title: Brain tumor stem cells: Molecular characteristics and their impact on therapy.
abstract: Glioblastoma (GBM) is the most prevalent primary brain tumor and ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding brain cancer genetics and modeling these tumors with new targeted therapies being tested, but these advances have not translated into substantially improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, the first-line treatment for glioblastoma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to healthy brain tissue and development of radioresistance. Therapeutic resistance is attributed at least in part to a cell population within the tumor that possesses stem-like characteristics and tumor propagating capabilities, referred to as cancer stem cells. Within GBM, the intratumoral heterogeneity is derived from a combination of regional genetic variance and a cellular hierarchy often regulated by distinct cancer stem cell niches, most notably perivascular and hypoxic regions. With the recent emergence as a key player in tumor biology, cancer stem cells have symbiotic relationships with the tumor microenvironment, oncogenic signaling pathways, and epigenetic modifications. The origins of cancer stem cells and their contributions to brain tumor growth and therapeutic resistance are under active investigation with novel anti-cancer stem cell therapies offering potential new hope for this lethal disease.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Schonberg
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States; Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lubelski
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States; Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, United States. Electronic address: richj@ccf.org.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D011836:Radiation Tolerance; D015398:Signal Transduction
keywords: Epigenetics; Glioma stem cells; Hypoxia; Microenvironment; Therapeutic resistance