Developing resistance to chemotherapy is a nearly
universal, ultimately lethal consequence for cancer
patients with solid tumors – such as those of the
breast, prostate, lung and colon – that have
metastasized, or spread, throughout the body. A team
of scientists led by Fred Hutchinson Cancer Research
Center has discovered a key factor that drives this
drug resistance – information that ultimately may be
used to improve the effectiveness of therapy and buy
precious time for patients with advanced cancer.
They describe their findings online Aug. 5 in
advance of print publication in Nature Medicine.
"Cancer cells inside the body live in a very complex
environment or neighborhood. Where the tumor cell
resides and who its neighbors are influence its
response and resistance to therapy," said senior
author Peter S. Nelson, M.D., a member of the
Hutchinson Center's Human Biology Division.
Nelson and colleagues found that a type of normal,
noncancerous cell that lives in cancer's
neighborhood – the fibroblast – when exposed to
chemotherapy sustains DNA damage that drives the
production of a broad spectrum of growth factors
that stimulate cancer growth.
Under normal circumstances, fibroblasts help
maintain the structural integrity of connective
tissue, and they play a critical role in wound
healing and collagen production.
Specifically, the researchers found that
DNA-damaging cancer treatment coaxes fibroblasts to
crank out a protein called WNT16B within the tumor
neighborhood, or microenvironment, and that high
levels of this protein enable cancer cells to grow,
invade surrounding tissue and resist chemotherapy.
The researchers observed up to 30-fold increases in
WNT production – a finding that was "completely
unexpected," Nelson said. The WNT family of genes
and proteins plays an important role in normal
development and also in the development of some
cancers but, until now, was not known to play a
significant role in treatment resistance.
"Cancer therapies are increasingly evolving to be
very specific, targeting key molecular engines that
drive the cancer rather than more generic
vulnerabilities, such as damaging DNA. Our findings
indicate that the tumor microenvironment also can
influence the success or failure of these more
precise therapies." In other words, the same cancer
cell, when exposed to different "neighborhoods," may
have very different responses to treatment.
The major clinical reason that chemotherapy
ultimately fails in the face of advanced cancer,
Nelson said, is because the doses necessary to
thoroughly wipe out the cancer would also be lethal
to the patient. "In the laboratory we can 'cure'
most any cancer simply by giving very high doses of
toxic therapies to cancer cells in a petri dish.
However, in people, these high doses would not only
kill the cancer cells but also normal cells and the
host." Therefore, treatments for common solid tumors
are given in smaller doses and in cycles, or
intervals, to allow the normal cells to recover.
This approach may not eradicate all of the tumor
cells, and those that survive can evolve to become
resistant to subsequent rounds of anti-cancer
therapy.
For the study the team of researchers – which also
involved investigators at the University of
Washington, Oregon Health and Science University,
the Buck Institute for Research on Aging, the
Lawrence Berkeley National Laboratory – examined
cancer cells from prostate, breast and ovarian
cancer patients who had been treated with
chemotherapy.
The National Institutes of Health, the National
Cancer Institute, the Department of Defense and the
Prostate Cancer Foundation funded the research.
For more information, please visit
www.fhcrc.org .
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