Mount Sinai. US: Two existing cancer drugs turn on a gene that tells tumor cells to
remain inactive, according to a study led by researchers at the Icahn
School of Medicine at Mount Sinai and published today in Nature Communications.
Researchers discovered that the gene NR2F1, when switched on,
programs tumor cells to stay dormant. When the gene is switched off,
tumor cells divide and multiply as part of abnormal growth, potentially
allowing dormant cells to grow into tumors throughout the body
(metastasis). Combining the anticancer drugs azacytidine and retinoic
acid significantly increased the amount of active NR2F1 in tumor cells.
These patterns were found in mouse models of several cancers, and
confirmed in prostate cancer cells from human patients.
Results suggest that NR2F1 is a “master regulator” of tumor cell
growth, influencing several genes that determine whether cells remain
inactive, or quiescent in medical terms. According to the study, NR2F1
exerts control over long lasting programs in stem cells in the human
embryo, where it directs cells to stop growing and become specialized
cells (neurons) for life. This function suggests that NR2F1 may exert a
long-lasting effect on tumor cells, keeping them dormant after they have
broken off from an original tumor.
“Our results explain why some tumor cells scattered through the body
are committed to remaining harmless for years, while others cause active
disease,” said Julio A. Aguirre-Ghiso, PhD, Professor of Medicine,
Hematology and Medical Oncology, and Otolaryngology at the Icahn School
of Medicine. “In finding this master switch we found a way to analyze
tumor cells before treatment to determine the risk of a cancer
recurrence or metastasis.”
“Azacytidine and retinoic acid, the latter a form of vitamin A,
prevented tumor cells from rapidly multiplying, restored normal cell
function, and activated several tumor suppressor genes that are often
turned off in tumors,” said study co-leader Maria Soledad Sosa, PhD, a
postdoctoral fellow in Hematology at the Icahn School of Medicine. “We
now have strong evidence that combining these well-known drugs may have a
profound, long-lasting therapeutic effect.”
The current study builds on the research team’s earlier finding that
lowering amounts of tumor suppressor genes TGFβ2 and p38 awakened
dormant tumor cells, fueling metastatic tumor growth. Azacytidine and
retinoic acid restored TGFβ2 expression and p38 activation to drive
tumor cell dormancy.
This study was supported by grants from the Samuel Waxman Cancer
Research Foundation, National Cancer Institute, National Institute of
Environmental Health Sciences, New York State Stem Cell Science program,
JJR Foundation and Hirschl/Weill-Caulier Trust, Department of Defense
and Janssen Research and Development LLC.
About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed
to providing distinguished care, conducting transformative research, and
advancing biomedical education. Structured around seven member hospital
campuses and a single medical school, the Health System has an
extensive ambulatory network and a range of inpatient and outpatient
services—from community-based facilities to tertiary and quaternary
care.
The System includes approximately 6600 primary and specialty care
physicians, 12-minority-owned free-standing ambulatory surgery centers,
over 45 ambulatory practices throughout the five boroughs of New York
City, Westchester, and Long Island, as well as 31 affiliated community
health centers. Physicians are affiliated with the Icahn School of
Medicine at Mount Sinai, which is ranked among the top 20 medical
schools both in National Institutes of Health funding and by U.S. News
& World Report.
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