GAME-CHANGING new discovery re cancer stem cells!!!

[Lani]

Scientists identify a surprising new source of cancer stem cells
[Whitehead Institute for Biomedical Research]

CAMBRIDGE, Mass. (April 11, 2011) - Whitehead Institute researchers have discovered that a differentiated cell type found in breast tissue can spontaneously convert to a stem-cell-like state, the first time such behavior has been observed in mammalian cells. These results refute scientific dogma, which states that differentiation is a one-way path; once cells specialize, they cannot return to the flexible stem-cell state on their own.

This surprising finding, published online this week in the Proceedings of the National Academy of Sciences (PNAS), may have implications for the development of cancer therapeutics, particularly those aimed at eradicating cancer stem cells.

"It may be that if one eliminates the cancer stem cells within a tumor through some targeted agent, some of the surviving non-stem tumor cells will generate new cancer stem cells through spontaneous de-differentiation," says Whitehead Founding Member Robert Weinberg. Cancer stem cells are uniquely capable of reseeding tumors at both primary and distant sites in the body.

During differentiation, less-specialized stem cells mature into many different cell types with defined functions. These differentiated cells work together to form tissues and organs. In breast tissue, for example, differentiated basal cells and luminal cells combine to form milk ducts.

While analyzing cells from human breast tissue, Christine Chaffer, who is a postdoctoral researcher in the Weinberg lab and first author of the PNAS paper, observed a small number of living basal cells floating freely in the tissue culture medium.

Intrigued by the cells' unusual behavior, Chaffer conducted further targeted investigations, including injection of the floating basal cells into mice. After 12 weeks she found that the injected basal cells gave rise to milk duct-like structures containing both basal and luminal cells—a clear indication that the floating cells had de-differentiated into stem-like cells.

Until now, no one has shown that differentiated mammalian cells, like these basal cells, have the ability to spontaneously revert to the stem-like state (a behavior described as plasticity).

To see if basal cells could become cancer stem cells, Chaffer inserted cancer-causing genes into the cells. When these transformed cells were injected into mice, the resulting tumors were found to include a cancer stem cell population that descended from the original injected basal (more differentiated) cells. These results indicate that basal cells in breast cancer tumors can serve as a previously unidentified source of cancer stem cells.

As research for new cancer therapies has recently focused on eliminating cancer stem cells, Weinberg cautions that the plasticity seen in these basal cells suggests a more complicated scenario than previously thought.

"Future drug therapies that are targeted against cancer will need to eliminate the cancer stem cells and, in addition, get rid of the non-stem cells in tumors - both populations must be removed," says Weinberg, who is also a professor of biology at MIT. "Knocking out one or the other is unlikely to suffice to generate a durable clinical response."

Chaffer is now focusing on what actually prompts these flexible cells to de-differentiate, and in the case of cancer cells, how to stop the cells from converting into cancer stem cells.

"This plasticity can occur naturally, and it seems that the trigger may be a physiological mechanism for restoring a pool of stem cells," says Chaffer. "We believe that certain cells are more susceptible to such a trigger and therefore to conversion from a differentiated to a stem-like state, and that this process occurs more frequently in cancerous cells."

In the case of normal epithelial cells, the observed behavior may also allow patient-specific adult stem cells to be derived without genetic manipulation, holding promise for degenerative disease therapy.

This research was supported by the National Health and Medical Research Council of Australia, National Institutes of Health (NIH), Massachusetts Institute of Technology's Ludwig Center for Molecular Oncology, the Breast Cancer Research Foundation, and a Department of Defense (DoD) Breast Cancer Research Program (BCRP) Idea Award.

[Ellie F]

Lani-I have read this 3 times! Is the research saying that some ordinary cells can become stem cells or am I on the wrong track altogether? Could this explain why even when the 'original' stem cells are eradicated by treatment other cells can take on these characteristics and spread elsewhere?
Thanks
Ellie

[Lani]

when we all started out as an egg which was penetrated by a sperm whose nuclear chromosomes mixed with the egg's and one cell divided into two, and then into four and so on, all cells started out without specialization and gradually got more and more specialized. Similar, normal stem cells lie in reserve in tissues to become more specialized and replace specialized cells as they need it.

What we didn't know is that these specialized cells can later de-differentiate ie, de-specialize and become a cell that can become lots of other things again.

Since it is not a one-way street, killing only the cancer stem cells may not prevent cancer from returning IF there is a way for differentiated cells to return to being cancer stem cells. We do not know if this is true yet, but it is concerning.

It comes from the lab of probably THE MOST RESPECTED cancer researcher in the world, Robert Weinberg(from what I ascertain from all the meetings I attend--he is spoken of with reverence), so it bears watching.

[Ellie F]

Thanks Lani
If this proves to be true it may result in a quantum shift in thinking of how we treat cancer?

Really appreciate you taking the time to explain in simple terms.

Ellie

Why such a big fuss???? Didn't we know about de-differentiation long back?

