Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma.
The formation of human malignant gliomas is thought to involve the accumulation of multiple genetic alterations. To define the function of specific alterations in glioma formation, we serially introduced genetic alterations functionally equivalent to those noted in human malignant gliomas into normal human astrocytes (NHAs). We then monitored the ability of each of these alterations to contribute to the growth of otherwise genetically stable NHAs into intracranial malignant gliomas. Using this model, we show that expression of human telomerase catalytic component (hTERT), but not E7-mediated inactivation of pRb or E6/E7-mediated inactivation of p53/pRb, was sufficient to initiate the tumorigenic process by circumventing cellular senescence in astrocytes. hTERT expression, even in combination with inactivation of p53/pRb, did not transform astrocytes. These alterations together, however, cooperated with ras pathway activation (initiated by expression of mutant H-Ras), but not with phosphatidylinositol 3-kinase pathway activation (initiated by expression of myristoylated Akt) or epidermal growth factor receptor activation, to allow for the formation of intracranial tumors strongly resembling p53/pRb pathway-deficient, telomerase-positive, ras-activated human grade III anaplastic astrocytomas. These results identify four pathways as key in the development of human anaplastic astrocytomas.
Sonoda
Y
Y
Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California 94115, USA.
Ozawa
T
T
Hirose
Y
Y
Aldape
K D
KD
McMahon
M
M
Berger
M S
MS
Pieper
R O
RO
D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D001254:Astrocytoma / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D050725:Papillomavirus E7 Proteins; D012313:RNA; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000502:physiology
D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; D018631:ras Proteins