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Researchers at Trinity College Dublin revealed new findings that could offer a means of fighting resistance to treatment for people with esophageal cancer. Resistance to radiotherapy is a major stumbling block in the treatment of this cancer.

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For the first time, the research team led by Stephen Maher, PhD, Ussher Assistant Professor in Translational Oncology at Trinity, have discovered that a molecule lost from cancer stem cells, called miR-17, is important in driving esophageal tumor resistance to radiotherapy.


The team of scientists, which incorporated specialists from Trinity, St. James's Hospital Dublin, the Coombe Women and Infant's University Hospital, and the University of Hull in the U.K., demonstrated populations of tumor cells that had higher numbers of cancer stem cells formed larger, more aggressive tumors. They also demonstrated the cancer stem cells were more resistant to radiation-induced cell death (Oncotarget 2016; doi: 10.18632/oncotarget.13940).


Many esophageal cancer patients receive radiotherapy and chemotherapy to shrink their tumor prior to surgery and this forms a key part of their treatment. Unfortunately, while a subset of patients have excellent responses to treatment, the majority of patients are actually resistant to various degrees and subjected to treatment side effects and an unnecessary delay to surgery, which can worsen their overall prognosis. To date, there hasn't been a way to test that patients will respond well to radiotherapy or reduce resistance to radiotherapy.


"This work is extremely important in understanding why tumors are inherently resistant to radiotherapy, and how they can acquire resistance. Our findings strongly suggest that it is the cancer stem cell population that we need to destroy if treatment is going to be effective in our esophageal cancer patients," said Maher.


"Up until recently cancer stem cells were largely considered hypothetical, as there were no clear ways to identify and isolate them. In this study, we spent a tremendous effort in identifying tumor cells that had biological markers normally characteristic of stem cells. Once we had identified these stem-like tumour cells, we isolated them and started to pick apart their biology," continued Maher.


The work, predominantly performed by Niamh Lynam-Lennon, PhD, an Irish Research Council-funded Senior Research Fellow with Trinity's Department of Surgery, showed the population of cancer stem cells could be further broken down into smaller groups, which had distinct radiation sensitivity profiles. Further genetic analysis revealed the levels of a powerful gene-regulating molecule, called miR-17, were particularly low in the cancer stem cells that were most resistant to radiation. In patient samples, miR-17 was found to be much lower in the tumors of patients who did not respond to treatment.


"Interestingly, in the lab we found that if we put a synthetic version of miR-17 into the resistant cells they became more sensitive to radiation. Going forward, we could use synthetic miR-17 as an addition to radiotherapy to enhance its effectiveness in patients. This is a real possibility as a number of other synthetic miR-molecules are currently in clinical trials for treating other diseases," said Lynam-Lennon.


Esophageal adenocarcinoma incidence has increased 600 percent over the past 3 decades, representing the largest increase in incidence of any disease of any kind over the same time period, and rates are projected to continue increasing over the next 20 years.