What is Stem Cell: [StemCells] Cancer / Adult SCs regen. med. boon Sci Am / EurekAlert

Adult Cells Steal Trick from Cancer to Become Stem Cell-Like
A route used by tumor cells to spread could be exploited to make stem
cells for regenerative medicine and cancer therapies
By Nikhil Swaminathan

GOING MOBILE: Cells that have undergone the transfer from epithelial
to mesenchymal are stem cell-like in their properties.
COURTESY OF SENDURAI MANI
In a boon to cancer treatment and regenerative medicine, scientists
have discovered that a trick used by tumor cells that allows them to
migrate around the body can cause normal, adult cells to revert into
stem cell–like cells.

Large quantities of these reverted cells could be used to treat
anything from spinal cord injury to liver damage without the risk of
tissue rejection, said Robert Weinberg, a biologist at the
Massachusetts Institute of Technology's Whitehead Institute for
Biomedical Research and co-author of a study appearing in Cell.
Learning more about how cancer cells move around the body is also
providing scientists with new insights that could thwart the spread
of the disease.

The key to the process is a better understanding of developmental
changes in the body's two primary cell types: epithelial cells (those
that constitute the skin and most internal organs) and mesenchymal
cells (which make up connective tissue). The key difference between
the two cell categories is that epithelial cells adhere very tightly
to one another, making sheetlike layers, whereas mesenchymal cells
are only loosely bound and can migrate within the body. In the
developing embryo, an initial group of epithelial cells undergoes a
shift called an "epithelial to mesenchymal transition" (EMT) to form
bones, blood and cartilage as well as the heart.

Likewise, some cancerous cells can perform a temporary EMT
transformation to the mobile mesenchymal form. The conversion
improves the cells' tumor-forming ability, cutting the number of
tumor cells required to form a carcinoma from one million to just
10,000, the researchers say.

"More than 80 percent of cancer in humans occurs in epithelial
cells," says study co-author Sendurai Mani, an assistant professor of
molecular pathology at the University of Texas' M.D. Anderson Cancer
Center in Houston and a former postdoc in Weinberg's lab. Previous
work in Weinberg's lab had shown that after a tumor forms in one part
of the body, some of the cancer cells undergo EMT, Mani explains. The
now-mesenchymal cells can then travel to a remote site, where they
eventually convert back to their epithelial state and clump together
into a secondary tumor.

Working with human breast tissue, the new study's authors attempted
to induce EMT in normal cells; they figured they would just get
fibroblasts, a type of connective tissue that is important in wound
healing. When they looked closely, however, they noted that the
transformed cells had surface proteins that were common to stem
cells. Cultured in the lab, the changed cells showed an ability to
differentiate into (or become) two discrete cells found in breast
tissue. And the transformed cells proved to be very similar to actual
stem cells from both mice and humans.

"What we're doing is inducing dedifferentiation," Mani says. He noted
that it's not yet clear how far these cells can go down the path to
immaturity—and, with it, the ability to become any tissue in the
body. "We found, surprisingly, that EMT and stem cells could be
linked; we show that, yes, they are very closely linked."

Mani says that the scientists may next pursue two paths: The team can
determine how to stop cancer cells from undergoing this
transformation in the first place. Second—a path they are already
pursuing—they can gauge these transformed adult cells' worth as stem
cell surrogates for regenerative medicine.

As far as the promise of regenerative therapies, the team will
attempt to determine just how stem cell–like these cells are by
inducing EMT in epithelial cells from the mammaries of mice to see if
they can grow a breast in the lab. If they succeed, they can be
reasonably confident that epithelial cells can be taken from a
patient and used to regenerate damaged tissue in that same person.

http://www.sciam.com/article.cfm?id=adult-cells-steal-trick-f

---
Embryonic pathway delivers stem cell traits
CAMBRIDGE, Mass. (May 15, 2008) – Studies of how cancer cells spread
have led to a surprising discovery about the creation of cells with
adult stem cell characteristics, offering potentially major
implications for regenerative medicine and for cancer treatment.

Some cancer cells acquire the ability to migrate through the body by
re-activating biological programs that have lain dormant since the
embryo stage, as the lab of Whitehead Member Robert Weinberg has
helped to demonstrate in recent years. Now scientists in the Weinberg
lab have shown that both normal and cancer cells that are induced to
follow one of these pathways may gain properties of adult stem cells,
including the ability to self-renew.

In a paper published online by Cell on May 15, former postdoctoral
researcher Sendurai Mani and his colleagues demonstrated in mice and
in human cells that cells that have undergone an "epithelial-to-
mesenchymal" (EMT) transition acquire several important
characteristics of stem cells. Conversely, the researchers also
showed that naturally existing normal stem cells as well as tumor-
seeding cancer stem cells show characteristics of the post-EMT cells,
including the acquisition of mesenchymal cell traits, which are
usually associated with connective tissue cells.

Epithelial cells, which make up most of the human body, bind together
in sheet-like structures. In embryonic development, the EMT process
breaks up cell-cell adhesion in the epithelial layer, and converts
epithelial cells into more loosely associated mesenchymal cells. In
the context of cancer development, some cancer cells within a primary
cancer may undergo an EMT, migrate through the body to their end
destination, and there resume their epithelial form through a reverse
process (the mesenchymal-to-epithelial transition).

Mani and his colleagues have identified FOXC2, one of the key genes
involved in invasion and metastasis. In addition, FOXC2 appears to
program the metastatic ability of some breast cancers.

Mani knew that during embryonic development, FOXC2 expression is
restricted to mesoderm and mesoderm-derived cells when they are in an
undifferentiated state, and its expression disappears once these
cells differentiate. Similarly, his experiments showed that
epithelial cells that undergo EMT express FOXC2, but that expression
is lost when they revert back to an epithelial state.

