Forever young: Differentiation blocked in tumor stem cells
A new comparison of normal stem cells and cancer stem cells reveals
that the cancer stem cells are abnormally trapped at an early stage
of development. The research, published by Cell Press in the January
issue of Cancer Cell, significantly advances the understanding of
glioma pathophysiology and provides new directions for design of
therapeutic strategies that are targeted to specific types of tumors.
Tumor-initiating cells with stem like properties (TICs) are thought
to be a small population of tumor cells that have many
characteristics in common with normal stem cells (NSCs) in that they
are self-replicating and capable of giving rise to populations of
differentiated cells. Previous research has demonstrated that TICs
are present in different types of brain tumors, including
glioblastomas. Although the TICs share many properties with NSCs,
they are known to possess genetic aberrations that support a
tumorigenic phenotype.
"Thus far, there have been few, if any, reports demonstrating exactly
where along the developmental pathway of tissue-specific stem cell
maturation and differentiation tumor stem cells arise, and which, if
any, of the intrinsic stem cell signaling pathways are perturbed in
tumor stem cells remains largely unknown," explains Dr. Howard A.
Fine from the National Cancer Institute in Bethesda, Maryland. To
better understand the development and differentiation pathways that
play a significant role in cancer stem cells, Dr. Fine and colleagues
isolated TICs from primary human glioblastomas and compared them to
human and mouse NSCs at various developmental stages.
The researchers found that the TICs isolated from an adult patient
are more similar to early embryonic stem cells than to later
embryonic or adult-derived stem cells. Specifically, the TICs appear
to be stuck at this early developmental stage, at least in part, due
to epigenetic repression of bone morphogenic protein receptor 1B
(BMPR1B) expression mediated through a polycomb repressive complex.
BMPs are known to mediate proliferation, differentiation and
apoptosis in NSCs, depending on the stage of cell development and the
local environment. Importantly, forced expression of the silenced
BMPR1B restored normal differentiation capacity to the isolated TICs,
halting further cell division and inducing terminal differentiation.
"Our research provides an example of a temporally deregulated and
aberrantly fixed normal stem cell developmental block to
differentiation contributing to the pathogenesis of a human tumor.
Not only will such insights pave the way for a more thorough
understanding of tumor stem cell biology, but they also identify
BMPR1B as a promising molecular target and open the potential for
targeted therapeutic approaches for agents that can induce terminal
differentiation of tumor stem cells," offers Dr. Fine.
###
The researchers include Jeongwu Lee, Myung Jin Son, Kevin Woolard,
Nicholas M. Donin, Aiguo Li, Chui H. Cheng, Svetlana Kotliarova, Yuri
Kotliarov, Jennifer Walling, Susie Ahn, Misuk Kim, Mariam Totonchy,
Thomas Cusack, Chibawanye Ene, Hilary Ma, Qin Su, Jean Claude
Zenklusen, Wei Zhang, Dragan Maric, and Howard A. Fine of the Neuro-
Oncology Branch, National Cancer Institute, National Institute of
Neurological Diseases and Stroke, National Institutes of Health in
Bethesda.
This research was supported by the Intramural Research Program of the
NIH, National Cancer Institute, Center for Cancer Research.
Lee et al.: "Epigenetic-
Morphogenetic Protein Pathway Inhibits Differentiation of
Glioblastoma-
January 2008. DOI 10.1016/j.ccr.
Public release date: 7-Jan-2008
Contact: Cathleen Genova
cgenova@cell.
617-397-2802
Cell Press
http://www.eurekale
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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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