Public HealthTargeting Breast Cancer Stem Cells In Mice
Cancer develops when cells known as cancer stem cells begin to divide in
an uncontrolled manner. Researchers from the University of Michigan
Comprehensive Cancer Center have identified roles for the gene PTEN, which
is already well known for its ability to suppress tumor growth, and for
several pathways linked to PTEN in the growth of cells that give rise to
breast cancer. The work, published in this week"s issue of the open-access
journal PLoS Biology, also reports that a drug that interferes with the
activity of one of these pathways leads to a 90 percent decrease in the
number
of cells able to form tumors in mice.
PTEN is the most frequently inactivated tumor suppressor gene in several
cancers, including breast cancer, where it is inactivated in about 40
percent
of patients. PTEN inactivation is associated with poor patient outcomes,
aggressive tumor growth, and resistance to chemotherapy and current
targeted
therapies.
Researchers first deleted PTEN from tumor cells grown in cell culture and
from tumors in mice, and found an increase in the number cells able to
form
new tumors, which suggests that PTEN influences the cancer stem cell
population. They also looked at pathways associated with PTEN and reported
that
the activity of the PI3-K/Akt pathway also regulates the size of the
tumor-forming cell population by activating the Wnt pathway, another
pathway
previously implicated in multiple cancer types.
"Although there has been considerable progress in identifying cancer stem
cells in a variety of tumor types, the pathways that drive the
transformation of these cells are not well understood," says lead study
author Hasan Korkaya, D.V.M., Ph.D., a research investigator in internal
medicine at the University of Michigan Medical School.
Stem cells in breast cancer represent fewer than 5 percent of the cells in
a tumor but are believed to be responsible for fueling a tumor"s growth
and spread. Researchers believe that the ultimate cure of cancer will
require killing these cancer stem cells.
In the current study, researchers looked at a drug called perifosine,
which inhibits the Akt pathway. Tumors in mice were treated with
perifosine or
docetaxel, a standard chemotherapy drug. The docetaxel alone treatment
showed no effect on the number of tumor-forming cells, but the addition of
perifosine reduced the tumor-forming cell population by up to 90 percent.
Additionally, cells treated with perifosine - either with or without
docetaxel - were less likely to form tumors when reintroduced into mice
when compared to cells treated with docetaxel alone. These results suggest
that perifosine specifically targets the breast cancer stem cell
population.
"This is most exciting since perifosine and other drugs that target this
pathway are currently in clinical development. If cancer stem cells do
contribute to tumor relapse, then adding drugs that target these cells may
help to make our current therapies more effective," says study senior
author Max S. Wicha, M.D., Distinguished Professor of Oncology and
director of the University of Michigan Comprehensive Cancer Center.
Funding: This work was funded by the National Institutes of Health (NIH)
grants CA129765 and CA101860, by the Taubman Institute, and in part by the
University of Michigan Cancer Center NIH support grant 5 P 30 CA46592. The
funders had no role in study design, data collection and analysis,
decision
to publish, or preparation of the manuscript.
Competing interests statement: MSW holds equity in and is a scientific
consultant for OncoMed Pharmaceuticals.
Citation:
"Regulation of Mammary Stem/Progenitor Cells by÷ PTEN/Akt/b-Catenin Signaling."
Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, et al. (2009)
PLoS Biol 7(6): e1000121. doi:10.1371/journal.pbio.1000121
Plos Biology