December 17, 2007
Cold Spring Harbor Laboratory Scientists Report Ability to
Identify and Repress Breast Cancer Stem Cells in Mouse Tissue
An approach based on the manipulation of microRNAs
Cold Spring Harbor, NY – By manipulating highly specific gene-
regulating molecules called microRNAs, scientists at Cold Spring
Harbor Laboratory (CSHL) report that they have succeeded in singling
out and repressing stem-like cells in mouse breast tissue – cells
that are widely thought to give rise to cancer.
Dr. Greg Hannon
"If certain forms of breast cancer do indeed have their origin in
wayward stem cells, as we believe to be the case, then it is critical
to find ways to selectively attack that tumor-initiating population,"
said Gregory Hannon, Ph.D., CSHL professor and Howard Hughes Medical
Institute Investigator. Hannon also is head of a lab focusing on
small-RNA research at CSHL and corresponding author of a paper
reporting the new research, published in the latest issue of Genes
and Development.
"We have shown that a microRNA called let-7, whose expression has
previously been associated with tumor suppression, can be delivered
to a sample of breast-tissue cells, where it can help us to
distinguish stem-like tumor-initiating cells from other, more fully
developed cells in the sample. Even more exciting, we found that by
expressing let-7 in the sample, we were able to attack and
essentially eliminate, very specifically, just that subpopulation of
potentially dangerous progenitor cells."
The study was done in collaboration with Senthil Muthuswamy Ph.D., an
expert in breast cancer research who heads a CSHL lab focusing on
understanding the changes in the biology of breast epithelial cells
during the initiation and progression of cancer. Dr. Muthuswamy
emphasized that a key ingredient that made this study successful is
the use of a mouse breast-derived model cell system called COMMA-1D
that not only includes differentiated cells but also stem-like
progenitors, in varying stages of maturity, or differentiation.
Dr. Senthil Muthuswamy
Unexpected Impact of Conventional Chemotherapy
No therapies currently exist that target stem-like tumor-initiating
cells, whose existence in diverse tissues including breast, lung,
brain and colon, as well as in the blood, has been demonstrated in a
line of research stretching back to 2001. In that year, John E. Dick
of the University of Toronto identified cancer stem cells in the
blood of leukemia patients.
The cancer stem cell hypothesis is controversial, in part, because of
the challenge it represents for current cancer therapy, which regards
all tumor cells as potentially capable of spreading the disease, and
which seeks to reduce tumor mass and destroy the maximum possible
number of tumor cells. In the cancer stem cell hypothesis, reduction
of tumor volume alone will not suffice if the stem cells which
originally gave rise to the cancer are not specifically targeted and
destroyed.
The new Cold Spring Harbor Laboratory research not only suggests one
possible way of accomplishing this therapeutic goal – the Hannon lab
is initiating a demonstration study in mice – but it also
demonstrated that one component of a chemotherapy cocktail currently
used as first-line therapy against certain kinds of breast cancer has
the potential to actually enrich the subpopulation of stem-like cells
that serve as cancer progenitors.
"We found that administration of cyclophosphamide in our mouse cell
sample had the effect of enriching for these cells," Hannon
said, "which suggests that we need to look carefully at these
therapies in model systems to see if the effects we see in cell
culture are mirrored in real tumors – and then, to gauge what effect
that has on metastasis and relapse following therapy."
It has been known for some time that stem and progenitor cells
possess unique defenses, as compared with mature, or differentiated
cells, which, unlike their stem-like "mothers" do not have the
capacity to renew themselves or to generate multiple cell-types.
Stem cells, for instance, are thought to be able to "pump" toxins out
of their cellular domain, much as do fully differentiated tumor cells
that have developed resistance to chemotherapy.
"A Role for microRNAs in Maintenance of Mouse Mammary Epithelial
Progenitor Cells" appears in Genes and Development on December 15,
2007. The complete citation is as follows: Ingrid Ibarra, Yaniv
Erlich, Senthil K. Muthuswamy, Ravi Sachidanandam, and Gregory
Hannon. The paper is available online at:
http://www.genesdev
Cold Spring Harbor Laboratory (CSHL) is a private, non-profit
research and education institution dedicated to exploring molecular
biology and genetics in order to advance the understanding and
ability to diagnose and treat cancers, neurological diseases, and
other causes of human suffering.
For more information, visit www.cshl.edu.
http://www.cshl.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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