Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma

Transformed stem cells have been isolated from some human cancers. We report that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells. Similar, yet not identical, to their normal neural stem cell counterpart, these precursors emerge as unipotent (astroglial) in vivo and multipotent (neuronal-astroglial-oligodendroglial) in culture. More importantly, these cells can act as tumor-founding cells down to the clonal level and can establish tumors that closely resemble the main histologic, cytologic, and architectural features of the human disease, even when challenged through serial transplantation. Thus, cells possessing all of the characteristics expected from tumor neural stem cells seem to be involved in the growth and recurrence of adult human glioblastomas multiforme.

[1]  M. Nistér,et al.  Platelet-Derived Growth Factor Receptor-α in Ventricular Zone Cells and in Developing Neurons , 2001, Molecular and Cellular Neuroscience.

[2]  C. Svendsen,et al.  Human Neural Stem Cells: Isolation, Expansion and Transplantation , 1999, Brain pathology.

[3]  V. Gallo,et al.  Postnatal NG2 proteoglycan–expressing progenitor cells are intrinsically multipotent and generate functional neurons , 2003, The Journal of cell biology.

[4]  E. Parati,et al.  Isolation and Cloning of Multipotential Stem Cells from the Embryonic Human CNS and Establishment of Transplantable Human Neural Stem Cell Lines by Epigenetic Stimulation , 1999, Experimental Neurology.

[5]  W. Hahn,et al.  Telomerase and tumorigenesis. , 2003, Cancer letters.

[6]  S. Goldman.  Glia as neural progenitor cells , 2003, Trends in Neurosciences.

[7]  R. Wechsler-Reya,et al.  Getting at the Root and Stem of Brain Tumors , 2004, Neuron.

[8]  R. Galli,et al.  Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system. , 2002, Development.

[9]  M. Raff,et al.  Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. , 2000, Science.

[10]  R. Coggeshall,et al.  Region-specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat , 2002, Nature Neuroscience.

[11]  D. Steindler,et al.  Human cortical glial tumors contain neural stem‐like cells expressing astroglial and neuronal markers in vitro , 2002, Glia.

[12]  Scott Pollack,et al.  Growth factors regulate the survival and fate of cells derived from human neurospheres , 2001, Nature Biotechnology.

[13]  T. Jang,et al.  Neural stem cells and neuro‐oncology: Quo vadis? , 2003, Journal of cellular biochemistry.

[14]  K. Mikoshiba,et al.  Transformation of astrocytes in transgenic mice expressing SV40 T antigen under the transcriptional control of the glial fibrillary acidic protein promoter. , 1995, Cancer research.

[15]  K. Black,et al.  Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. , 2002, Cancer research.

[16]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[17]  J. Dick,et al.  Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity , 2004, Nature Immunology.

[18]  David J. Anderson,et al.  Prospective Identification, Isolation by Flow Cytometry, and In Vivo Self-Renewal of Multipotent Mammalian Neural Crest Stem Cells , 1999, Cell.

[19]  H. Varmus,et al.  Modeling mutations in the G1 arrest pathway in human gliomas: overexpression of CDK4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes. , 1998, Genes & development.

[20]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[21]  L. Kanz,et al.  Characterization of Purified and Ex Vivo Manipulated Human Hematopoietic Progenitor and Stem Cells in Xenograft Recipients , 1999, Annals of the New York Academy of Sciences.

[22]  S. Weiss,et al.  A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  A. Álvarez-Buylla,et al.  Multipotent Neural Stem Cells Reside into the Rostral Extension and Olfactory Bulb of Adult Rodents , 2002, The Journal of Neuroscience.

[24]  S. Weiss,et al.  Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. , 1996, Developmental biology.

[25]  M. Herman,et al.  Differentiation and anaplasia in central neuroepithelial tumors. , 1984, Progress in experimental tumor research.

[26]  R. Galli,et al.  Emx 2 regulates the proliferation of stem cells of the adult mammalian central nervous system , 2002 .

[27]  M. Carpenter,et al.  In Vitro Expansion of a Multipotent Population of Human Neural Progenitor Cells , 1999, Experimental Neurology.

[28]  M. Gulisano,et al.  Nested expression domains of four homeobox genes in developing rostral brain , 1992, Nature.

[29]  Martin A. Nowak,et al.  Cell biology: Developmental predisposition to cancer , 2003, Nature.

[30]  A. Hui,et al.  Establishment and characterization of a human cell line from paediatric cerebellar glioblastoma multiforme , 2000, Neuropathology and applied neurobiology.

[31]  T. Orfeo,et al.  One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. , 1977, Journal of the National Cancer Institute.

[32]  T. Kondo,et al.  Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Lene Rask,et al.  Astroglial c-Myc Overexpression Predisposes Mice to Primary Malignant Gliomas* , 2003, The Journal of Biological Chemistry.

[34]  Mitchel S. Berger,et al.  Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration , 2004, Nature.

[35]  H. Taylor,et al.  Transcriptional Repression of Peri-Implantation EMX2 Expression in Mammalian Reproduction by HOXA10 , 2003, Molecular and Cellular Biology.

[36]  M. Scott,et al.  The developmental biology of brain tumors. , 2001, Annual review of neuroscience.

[37]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[38]  P Gruss,et al.  Dentate gyrus formation requires Emx2. , 1996, Development.

[39]  E. Jauniaux,et al.  Human Neural Precursor Cells Express Low Levels of Telomerase in Vitro and Show Diminishing Cell Proliferation with Extensive Axonal Outgrowth following Transplantation , 2000, Experimental Neurology.

[40]  R. Galli,et al.  Regulation of Neuronal Differentiation in Human CNS Stem Cell Progeny by Leukemia Inhibitory Factor , 2000, Developmental Neuroscience.

[41]  E. Parati,et al.  Epidermal and Fibroblast Growth Factors Behave as Mitogenic Regulators for a Single Multipotent Stem Cell-Like Population from the Subventricular Region of the Adult Mouse Forebrain , 1999, The Journal of Neuroscience.

[42]  J. Winkler,et al.  High Efficacy of Clonal Growth and Expansion of Adult Neural Stem Cells , 2003, Laboratory Investigation.

[43]  G. Finocchiaro,et al.  Gene therapy of experimental brain tumors using neural progenitor cells , 2000, Nature Medicine.

[44]  Christopher S Potten,et al.  1 – Stem cells and cellular pedigrees – a conceptual introduction , 1997 .

[45]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  S. Fedoroff,et al.  Protocols for Neural Cell Culture , 1997, Humana Press.

[47]  K. Black,et al.  The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. , 2002, Cancer research.

[48]  M. Loeffler,et al.  Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. , 1990, Development.

[49]  A. Álvarez-Buylla,et al.  Identification of neural stem cells in the adult vertebrate brain , 2002, Brain Research Bulletin.

[50]  M. Varella‐Garcia,et al.  Establishment and characterization of a human glioblastoma multiforme cell line. , 1998, Cancer genetics and cytogenetics.

[51]  K. Hoang-Xuan,et al.  Primary brain tumours in adults , 2003, The Lancet.

[52]  K. Trott,et al.  12 – Tumour stem cells , 1997 .

[53]  Daniel H. Geschwind,et al.  Cancerous stem cells can arise from pediatric brain tumors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[54]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[55]  E. Parati,et al.  Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  K. Black,et al.  Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer , 2002, Cancer Gene Therapy.

[57]  Irving L. Weissman,et al.  Normal and leukemic hematopoiesis: Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[58]  R. DePinho,et al.  Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. , 2002, Cancer cell.