Cancer stem cells in solid tumors
Introduction
The cancer stem cell (CSC) model of tumor development and progression states that tumors, like normal adult tissues, contain a subset of cells that both self renew and give rise to differentiated progeny. As in other tissues, the stem cells are a minority of the whole organ, and are the only cells that can maintain tumor growth indefinitely. The remaining cells, though actively proliferating and making up the majority of the cells in the tumor, are also differentiating and destined to die. The self renewal properties of the CSCs are thus the real driving force behind tumor growth. The identification of markers that allow the prospective isolation of CSCs from whole tumor tissues will allow us to develop an understanding of several important biological properties of CSCs: first, what is the cell of origin for a given tumor? Second, what are the signaling pathways that drive self renewal and/or differentiation of CSCs? Third, are there molecules uniquely expressed on CSCs, regardless of whether they are functional, that will allow targeted therapies to be developed? Fourth, what are the mechanisms by which CSCs escape conventional therapies and can we defeat these mechanisms? Answers to these questions should lead to the development of therapies that target the CSC population and eliminate the ‘engine’ that drives tumors to grow, invade, and seed metastatic lesions. The challenges involved in identifying a CSC population from a solid tumor, and recent successes in this area are described in this review, as well as early studies that represent the first steps toward understanding the biological properties of these cells.
Section snippets
Identification of markers for the prospective isolation of cancer stem cells
A recent AACR workshop stated that ‘cancer stem cells can … only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor’ [1]. The most widely accepted assay to validate a candidate CSC population is therefore tumor initiation and serial transplantation in immunocompromised mice, where the tumor that grows in the mice recapitulates the heterogeneity of the primary patient tumor. This was first achieved for human acute myeloid leukemia (AML). The
Understanding the biological properties of CSC
Once CSCs have been identified, the real work begins, which is the characterization of their molecular and biological properties, in hopes of identifying ways to specifically target and eradicate these cells in cancer patients. This is a new field in which we have barely begun to scratch the surface because of the only very recent ability to prospectively isolate CSCs from various tumors. Some of the approaches towards gaining a deeper understanding of CSC biology that have been reported are
Conclusions
The CSC field, particularly in the area of solid tumors, is a very young one. A model of solid tumor stem-cell biology is shown in Figure 1, highlighting the properties that are currently viewed as important for tumor growth, and that may represent therapeutic targets. We are still in the very technically challenging stage of identifying the methods that will allow us to prospectively isolate CSCs from various solid tumors, and most importantly, to demonstrate in vivo that the populations we
Conflict of interest
ILW has stock in Amgen, Inc., was a member of the Amgen scientific advisory board, and is a cofounder and member of the Board of Directors of Cellerant, Inc., and Stem Cells, Inc.
Acknowledgements
This work was supported in part by National Institutes of Health Grants R01CA086017 and R01CA086065 and an anonymous gift fund for Cancer Stem Cell research at Stanford University. In addition LEA is a recipient of a Stanford Comprehensive Cancer Center Developmental Research Award.
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