treat with radiation," said Saha. "And often they can't use aggressive doses of radiation even for other organs in the area because of the sensitivity of the epithelium. They have to be very, very careful."
RIGS also occurs when people are subjected to radiation through a nuclear accident or a nuclear attack. "This is hugely significant- the government has been investing in research for an effective countermeasure for terrorism involving radiation," says Saha. "The problem is, it's hard to treat someone post-radiation because the damage happens so fast, and the patient typical dies in seven to 10 days."
Macrophages, the Pac-Men for cellular debris, help intestinal stem cells regenerate
While Saha was still at the Albert Einstein College of Medicine in New York, his research team began with the knowledge that one reason RIGS is so hard to treat is that the abdominal area of the body has a high turnover of intestinal stem cells. Cells like these that divide quickly are especially susceptible to damage from radiation because their DNA gets more exposed.
To figure out how to get around that, the researchers needed to know more about the biology of the epithelium, specifically how intestinal stem cells (ISCs) renew and proliferate. They published their first discovery six years ago, after they injected radiation-injured mice with stromal cells, a mixture of different cell types that make up connective tissue, and found that they stimulated intestinal stem cell regeneration and lessened the damage done by RIGS.
Now they knew that ISCs depend on the stromal niche to reproduce new cells, and of the different types of stromal cells, the macrophages were critical. Macrophages are white blood cells that eat up cellular debris, especially infected cells.
"We knew that macrophages are the missionaries of the immune system," said Saha. "But we learned they also assist in organ growth, repair, and regeneration."
The question was how?
Solving the mystery of intestinal stem cell renewal
The first question for Saha, who had by then moved to KU Medical Center, was whether macrophages can help intestinal stem cells self-renew and multiply. The researchers had read studies showing that WNT proteins- a family of proteins that regulate the proliferation of cells, and related signaling- were very important for the intestinal stem cell renewal and proliferation. Moreover, they have found that macrophages also release these WNT proteins.
To learn more, the researchers set up a mouse model to halt the release of all 19 varieties of WNTs specifically produced by macrophages. They found that mice without macrophage-derived WNT were much more sensitive to radiation and had more severe intestinal injury from radiation compared to mice who had not been treated. "This told me that macrophage-derived WNT is important for intestinal resistance to radiation," said Saha.
For Saha, this discovery made for one of his best days in the lab, but it also was just the first finding. Additional studies showed that damage could be repaired in mice treated with macrophages capable of releasing WNT proteins. The intestinal epithelium was repaired, and the intestinal stem cells were also rescued.
Multiple subsequent studies have since reinforced their findings. They have confirmed that WNT release by macrophages is essential to the regeneration of intestinal stem cells and repair of epithelial tissue. Interestingly, in mice not exposed to radiation, WNTs don't seem critical to keeping the intestines healthy. But where there is a need for regeneration, they become critical.
"We were very much surprised," Saha said. "Macrophages are known for immune system surveillance, but now we know that they can get involved in organ repair."
It's all in the packaging
Working in collaboration with Andrew Godwin, Ph.D., deputy director of the University of Kansas Center Center, and his team, Saha's team also observed that macrophages release the WNTs via extracellular vesicles, tiny sacs of membrane released from the surface of cells. "That was not known," said Saha. "Now we know how WNTS are transported in the system."
Armed with this knowledge, researchers can begin to think about developing therapies using macrophage-derived WNT to allow doctors to treat gastrointestinal cancers more aggressively and lessen the damage done in the event of a nuclear mishap.
Saha's team is currently working to develop small molecules that can modulate these macrophages to augment their role in regeneration. "We are confident that we can come up with an answer for the mitigation of acute radiation syndrome very soon," he said.