Brain tumor stem cells: the cancer stem cell hypothesis writ large

Abstract

Brain tumors, which are typically very heterogeneous at the cellular level, appear to have a stem cell foundation. Recently, investigations from multiple groups have found that human as well as experimental mouse brain tumors contain subpopulations of cells that functionally behave as tumor stem cells, driving tumor growth and generating tumor cell progeny that form the tumor bulk, but which then lose tumorigenic ability. In human glioblastomas, these tumor stem cells express neural precursor markers and are capable of differentiating into tumor cells that express more mature neural lineage markers. In addition, modeling brain tumors in mice suggests that neural precursor cells more readily give rise to full blown tumors, narrowing potential cells of origin to those rarer brain cells that have a proliferative potential. Applying stem cell concepts and methodologies is giving fresh insight into brain tumor biology, cell of origin and mechanisms of growth, and is offering new opportunities for development of more effective treatments. The field of brain tumor stem cells remains very young and there is much to be learned before these new insights are translated into new patient treatments.

Figure 1

Brain tumor stem cell assay development. Brain tumor stem cells can be interrogated in stem cell assays in vivo and in vitro. The gold standard for identification of a cancer stem cell involves a sort of the stem cell population from the bulk population directly from freshly isolated tissue, and then analysis compared to bulk in an in vivo orthotopic transplantation assay. Cancer stem cells can also be isolated by selection in culture, in defined media with growth factors in the absence of serum. Fresh tumors can also be xenografted directly to expand tumor cell populations, but this method may also select for populations favored to survive in immunodeficient mice. Therefore, only a fresh sort allows comparison between putative stem cell population and bulk population. A full hierarchy of the original patient tumor is no longer available after culture, and possibly, after xenografting. Stem cells in vitro, however, give opportunities to probe mechanisms of self renewal, proliferation and differentiation, as well as to perform chemical and genetic screens. Findings on in vitro systems must be validated in vivo, ideally back to freshly sorted cells.

Figure 2

Cancer Stem Cells and Therapeutic Opportunities. From a conceptual standpoint, applying stem cell thinking to cancer opens up new therapeutic opportunities. Self renewal, as a subset of proliferation, becomes a critical process for targeting. The stem cell's supportive niche can be attacked. If one can block stem cell generation of progeny that cause clonal expansion, perhaps tumor bulk progression can be slowed. Proliferation of tumor “progenitors”, if they are more rapidly proliferative than stem cells (unproven as of yet), will be an important target. Promotion of differentiation, particularly if terminally differentiated cell types can be generated, such as neurons, may be another useful strategy. Of course, killing all tumor cells, and particularly tumor stem cells should be a goal, by further sensitizing them to conventional therapy, or targeting molecular pathways responsible for stem cell behavior. Migration, a property of normal brain precursor cells, will be important to target, if this is also a property of the cancer stem cell.