[Lani]

Not de-differentiation to the point of a stem cell it would seem

[Margerie]

wonder if this will eventually affect the mastectomy versus lumpectomy debate

This article has come online on 16th April
Link:
http://www.pnas.org/content/early/20....full.pdf+html

[Rich66]

Unregistered,
Please provide at least a summary of findings

Normal and neoplastic nonstem cells can
spontaneously convert to a stem-like state
Christine L. Chaffera,b, Ines Brueckmanna, Christina Scheela,b, Alicia J. Kaestlia, Paul A. Wigginsa,
Leonardo O. Rodriguesa,b, Mary Brooksa,b, Ferenc Reinhardta,b, Ying Suc, Kornelia Polyakc, Lisa M. Arendtd,e,
Charlotte Kuperwasserd,e, Brian Bieriea,b, and Robert A. Weinberga,b,f,1
aWhitehead Institute for Biomedical Research, Cambridge, MA 02142; bLudwig MIT Center for Molecular Oncology, Cambridge, MA 02139; cDepartment
of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; dDepartment of Anatomy and Cellular Biology, Sackler School, Tufts University
School of Medicine, Boston, MA 02111; eMolecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111; and fDepartment of Biology,
Massachusetts Institute of Technology, Cambridge, MA 02139
Contributed by Robert A. Weinberg, March 2, 2011 (sent for review December 8, 2010)
Current models of stem cell biology assume that normal and
neoplastic stem cells reside at the apices of hierarchies and differentiate
into nonstem progeny in a unidirectionalmanner. Here we
identify a subpopulation of basal-like human mammary epithelial
cells that departs from that assumption, spontaneously dedifferentiating
into stem-like cells. Moreover, oncogenic transformation
enhances the spontaneous conversion, so that nonstem cancer cells
give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We
further show that the differentiation state of normal cells-of-origin is
a strong determinant of posttransformation behavior. These findings
demonstrate that normal and CSC-like cells can arise de novo from
more differentiated cell types and that hierarchical models of mammary
stem cell biology should encompass bidirectional interconversions
between stem and nonstem compartments. The observed
plasticity may allow derivation of patient-specific adult stem cells
without genetic manipulation and holds important implications for
therapeutic strategies to eradicate cancer.

Discussion:

The most unanticipated discovery that has emerged from this
study is the plasticity that we can now ascribe to human mammary
epithelial cells. We have shown that differentiated mammary
epithelial cells can convert to a stem-like state, doing so in
an apparent stochastic manner in vitro. This conversion occurs
in transformed and nontransformed HMECs isolated from cell
lines and primary tissue. In each case, the conversion proceeded
without genetic manipulation.
These findings represent a profound divergence from the
currently accepted unidirectional hierarchical model of mammary
epithelial cells and have widespread implications for the
use of cultured cells. In mammalian cells, the idea that nonstem
cells dedifferentiate to form functional stem cells has been restricted
to the notion that progenitor cells can reacquire stem
cell activity in mouse differentiating spermatogonia (26). As
such, our work demonstrates in mammalian cells that differentiated
epithelial cells can revert to a stem-like state.
Our findings also hold implications for the development of
anticancer therapeutics. As we previously reported, cells that
have been forced experimentally into a mesenchymal/stem-like
state can be used to screen for candidate therapeutic agents that
specifically target CSCs (27); the intent here was to eliminate
these cells and thereby deprive tumors of their ability to regenerate
and thrive following initial therapy. However, if non-
CSCs can spontaneously dedifferentiate into CSCs, then targeting
CSC populations will, on its own, be unlikely to yield durable
clinical responses, because the therapeutic eradication of existing
CSC populations might be followed by their regeneration from
non-CSCs within the tumor under treatment. Given the present findings, the known ability of microenvironmental
signals to provoke epithelial–mesenchymal transitions
(EMTs) and the close connection between passage through an
EMT and entrance into a stem-cell state, we suspect that the
presently observed spontaneous conversion in vitro may be
augmented in vivo by contextual signals in the tumor microenvironment,
such as those that drive the EMT (28, 29). Relevant
here are studies demonstrating that hypoxia-inducible factors
(HIFs) can induce the EMT phenotype and promote metastasis
and the CSC phenotype (30, 31). Spontaneous dedifferentiation
in vivo may involve the reactivation of one or more of the described
pluripotency factors (Oct4, Klf4, c-myc, and Sox-2) (32).
Hence, the representation of CSCs within tumor cell populations
is likely to be influenced both by contextual signals and by the
intrinsic phenotypic plasticity of these cells, as observed here.
The ability of non-CSCs to convert into CSCs in vivo might
resolve many of the current inconsistencies of the CSC model. In
particular, the observed plasticity that was once reserved for CSCs
alone can now be associated with nonstem cells. As such, CSC
populations may differ profoundly between various tumor types
according to the inherent plasticity of cells in their respective
nonstem fractions and their ability to spawn CSCs de novo.
The present observations lend further support to the emerging
view that the biological state of cells-of-origin is an important
determinant of the phenotype of their transformed derivatives
(8, 9), where experimental transformation of cells that have a
phenotype related to that of mammary stem cells generates cell
populations with a high frequency of tumor-initiating cells
(∼1:1,420–1:1,804 cells) and metastasis, which contrasts with the
low tumor-initiating ability and nonmetastatic nature of tumors
derived via transformation of more differentiated cell types.
The present findings hold the implication that patient- and
tissue-specific stem-like cells may one day be created in vitro via
spontaneous conversion of a patient’s own terminally differentiated
epithelial cells, a process that would not require any genetic
alteration of these cells. Such stem-like cells could be important
for regenerative therapies. Our results further emphasize the
pathological implications of cellular plasticity in cancer development,
progression, and recurrence. Further research needs to be
undertaken to determine the mechanism underlying the de novo
generation of CSCs from non-CSCs in vivo, with the promise
of potential novel targets for future cancer therapies aimed at
eradicating CSCs.

[StephN]

Pardon my pea brain question, but does this have anything to do with the pathology report stating "poorly differentiated cells?"

This was regarding my biopsy report, and I was told this phrase indicated aggressive disease.