Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas

Hao Ding, Luba Roncari, Patrick Shannon, Xiaoli Wu, Nelson Lau, Jana Karaskova, David H. Gutmann, Jeremy A. Squire, Andras Nagy, Abhijit Guha

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V12Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V12Ha-ras transgene expression. Chimeras expressing high levels of V12Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.

Original languageEnglish
Pages (from-to)3826-3836
Number of pages11
JournalCancer Research
Volume61
Issue number9
Publication statusPublished - 1 May 2001
Externally publishedYes

Cite this

Ding, H., Roncari, L., Shannon, P., Wu, X., Lau, N., Karaskova, J., ... Guha, A. (2001). Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Research, 61(9), 3826-3836.
Ding, Hao ; Roncari, Luba ; Shannon, Patrick ; Wu, Xiaoli ; Lau, Nelson ; Karaskova, Jana ; Gutmann, David H. ; Squire, Jeremy A. ; Nagy, Andras ; Guha, Abhijit. / Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. In: Cancer Research. 2001 ; Vol. 61, No. 9. pp. 3826-3836.
@article{9f60fdbee4064377990026e1ee7ad569,
title = "Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas",
abstract = "Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V12Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V12Ha-ras transgene expression. Chimeras expressing high levels of V12Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.",
author = "Hao Ding and Luba Roncari and Patrick Shannon and Xiaoli Wu and Nelson Lau and Jana Karaskova and Gutmann, {David H.} and Squire, {Jeremy A.} and Andras Nagy and Abhijit Guha",
year = "2001",
month = "5",
day = "1",
language = "English",
volume = "61",
pages = "3826--3836",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research",
number = "9",

}

Ding, H, Roncari, L, Shannon, P, Wu, X, Lau, N, Karaskova, J, Gutmann, DH, Squire, JA, Nagy, A & Guha, A 2001, 'Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas' Cancer Research, vol. 61, no. 9, pp. 3826-3836.

Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. / Ding, Hao; Roncari, Luba; Shannon, Patrick; Wu, Xiaoli; Lau, Nelson; Karaskova, Jana; Gutmann, David H.; Squire, Jeremy A.; Nagy, Andras; Guha, Abhijit.

In: Cancer Research, Vol. 61, No. 9, 01.05.2001, p. 3826-3836.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas

AU - Ding, Hao

AU - Roncari, Luba

AU - Shannon, Patrick

AU - Wu, Xiaoli

AU - Lau, Nelson

AU - Karaskova, Jana

AU - Gutmann, David H.

AU - Squire, Jeremy A.

AU - Nagy, Andras

AU - Guha, Abhijit

PY - 2001/5/1

Y1 - 2001/5/1

N2 - Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V12Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V12Ha-ras transgene expression. Chimeras expressing high levels of V12Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.

AB - Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V12Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V12Ha-ras transgene expression. Chimeras expressing high levels of V12Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.

UR - http://www.scopus.com/inward/record.url?scp=0035328722&partnerID=8YFLogxK

M3 - Article

VL - 61

SP - 3826

EP - 3836

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 9

ER -