Chemotherapy Drugs Induce Stem Cells, Leading to Tumour Recurrence
Researchers from the University of Massachusetts Amherst and Harvard Medical School tested chemotherapy drugs and found that several have a serious side effect: Inducing hyper proliferation in stem cells that could lead to tumour recurrence.
They discovered that chemotherapeutics that stop fast growing tumours have the opposite effect on stem cells – causing them to divide too rapidly. According to Michele Markstein, a molecular biologist at UMass, this was a surprise, because it showed that the same drug could have opposite actions on cells in the same animal. “Not only is the finding of clinical interest, but with this study we used an emerging new non-traditional tool for assessing drugs using stem cells in the fruit fly gut."
"We did these experiments in the fly because Drosophila stem cells, in the intestine, are very much like the stem cells in our intestine, and it’s a lot easier to do experiments in flies than humans or even mice." she added.
Together with Samantha Dettorre of UMass and Norbert Perrimon of Harvard, Markstein pioneered large-scale chemical screening in adult fruit flies that they feel will be useful for testing other chemicals. Conventional in vitro cell screens can identify drugs that act directly on stem cells, the authors note, but they cannot test and identify drugs that act on the all-important microenvironment, which provides cues for stem cell division, differentiation, and death.
The researchers developed new technology to determine the size of tumours inside each fly gut. The previous standard in the field was to dissect flies to visualize tumours, which are typically labelled green with green fluorescent protein. In the new method, the researchers decided to use a different label, an enzyme from fireflies called luciferase. This allows them to measure tumour size simply by crushing the flies en masse, rather than dissecting them one-by-one.
Then, they tested the effect of 88 chemotherapy drug samples currently in clinical use. After demonstrating that flies are sensitive to human chemotherapy drugs, they obtained a library of over 6,000 small molecules from the Harvard Institute of Chemistry and Cellular Biology, to screen for novel drugs. The screen identified new compounds, three of which are from Chinese medicinal extracts that can inhibit tumours without causing the side effect.
"We systematically fed the FDA-approved drugs to the flies and found that 14 suppressed tumour growth in the intestine. This was a great result, validating the relevance of flies as a clinical model. It was also very interesting; however, that we found that half these tumour-suppressing drugs had the opposite effect on the non-tumour stem cells, causing them to over-proliferate. This resulted in small growths or ’tumours,’ that with the right genetic background could potentially become cancerous." said Markstein.
Overall, the authors conclude that screening in whole animals such as flies pays off, and is necessary to detect effects that involve more than one cell type. Indeed, Markstein argues that the impact of a chemotherapy drug on the stem cell microenvironment is just as important as its impact on the stem cell itself.
Source of this article:
Systematic screen of chemotherapeutics in Drosophila stem cell tumours
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