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Oncology |
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| 28 Mar 2009 | Viewed: 214 | |
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Adult stem cells
and their more committed kin, progenitor cells, are prized by medical
researchers for their ability to produce different types of specialized
cells. The potential of using these cells to repair or replace damaged
tissue holds great promise for cancer therapies and regenerative
medicine. However, the question that must first be answered is what
determines the ultimate fate of a stem or progenitor cell? A team of
researchers led by Berkeley Lab's Mark LaBarge and Mina Bissell appear
to be well on the road to finding out.
Working with unique microenvironment microarrays (MEArrays) of
their own creation, LaBarge and Bissell and their collaborators have
shown that the ultimate fate of a stem or progenitor cell in a woman's
breast - whether the cell develops normally or whether it turns
cancerous - may depend upon signals from multiple microenvironments.
"We found that adult human mammary stem and progenitor cells
exhibit impressive plasticity in response to hundreds of unique
combinatorial microenvironments," said LaBarge, a cell and molecular
biologist in Berkeley Lab's Life Sciences Division. "Our results
further suggest that rational modulation of the microenvironmental
milieu can impose specific differentiation phenotypes on normal stem or
progenitor cells, and perhaps even impose phenotypically normal
behavior on malignant cells during tissue genesis. All of this points
to the rational manipulation of adult stem and progenitor cells as a
promising pathway for beneficial therapies."
Previous studies on how microenvironments affect the development of
adult human stem or progenitor cells have been based on the behavior of
these cells in culture (in vitro) where they are exposed to a single
molecular agent. However, when these cells are in an actual human being
(in vivo) they are surrounded by a multitude of other cells plus a
supporting network of fibrous and globular proteins called the
extracellular matrix (ECM), as well as many other nearby molecules, all
of which may be simultaneously sending them instructional signals.
"With our MEArrays, we can use combinations of proteins from a
select tissue to create multiple microenvironments on a single chip
about two square centimeters in area," said LaBarge. "We think this
approach will give us a much more realistic picture as to how stem and
progenitor cells actually behave in vivo."
Said Bissell, a Distinguished Scientist with Berkeley Lab's
Life Sciences Division and one of the world's leading researchers on
breast cancer, "We have demonstrated that each discrete cell fate
decision requires the integration of multiple pathways, and we have
identified combinations of components in the human mammary
microenvironment that impose distinct cell fates. These results are
exciting because they indicate that we can test a large number of
effectors and determine which ones to use to direct the fate of adult
stem and progenitor cells. This give hope that one day - sooner rather
than later - the information could be used for therapy."
Collaborating with LaBarge and Bissell on this study were
Jason Ruth, now at the University of Pennsylvania, Martha Stampfer of
Berkeley Lab, Celeste Nelson, now with Princeton University, and Rene
Villadsen, Agla Fridriksdottir and Ole Petersen, of the Panum Institute
in Denmark.
Human breast tissue harbors two types of epithelial cells:
luminal - the cells that are able to produce milk and generally the
ones that become cancerous; and myoepithelial - the cells that surround
the luminal cells and push milk down the ducts to the nipples, but
which rarely become cancerous. Like cells in other types of tissue
these breast epithelial cells are spawned from stem and progenitor
cells that despite being primitive - essentially a cellular blank slate
- possess the exact same genome as their differentiated daughters. Once
it was widely held that adult stem and progenitor cells intrinsically
"know" when to self-renew and when to differentiate into one specific
tissue cell or another based on pre-determined genetic programs.
However, pioneering research by Bissell, in which it has been
demonstrated that interactions between an epithelial breast cell and
its ECM play a major role in determining whether that cell becomes
cancerous, pointed the way to the idea that the ultimate fate of a stem
or progenitor cell is heavily influenced by interactions with its
neighboring microenvironments.
"Adult stem cells are maintained inside a specialized
microenvironment called a niche, whereas progenitor cells migrate to
surrounding microenvironments that are distinct from the one around the
niche," said LaBarge. "The ability of adult stem cells to
self-maintain, as well as to give rise to progenitor cells that are
targeted to become a specific tissue cell, indicates an ability to
respond to changing microenvironmental demands, which would mean that a
stem or progenitor cell is receiving instructional information from its
surroundings."
The fact that normal cells often lose their tissue-specific
functions when placed in culture is further evidence of cell fate being
tied in to signals from the microenvironment. However, proving such a
hypothesis has been difficult in the past because the composition of
cell microenvironments is extremely complex and requires a method by
which a combination of carefully choreographed interactions can be
observed. Given that experiments with human adult stem cell niches
cannot be done in vivo and that scientists can only learn so much from
mouse models, this means that cell culture studies must be done under
as close as possible to in vivo conditions.
"Our technology mimics actual in vivo conditions and enables
us to perform highly parallel functional analysis of combinatorial
microenvironments, and image analysis of 3-D organotypic cultures and
micro patterned culture substrata," said LaBarge. "The 3-D capability
is crucial because our studies show that orientation of the stem or
progenitor cells with respect to the signaling molecules can be
critical to what happens next."
The MEArrays were fabricated using micro patterning technology
originally adapted by co-author Nelson that LaBarge "tweaked." A robot
imprinted arrays of 2,304 individual combinations of molecules onto a
rubber-coated glass microscope slide (the rubber facilitates adsorption
of the proteins onto the slide). An individual MEArray consisted of 192
unique combinatorial microenvironments replicated 12 times, with a
plastic barrier running along the perimeter so that cell cultures could
be placed on top.
In addition to possible contributors to the stem cell niche,
the microenvironments also comprised many ECM and signaling molecules
that are expressed in the breast but had not been directly linked to
stem cell function before.
In all, adult mammary stem and progenitor cells were exposed
to 8,000 different combinations of breast tissue protein and biological
molecules. LaBarge, Bissell and their collaborators were able to
distinguish between effects resulting from cell interactions with other
cells and those resulting from cell interactions with the ECM or other
signaling molecules. Both immortalized and primary human breast
progenitors were analyzed with the MEArrays and the results were used
in conjunction with physiologically relevant 3-D human breast cultures.
This approach enabled the research team to identify conditions that
induced cells to convert into normal breast cell types as well as
conditions that kept the cells in their original, non-specialized
state.
One of the most intriguing results in this study was the
suggestion that modulation of stem and progenitor cell differentiation
pathways might be used to "normalize" malignant breast cells.
"Normal and malignant mammary epithelial cells in 3-D cultures
have distinct phenotypes," LaBarge said. "By impairing a signaling
pathway known as Notch, we are able to revert malignant breast cancer
cells to a normal phenotype."
In previous studies, Bissell and her group had identified
signaling pathways that could cause "phenotypic reversion" of breast
cancer cells but this had never been tried before with stem cells.
Said Bissell, "The MEArray approach may be able to teach us
how to direct stem cell function in a therapeutic setting and possibly
to re-program non-stem cells to acquire other stem cell fates."
While the MEArrays in this study were used to study adult stem
and progenitor cells in breast tissue, the technique should also be
applicable to any of the other 200 different types of tissue cells
within other organs, LaBarge said.
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Article adapted by Medical News Today from original press release.
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This research was supported in part by grants and a
distinguished Fellow Award from the U.S. Department of Energy's Office
of Biological and Environmental Research and low dose program, by
grants from the National Cancer Institute and from the U.S. Department
of Defense's breast cancer research program. LeBarge was a fellow of
the American Cancer Society.
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| News Source: Medical News Today |
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