JULY 2008 VOL 5 NO 7 NATURE CLINICAL PRACTICE ONCOLOGY 393 www.nature.com/clinicalpractice/onc SUMMARY Mechanisms of Disease: the role of stem cells in the biology and treatment of gliomas Jörg Dietrich,* Jaime Imitola and Santosh Kesari* INTRODUCTION Stem cells and their progeny coordinate the development, maintenance and repair of mam- malian tissues. In the adult nervous system, stem cells are tissue-specific with unique prop- erties, including the ability to self-renew, prolif- erate and differentiate into distinctive mature cell types via intermediate lineage-committed progenitor cells. The need for cells to divide and proliferate entails the risk of producing cells that could form the basis for a tumor by escaping mechanisms that control proliferation and programmed differentiation. 1 The concept that stem cells and lineage-committed progenitor cells underlie specific subtypes of cancers was initially studied in hematologic malignancies. 2–4 More recently, increasing evidence has suggested that many solid tumors, including gliomas and cancer of the breast, pancreas and colon harbor a subset of cancer cells—so called ‘cancer stem cells’—that share many of the developmental programs and features of their normal stem- cell counterparts. 5–7 This finding has produced enthusiasm in the field of cancer research, because of the mounting evidence that cancer stem cells have critical roles in tumor initia- tion, progression, metastasis, and resistance to conventional treatments. The concept of cancer as a disease of stem and progenitor cells has also stimulated the discus- sion about the putative ‘cell-of-origin’ in brain tumors and is likely to have profound implica- tions for tumor classification, the development of tumor models more representative of the tumor, and novel strategies for cancer therapy. Therapies designed to target cancer stem cells, however, might impair the function of normal stem and progenitor cell populations, which have a crucial role in the maintenance and regeneration of normal tissues in the brain. 8 The increasing depth of our understanding of the signaling pathways that govern self-renewal, proliferation, and differentiation in normal stem and progenitor cells will, therefore, allow the identification of the key differences between The study of neural stem cell and progenitor cell biology has improved our understanding of the biology of brain tumors in a developmental context. Recent work has demonstrated that brain tumors may harbor small subpopulations of cells that share characteristics of neural stem cells. There is still an ongoing debate about the specific role of these stem-like cells in cancer initiation, development and progression. Nonetheless, the concept of cancer stem cells has offered a new paradigm to understand tumor biology and resistance to current treatment modalities. Molecular aberrations in these cancer stem cells might be crucial targets for therapeutic intervention, with the hope of achieving more durable clinical responses. Recent studies have demonstrated that endogenous and transplanted neural stem cells and progenitor cells show a marked tropism to brain tumors. Although the mechanisms that govern these processes are poorly understood, the use of neural stem cells and progenitor cells as delivery vehicles for molecules toxic to tumors offers a promising experimental treatment strategy. This Review summarizes recent advances in the basic understanding of neural stem cell and cancer stem cell biology and the progress towards translating these novel concepts into the clinic. KEYWORDS brain tumor stem cells, cancer stem cells, gliomas, neural stem cells, progenitor cells J Dietrich is a Clinical Fellow in the Department of Neurology at Brigham and Women’s Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA. J Imitola is an Instructor in the Department of Neurology at Brigham and Women’s Hospital and affiliated faculty of the Harvard Stem Cell Institute, Harvard Medical School, and S Kesari is an Assistant Professor at Harvard Medical School, Boston, MA, USA. Correspondence *Department of Neurology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA jdietrich1@partners.org *Center for Neuro-Oncology, Dana-Farber Cancer Institute, SW430, 44 Binney Street, Boston, MA 02115, USA skesari@partners.org Received 14 May 2007 Accepted 1 November 2007 Published online 3 June 2008 www.nature.com/clinicalpractice doi:10.1038/ncponc1132 REVIEW CRITERIA Information for this Review article was derived from searching the PubMed and MEDLINE databases for articles published up to 1 August 2007. The following search terms were used: “neural stem cells”, “neural progenitor cells”, “cancer stem cells”, “glioma”, “glioma models”, “stem cell based therapies”, and “glioma therapy”. Only articles published in English were considered. Special attention was paid to articles with a high impact in the field of cancer and stem cell biology and to articles with outstanding clinical and laboratory evidence. Whenever possible, primary resources have been quoted. SUMMARY REVIEW