In collaboration with Andrea Richardson and Jeffery Kutok,
pathologists at Boston's Brigham and Women's Hospital, Mani went on
to study FOXC2 expression in normal human breast tissue. It turned
out that such cells were located precisely where researchers expect
to find mammary epithelial stem cells.

As he pondered these findings and the earlier results about FOXC2's
role in metastasis, Mani wondered: Just what were these cells
generated by EMT that expressed FOXC2"

Were they simply fibroblasts, the most common cells in normal
connective tissue" Or were they actually stem cells"

"I asked Mai-Jing Liao, another postdoc in the Weinberg lab, to check
whether the cells generated by EMT would have any stem cell
properties," recalls Mani, now an assistant professor in the
department of molecular pathology at the University of Texas's M. D.
Anderson Cancer Center in Houston. "He said, `You must be out of your
mind, but it won't take more than half an hour to check.'"

Much to Liao's surprise, when he examined cells that had undergo an
EMT, his tests did highlight surface proteins that are key markers
for stem cells.

The researchers found that the cells that underwent the EMT process
were mesenchymal-like in appearance and demonstrated stem-cell
surface markers. The cells also displayed an increased ability to
grow in suspension, forming structures called mammospheres—another
trait of mammary stem cells. Some cells in the resulting mammospheres
showed, in turn, stem cell markers, indicating they could
differentiate into two kinds of mammary cells. And cells in the
mammospheres retained their stem cell properties even after the EMT
induction process was stopped.

Furthermore, when the Weinberg lab scientists isolated stem-cell-like
cells from cultured human mammary epithelial cells or from mouse
breast tissue, their properties were very similar to the EMT-induced
cells. Working with Kornelia Polyak of Dana-Farber Cancer Institute
and Harvard Medical School, Mani found that this was also true with
normal and tumor cells obtained from human patients.

"This for us is a very exciting discovery, not only because of its
unexpectedness but because it offers a route by which one could in
principle generate unlimited numbers of stem cells committed to
create a specific cell type," says Weinberg, who is also a professor
of biology at Massachusetts Institute of Technology. "One could
imagine, for example, that if one takes skin cells and induces them
to undergo an EMT, they could become skin stem cells."

Importantly, the researchers also demonstrated that inducing the EMT
process can produce cells with many characteristics of cancer stem
cells. (Beginning in 2003, scientists in various labs have identified
these self-renewing, tumor-seeding cells in a number of solid
tumors.)

This finding could help to answer a key question about metastasis:
When tumor cells spread into different sites, how do they multiply
enough to form a dangerous new tumor"

"If you take a population of human cancer cells that normally form a
tumor very inefficiently and induce an EMT, their tumor-initiating
abilities increase by about a hundred-fold, so that it takes about
10,000 cells rather than a million cells to form a tumor," says
Wenjun Guo, co-lead author on the paper and postdoctoral researcher
in the Weinberg lab. "This suggests cancer stem cells are using pre-
existing normal stem cell machinery to propagate their own self-
renewal and therefore their tumor-initiating ability."

Mani is continuing his research on the EMT/cancer stem cell
connection and its role in cancer metastasis at the M. D. Anderson
Cancer Center. Researchers in the Weinberg lab will investigate the
EMT process with other cell lines. They also will attempt to give
final proof in mice that the process creates completely defined stem
cells, by taking cells from mouse mammary fat pads, inducing an EMT
for some of the cells, returning the resulting cells to the fat pad,
and seeing if they can regenerate the mammary gland.

###
This research was supported by the Breast Cancer Research Foundation,
the MIT Ludwig Center for Molecular Oncology and the National Cancer
Institute. Mani was supported by a Department of Defense postdoctoral
fellowship.

Full citation:

Cell, online publication May 15, Print Edition, Volume 133 (4)
"The epithelial-mesenchymal transition generates cells with
properties of stem cells"
Sendurai A. Mani (1,3,9,10), Wenjun Guo (1,9), Mai-Jing Liao (1,9),
Elinor Ng Eaton (1), Ayyakkannu Ayyanan (4), Alicia Zhou (1), Mary
Brooks (1), Ferenc Reinhard (1), Cheng Cheng Zhang (1), Michail
Shipitsin (5,6), Lauren L. Campbell (5,7), Kornelia Polyak (5,6,7),
Cathrin Brisken(4), Jing Yang (1,8), Robert A. Weinberg (1,2,).

1. Whitehead Institute for Biomedical Research, 9 Cambridge Center,
Cambridge, MA 02142
2. Department of Biology and MIT Ludwig Center for Molecular
Oncology, Massachusetts Institute of Technology, Cambridge MA 02139
3. Department of Molecular Pathology, University of Texas M. D.
Anderson Cancer Center, 7435 Fannin St, Houston, TX 77054
4. Ecole polytechnique fédérale de Lausanne (EPFL) ISREC - Swiss
Institute for Experimental Cancer Research, CH-1066, Epalinges,
Switzerland
5. Department of Medical Oncology, Dana-Farber Cancer Institute,
Boston, MA 02115
6. Department of Medicine, Harvard Medical School, Boston, MA 02115
7. Program in Biological and Biomedical Sciences, Harvard Medical
School, Boston, MA 02115
8. Department of Pharmacology, University of California, San Diego,
School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0636
9. These authors contributed equally to this work

Public release date: 15-May-2008
Contact: Cristin Carr
carr@wi.mit.edu
617-324-0460
Whitehead Institute for Biomedical Research

http://www.eurekalert.org/pub_releases/2008-05/wifb-epd050808.php

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