Tumor (cancer) stem cells (CSCs) are hypothesized to be a distinct and probably small subpopulation of tumor cells which are similar to normal stem cells, with resulting ability to renew themselves, differentiate into other cell types, and produce new tumor cells (thus fueling tumor growth).  In contrast, the remaining majority of tumor cells are assumed to lack these abilities.

The existence of distinct CSCs is still under debate.  For example, Kern and Shibata 2007 use quantitative arguments, relying on apparent inconsistencies in data, to conclude that "tumorigenic behavior might be a varying probabilistic potential for all tumor cells rather than [a] quantal and deterministic feature of a minority of tumor cells."  Also see Kelly et al 2007, who argue that "tumor growth need not be driven by rare cancer stem cells."  Further, see Yoo and Hatfield 2008, who "show that all colonies derived from randomly chosen single cells in mouse lung and breast cancer cell lines form tumors following allografting histocompatible mice," which "suggests that the majority of malignant cells rather than CSC can sustain tumors and that the cancer stem cell theory must be reevaluated."

Despite this controversy, the majority of researchers currently appear to believe that the evidence is fairly strong for the existence of distinct tumor stem cells in the particular case of brain tumors.  For a very readable, short, and recent editorial along these lines, see Boockvar and Howard 2008.  Some key points from this paper are as follows:

• "Evidence strongly indicates that cancer stem cells (CSCs) drive tumorigenesis, as these cells possess self-renewal and tumorigenic capacity absent in the majority of tumor cells."
• CSCs appear to be slowly cycling and therefore relatively quiescent, which may increase their resistance to most cytotoxic treatments.  Other possible mechanisms of CSC treatment resistance include membrane-bound pumps to efflux cytotoxic chemotherapy out of the cell, and activation of robust DNA damage repair in response to radiotherapy.  (See Bi et al 2007 and Kang and Kang 2007.  Also see Bao et al 2006 for a study indicating that CSCs may also promote resistance to radiotherapy via increased activation of DNA damage repair.)
• Although cytotoxic treatment often initially produces tumor shrinkage, CSCs which survive treatment would have the capacity to repopulate a tumor, leading to eventual recurrence, as is commonly clinically observed.
• "Recurrent GBM tissue obtained from patients contains a significantly higher percentage of putative CSCs, as compared with their respective newly diagnosed tumors."
• The difference between CSCs and other tumor cells "likely explains why cancer cell line-based preclinical models have been poorly predictive of therapeutic utility against GBM."
• "GBM is well suited for preclinical, in vitro screening of anti-CSC agents because GBM CSCs can be readily derived using the neurosphere assay."
• "Agents that selectively kill CSCs would probably not affect the size of the tumor mass at all.  Therefore, progression-free survival or time to progression may be more appropriate end points for determining the effectiveness of therapeautic agents against CSCs."
• It is unclear whether the CD133 cell surface marker can adequately differentiate between GBM CSCs versus other GBM tumor cells, since CD133- GBM cells have been found which appear to fulfill all stem cell criteria.
• "CSCs are believed to reside within a niche that supports their viability.  The interaction between the supportive stroma and vasculature of the niche and CSCs themselves needs to be understood so that both cancer-sustaining cells and their microenvironment can be eradicated."  (See Gilbertson and Rich 2007.)
• "The mounting evidence that the growth of GBM is driven by biologically distinct CSCs dictates re-examination of how anti-cancer therapies are developed and evaluated.  There is a clear need for agents that target these cancer-sustaining cells."  (See Korkaya and Wicha 2007.)
• Cyclopamine has been identified as an agent which may be effective in targeting tumor stem cells (see Section 4.2 of this website).
• CSCs share some features with normal neural stem cells.  This may make it difficult to target CSCs while sparing normal brain tissue and avoiding neurological deficits.

In addition to cyclopamine, TMZ may also target CSCs in GBM (see Beier et al 2008).

For more detailed discussion, see Sakariassen et al 2007 and Tang et al 2007.  Also see Jandial et al 2008 for a paper which provides some discussion specifically on the role of the tumor microenvironment.

For a general discussion of CSCs which is not specific to brain tumors, see NCI CSC Executive Summary and Dalerba et al 2007.

For a recent reviews of CSCs in solid tumors, see Visvader and Lindeman 2008 (published in Nature Reviews Cancer) and Zhou et al 2009 (published in Nature Reviews Drug Discovery).

For a discussion of potential relationships between CSCs, treatment resistance, recurrence, and survival, using chronic myeloid leukemia (CML) as a model cancer, see Blagosklonny 2005.  Blagosklonny argues that "oncogenic resistance" among proliferating cells, rather than tumor renewal by CSCs, may account for lack of survival benefit despite initial response to treatment, but that "resistance can be exploited for therapeutic advantage."