Researchers have identified one mechanism through which cancer stem cells survive to radiation therapy, which may lead to the development of new therapies that increase their sensitivity and thus decrease the likelihood of the cancer coming back.
The study, “Inhibition of the glucocorticoid receptor results in an enhanced miR-99a/100-mediated radiation response in stem-like cells from human prostate cancers,” published in Oncotarget, also shows that a standard hormone supplement, Decadron (dexamethasone), used to boost patients’ energy levels following radiation therapy, may increase the chances of the cancer returning.
Radiation therapy (RT) is a major primary treatment option for localized early stage prostate cancer and regionally un-resectable advanced PCa. Despite significant improvements in radiation therapy, almost one-third of patients still recur within 10 years after the treatment.
A number of studies have shown that a small population of cells within the tumor, called cancer stem cells, are more resistant to radiotherapy than the majority of cells, and are directly responsible for tumor reappearance. Cancer stem cells (CSCs) have the ability to reproduce themselves and sustain the cancer, much like what is seen in healthy tissues where normal stem cells renew and sustain the body’s organs and tissues.
Because CSCs can generate new tumors, if the therapies are not destroying the CSCs the tumor will grow back and most likely be resistant to the previously used therapy.
To understand why CSCs were resistant to radiation therapy the researchers examined a particular family of proteins called SMARCs, known to be involved in radiation sensitivity. They found that the SMARC proteins, which repair damages in the DNA following injuries, helped keep the CSCs alive following radiation therapy.
Importantly, the team found that Decadron treatment, which commonly is given to patients to boost their energy levels after radiation therapy, made the cells more resistant to cancer treatment.
“This was a really unexpected result of our investigation, so we took a slightly different direction in order to find out why these stem cells would become more resistant to cancer treatment,” professor Norman Maitland at the Department of Biology, University of York, said in a press release.
They found that a family of microRNAs, miR-99a and miR-100, was regulating this process. This family of molecules can halt DNA damage repair by preventing the production of the SMARC proteins.
Analysis of the expression of these microRNAs in CSCs showed they were expressed at very low levels, which allowed the CSCs to efficiently repair their DNA following radiation and be resistant to the treatment.
“When more glucocorticoid hormones are ingested, the levels of MicroRNAs decrease even further, resulting in an increase in SMARCs,” Maitland said. “Hormone injections to counter the energy-sapping effects of radiotherapy and chemotherapy have been a standard part of after-care for 15 years or more, so we were surprised to find that the treatment was actually to the detriment of radiotherapy,” he added.
Given the association between glucocorticoid hormones and resistance to radiation therapy, the team then sought to examine what would happen if they blocked the natural levels of these hormones, using Mifeprex (mifepristone).
Results showed that Mifeprex increased the levels of the microRNAs, and thus decreased the SMARC proteins and DNA-damage repair, which reduced the cell’s ability to be resistant to radiation.
The researchers believe this treatment approach has the potential to influence better responses to the same dose of radiation therapy.
“We now need to move into clinical trials to see whether blocking, rather than boosting, the glucocorticoid in patients could bolster the success rate of radiotherapy,” Maitland said. “It would ultimately mean that the patient is more tired after treatment, but there are other non-hormone treatments that could be used to improve energy levels that would not interfere with how we now believe stem cells to behave in cancer.”
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