Troubling
side effect seen by UMass Amherst and Harvard team
UMassAmherst,
Janet Lathrop, March 10, 2014
 |
| Michele Markstein |
AMHERST,
Mass.– Using a new approach to systematically test chemotherapy drugs in an
unusual animal model, a research team led by University of Massachusetts
Amherst molecular biologist Michele Markstein, with Norbert Perrimon at Harvard
Medical School, report that several have a serious side effect: Inducing hyper
proliferation in stem cells that could lead to tumor recurrence.
Markstein
says, “We discovered that several chemotherapeutics that stop fast growing
tumors have the opposite effect on stem cells in the same animal, causing them
to divide too rapidly. This was a surprise, because it showed that the same
drug could have opposite actions on cells in the same animal: Suppressing tumor
growth on one cell population while initiating growth in another. 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.”
She adds,
“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.” Their paper appears in the current issue of
Proceedings of the National Academy of Sciences.
Further,
Markstein explains, “When it comes to stem cells, it is important to conduct
studies in living animals because stem cells are acutely attuned to the other
cells in their microenvironment. Indeed the side effect that we observed is
caused by damage that the chemotherapy drugs cause to cells in the stem cell
microenvironment. The stem cells respond to this damage by hyper
proliferating.”
Markstein
and Samantha Dettorre at UMass, with Perrimon and colleagues at Harvard Medical
School, 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 flies
provide “ready-made stem cell microenvironments” that are
“difficult-to-impossible” to create in petri dishes, Markstein notes.
Specifically, she and her colleagues inserted a human cancer-causing gene in
the fly genome, turned on that gene in its intestinal stem cells, and found
that it did form fast-growing tumors.
To take
full advantage of Drosophila’s ready-made microenvironments, they developed new
technology to determine the size of tumors inside each fly gut. The previous
standard in the field was to dissect flies to visualize tumors, which are
typically labeled 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 tumor size simply by crushing the flies
en masse, rather than dissecting them one-by-one.
They asked
the National Cancer Institute for chemotherapy drug samples and received a
library of 88 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 tumors without causing the
side effect.
Markstein
recalls, “We systematically fed the FDA-approved drugs to the flies and found
that 14 suppressed tumor 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 tumor-suppressing drugs had
the opposite effect on the non-tumor stem cells, causing them to
over-proliferate. This resulted in small growths or ‘tumors,’ that with the right genetic
background could potentially because cancerous.”
These
results in the fly may seem surprising. But recent work by others reported a similar
effect in the drug doxorubicin in mice, Markstein points out. In mice,
doxorubicin induced cells to overgrow by triggering the TNF-alpha pathway while
in flies several chemotherapy drugs, including doxorubicin, triggered a
different pathway called JAK-STAT which has been conserved through evolution in
both flies and humans. Both pathways trigger the inflammatory response, which
is generally associated with cancer.
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.
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