Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma

Y. Sonoda, T. Ozawa, Yuichi Hirose, K. D. Aldape, M. McMahon, M. S. Berger, R. O. Pieper

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4956-4960
Number of pages5
JournalCancer Research
Volume61
Issue number13
Publication statusPublished - 01-07-2001
Externally publishedYes

Fingerprint

Critical Pathways
Astrocytoma
Human Development
Astrocytes
Glioma
Telomerase
Neoplasms
Phosphatidylinositol 3-Kinase
Aptitude
Cell Aging
Epidermal Growth Factor Receptor
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Sonoda, Y. ; Ozawa, T. ; Hirose, Yuichi ; Aldape, K. D. ; McMahon, M. ; Berger, M. S. ; Pieper, R. O. / Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. In: Cancer Research. 2001 ; Vol. 61, No. 13. pp. 4956-4960.
@article{c6c4b64b02b1400abb6220757738f1e9,
title = "Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma",
abstract = "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.",
author = "Y. Sonoda and T. Ozawa and Yuichi Hirose and Aldape, {K. D.} and M. McMahon and Berger, {M. S.} and Pieper, {R. O.}",
year = "2001",
month = "7",
day = "1",
language = "English",
volume = "61",
pages = "4956--4960",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. / Sonoda, Y.; Ozawa, T.; Hirose, Yuichi; Aldape, K. D.; McMahon, M.; Berger, M. S.; Pieper, R. O.

In: Cancer Research, Vol. 61, No. 13, 01.07.2001, p. 4956-4960.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma

AU - Sonoda, Y.

AU - Ozawa, T.

AU - Hirose, Yuichi

AU - Aldape, K. D.

AU - McMahon, M.

AU - Berger, M. S.

AU - Pieper, R. O.

PY - 2001/7/1

Y1 - 2001/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035392982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035392982&partnerID=8YFLogxK

M3 - Article

VL - 61

SP - 4956

EP - 4960

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 13

ER -