La Jolla, CA - Reviving a theory first proposed in the late 1800s that the
development of organs in the normal embryo and the development of cancers are
related, scientists at the Salk Institute for Biological Studies have studied
organ development in mice to unravel how breast cancers, and perhaps other
cancers, develop in people. Their findings provide new ways to predict and
personalize the diagnosis and treatment of cancer.
In a paper published
February 3 in Cell Stem Cell, the scientists report striking similarities
between genetic signatures found in certain types of human breast cancer and
those of stem cells in breast tissue in mouse embryos. These findings suggest
that cancer cells subvert key genetic programs that guide immature cells to
build organs during normal growth.
"Stem cells in a healthy developing
embryo have a GPS system to alert them about their position in the organ," says
Geoffrey Wahl, a professor in Salk's Gene Expression Laboratory, who led the
research. "The system depends on internal instructions and external signals from
the environment to tell the stem cell what to do and where to go in the body. It
stimulates the stem cells to grow and form more stem cells, or to change into
different cells that form complex organs, such as the breast. Our findings tell
us that this GPS system is broken during cancer development, and that may
explain why we detect stem-like cells in breast cancers."
between cancer and embryonic tissues was first proposed in the 1870s by
Francesco Durante and Julius Cohnheim, who thought that cancers originated from
cells in adults that persist in an immature, embryonic-like state. More
recently, scientists including Benjamin Spike, a co-first author on the current
work and post-doctoral fellow in the Wahl lab, have discovered that tumors often
contain cells with stem cell characteristics revealed by their genetic
As a result, many scientists and physicians are pursuing ways
to destroy stem-like cells in cancer, since such cells may make cancer more
resistant to treatment and may lead to cancer recurrence. The Salk scientists
are now characterizing the stem-like cells in certain forms of breast cancer to
arrest their growth.
Studying the genetic activity of organ-specific stem
cells is very difficult because the cells are very rare, and it is hard to
separate them from other cells in the organ. But, by focusing on tissue obtained
from mouse embryos, the Salk researchers were able for the first time to
identify and isolate a sufficiently large number of fetal breast stem cells to
begin to understand how their GPS works.
The Salk scientists first made
the surprising finding that these fetal breast stem cells were not fully
functional until just prior to birth. This observation suggested that a very
special landscape is needed for a cell to become a stem cell. The breast stem
cells at this late embryonic stage were sufficiently abundant to simplify their
isolation. This enabled their genetic signature to be determined, and then
compared to that of the stem-like cells in breast cancers.
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of the breast stem cells in the fetus were stunningly similar to the stem-like
cells found in aggressive breast cancers, including a significant fraction of a
virulent cancer subtype known as "triple-negative." This is important as this
type of breast cancer has until now lacked the molecular targets useful for
designing personalized therapeutic strategies.
"The cells that fuel the
development of tumors in the adult are unlikely to 'invent' entirely new
patterns of gene expression," says Benjamin Spike. "Instead, some cancer cells
seem to reactivate and corrupt programs that govern fetal tissue stem cell
function, including programs from their neighboring cells that constitute the
surrounding fetal stem cell landscape, or microenvironment." The discovery of
the shared genetic signatures provides a new avenue for scientists to explore
the links between development and cancer. By uncovering new biological markers,
the scientists hope to develop tests that individualize treatment by showing how
the GPS system of a tumor operates. This should help doctors to determine which
patients may benefit from treatment, and the correct types of treatment to
Doctors are already using drugs, such as Herceptin, that
specifically target malfunctioning genetic pathways in tumors, but no such
therapies are currently available for certain aggressive forms of the disease,
such as the triple negative subtype.
Although triple negative cancer
cells lack the three critical genetic markers that are currently used to guide
breast cancer treatment, the scientists' analysis suggests a strong reliance on
signaling through pathways similar to those that affect fetal breast stem cell
They found that the fetal breast stem cells are sensitive to a
class of targeted therapies that already exists, so these therapies might also
work in triple negative breast cancers. Laboratory studies and clinical trials
are currently underway to test this possibility.
"Substantial effort is
being expended to personalize cancer treatment by gaining a better understanding
of the genetics of an individual patient's cancer," Wahl says. "Our findings
offer a way to discover new targets and new drugs for humans by studying the
primitive stem cells in a mouse."
In addition to Spike, Dannielle Engle and
Jennifer Lin, both postdoctoral researchers in Wahl's laboratory, were also
co-first authors on the paper.
The research was sponsored by the Breast
Cancer Research Foundation, the US Department of Defense, the G. Harold &
Leila Y. Mathers Foundation and Susan G. Komen for the Cure.About the
Salk Institute for Biological Studies
The Salk Institute for Biological Studies
is one of the world's preeminent basic research institutions, where
internationally renowned faculty probe fundamental life science questions in a
unique, collaborative, and creative environment. Focused both on discovery and
on mentoring future generations of researchers, Salk scientists make
groundbreaking contributions to our understanding of cancer, aging, Alzheimer's,
diabetes and infectious diseases by studying neuroscience, genetics, cell and
plant biology, and related disciplines.
Faculty achievements have been
recognized with numerous honors, including Nobel Prizes and memberships in the
National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas
Salk, M.D., the Institute is an independent nonprofit organization and
architectural landmark.This article was first published on www.newswise.com.
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