Hypoxia is a microenvironmental hallmark of solid tumors that
induces stress responses, quiescence programs, and chemo and
radio-resistance. Until now it has been unclear how hypoxia in primary
tumors influences the fate of disseminated tumor cells (DTC's) in target
organs and how this is related to patient outcome.
A new study states
that primary tumor hypoxic microenvironments give rise to a
sub-population of dormant DTC's that evade therapy and may be the source
of disease relapse and poor prognosis.
‘Low oxygen found in many tumors may be a poor prognosis indicator because it activates more aggressive characteristics in tumor cells and also because it may allow numerous dormant cancer cells to evade chemotherapy.’
In a first of its kind study, Mount Sinai researchers have discovered
the conditions by which specific signals in primary tumors of head and
neck and breast cancers, pre-program cancer cells to become dormant and
evade chemotherapy after spreading.
Their findings, published in the issue of Nature Cell Biology
and featured on
the cover, could lead to new drug development, treatment options and
transform the way doctors care for cancer patients to treat metastatic
"This research highlights the signals in the primary tumor that
instruct disseminated cancer cells to become dormant," said the study's
senior investigator Julio A. Aguirre-Ghiso, Professor of Medicine,
Hematology and Medical Oncology, The Tisch Cancer Institute Icahn School
of Medicine at Mount Sinai.
"Dormant cells must be targeted to address
the whole spectrum of the disease and attacking the cancer. We hope
this research may lead to the use of dormancy markers in primary tumors
to assess the prevalence of disseminated cancer cells in secondary
organs and thus tailor treatments to eliminate these dormant and therapy
evading cancer cells."
Aguirre-Ghiso and a team of investigators from Albert Einstein
College of Medicine, SUNY Polytechnic Institute and University of
Wisconsin-Madison developed a device using a nano-technology tool,
biosensors, and advanced imaging technology to manipulate primary tumor
They created controlled hypoxic and non-hypoxic
niches in tumors by implanting the devices loaded with drugs that
induced hypoxia. These "fine-tuned" microenvironments in live tumors
allowed the researchers to isolate the cancer cells to determine how
they behaved when they moved from the primary tumor to the lungs.
investigators tracked the DTC's with genetically encoded biosensors to
see which cells were exposed to low oxygen, which cells were dormant,
and how they reacted to therapy
"This approach and the hypoxia biosensor and nano- and imaging
technology innovations developed by SUNY Polytechnic Institute and the
Integrated Imaging Program at Einstein allowed linking primary tumor
microenvironments to fate of DTCs in a way that was never before
attempted and at single cell resolution allowing definitive tests of
mechanism," said the study's co-corresponding senior investigator John
Condeelis, Professor and Co-Chair of Anatomy & Structural
Biology and Co-Director of the Integrated Imaging Program at Albert
Einstein College of Medicine.
The investigators discovered DTCs from hypoxic regions were still
able to grow into metastasis and more likely to enter dormancy as
opposed to cells from high oxygen levels in primary tumors. The
researchers thus found that hypoxic regions of the tumor could spread
not only rapidly, growing DTC's but also sending a large amount of them
into a "sleeping mode" whereby creating cells more efficient at evading
"This research is an important step to further explore the biology
of these dormant cells and design therapies that specifically address
this biology," explained Dr. Aguirre-Ghiso.
This study revealed that low oxygen found in many tumors may be a
poor prognosis indicator not only because it activates more aggressive
characteristics in tumor cells but also because it may allow numerous
dormant cancer cells to evade chemotherapy. The fact that researchers
found genes in the primary tumor that corrected with the dormant,
chemotherapy resistant behavior of cancer cells in distant organs
suggests that a marker test might be able to predict which patients
might be prone to carry more dormant drug resistant cancer cells.
"Recurrence of cancer after initial treatment remains a critical
unsolved problem for too many patients,"said William Oh, Chief,
Division of Hematology and Medical Oncology, and Professor of Clinical
Cancer Therapeutics at The Tisch Cancer Institute, Icahn School of
Medicine at Mount Sinai. "This highly innovative research provides a
novel path forward for targeting dormant cancer cells which may be
'hiding' from our available therapies and which may need additional
drugs to root them out and improve cure rates."