Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas

Niels A Jensen, Karen M Pedersen, Frederikke Lihme, Lene Rask, Jakob V Nielsen, Thomas E Rasmussen, Cathy Mitchelmore

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Malignant astrocytomas are common human primary brain tumors that result from neoplastic transformation of astroglia or their progenitors. Here we show that deregulation of the c-Myc pathway in developing astroglia predisposes mice to malignant astrocytomas within 2-3 weeks of age. The genetically engineered murine (GEM) gliomas harbor a molecular signature resembling that of human primary glioblastoma multiforme, including up-regulation of epidermal growth factor receptor and Mdm2. The GEM gliomas seem to originate in an abnormal population of glial fibrillary acidic protein-expressing cells in the ventricular zone and, analogous to human glioblastomas, exhibit molecular and morphological heterogeneity. Levels of connexin 43 in the majority of the tumors are unaltered from normal tissue, indicating that GEM tumors have retained the capacity to establish syncytial networks. In line with this, individual glioma foci are composed of a mixture of actively proliferating cells expressing c-Myc and proliferating cell nuclear antigen and less dividing bystander cells that express glial fibrillary acidic protein and the broad complex tramtrack bric-a-brac/poxvirus and zinc finger domain protein HOF. A subset of the transgenic mice harbored, in addition to brain tumors, vestigial cerebellums in which granule cell migration and radial Bergman glial cell differentiation were disturbed. These observations argue for a window of vulnerability during astrocyte development where c-Myc overexpression is sufficient to trigger the neoplastic process, presumably by inducing the sustained growth of early astroglial cells. This is in contrast to most other transgenic studies in which c-Myc overexpression requires co-operating transgenes for rapid tumor induction.
OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind278
Udgave nummer10
Sider (fra-til)8300-8
Antal sider8
ISSN0021-9258
DOI
StatusUdgivet - 2003

Fingeraftryk

Glioma
Tumors
Glial Fibrillary Acidic Protein
Glioblastoma
Ependymoglial Cells
Brain
Neoplasms
Connexin 43
Cells
Proliferating Cell Nuclear Antigen
Epidermal Growth Factor Receptor
Deregulation
Cell Movement
Cell Differentiation
Ports and harbors
Up-Regulation
Zinc
Tissue
Growth
Population

Citer dette

Jensen, N. A., Pedersen, K. M., Lihme, F., Rask, L., Nielsen, J. V., Rasmussen, T. E., & Mitchelmore, C. (2003). Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas. Journal of Biological Chemistry, 278(10), 8300-8. https://doi.org/10.1074/jbc.M211195200
Jensen, Niels A ; Pedersen, Karen M ; Lihme, Frederikke ; Rask, Lene ; Nielsen, Jakob V ; Rasmussen, Thomas E ; Mitchelmore, Cathy. / Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas. I: Journal of Biological Chemistry. 2003 ; Bind 278, Nr. 10. s. 8300-8.
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abstract = "Malignant astrocytomas are common human primary brain tumors that result from neoplastic transformation of astroglia or their progenitors. Here we show that deregulation of the c-Myc pathway in developing astroglia predisposes mice to malignant astrocytomas within 2-3 weeks of age. The genetically engineered murine (GEM) gliomas harbor a molecular signature resembling that of human primary glioblastoma multiforme, including up-regulation of epidermal growth factor receptor and Mdm2. The GEM gliomas seem to originate in an abnormal population of glial fibrillary acidic protein-expressing cells in the ventricular zone and, analogous to human glioblastomas, exhibit molecular and morphological heterogeneity. Levels of connexin 43 in the majority of the tumors are unaltered from normal tissue, indicating that GEM tumors have retained the capacity to establish syncytial networks. In line with this, individual glioma foci are composed of a mixture of actively proliferating cells expressing c-Myc and proliferating cell nuclear antigen and less dividing bystander cells that express glial fibrillary acidic protein and the broad complex tramtrack bric-a-brac/poxvirus and zinc finger domain protein HOF. A subset of the transgenic mice harbored, in addition to brain tumors, vestigial cerebellums in which granule cell migration and radial Bergman glial cell differentiation were disturbed. These observations argue for a window of vulnerability during astrocyte development where c-Myc overexpression is sufficient to trigger the neoplastic process, presumably by inducing the sustained growth of early astroglial cells. This is in contrast to most other transgenic studies in which c-Myc overexpression requires co-operating transgenes for rapid tumor induction.",
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Jensen, NA, Pedersen, KM, Lihme, F, Rask, L, Nielsen, JV, Rasmussen, TE & Mitchelmore, C 2003, 'Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas', Journal of Biological Chemistry, bind 278, nr. 10, s. 8300-8. https://doi.org/10.1074/jbc.M211195200

Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas. / Jensen, Niels A; Pedersen, Karen M; Lihme, Frederikke; Rask, Lene; Nielsen, Jakob V; Rasmussen, Thomas E; Mitchelmore, Cathy.

I: Journal of Biological Chemistry, Bind 278, Nr. 10, 2003, s. 8300-8.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas

AU - Jensen, Niels A

AU - Pedersen, Karen M

AU - Lihme, Frederikke

AU - Rask, Lene

AU - Nielsen, Jakob V

AU - Rasmussen, Thomas E

AU - Mitchelmore, Cathy

PY - 2003

Y1 - 2003

N2 - Malignant astrocytomas are common human primary brain tumors that result from neoplastic transformation of astroglia or their progenitors. Here we show that deregulation of the c-Myc pathway in developing astroglia predisposes mice to malignant astrocytomas within 2-3 weeks of age. The genetically engineered murine (GEM) gliomas harbor a molecular signature resembling that of human primary glioblastoma multiforme, including up-regulation of epidermal growth factor receptor and Mdm2. The GEM gliomas seem to originate in an abnormal population of glial fibrillary acidic protein-expressing cells in the ventricular zone and, analogous to human glioblastomas, exhibit molecular and morphological heterogeneity. Levels of connexin 43 in the majority of the tumors are unaltered from normal tissue, indicating that GEM tumors have retained the capacity to establish syncytial networks. In line with this, individual glioma foci are composed of a mixture of actively proliferating cells expressing c-Myc and proliferating cell nuclear antigen and less dividing bystander cells that express glial fibrillary acidic protein and the broad complex tramtrack bric-a-brac/poxvirus and zinc finger domain protein HOF. A subset of the transgenic mice harbored, in addition to brain tumors, vestigial cerebellums in which granule cell migration and radial Bergman glial cell differentiation were disturbed. These observations argue for a window of vulnerability during astrocyte development where c-Myc overexpression is sufficient to trigger the neoplastic process, presumably by inducing the sustained growth of early astroglial cells. This is in contrast to most other transgenic studies in which c-Myc overexpression requires co-operating transgenes for rapid tumor induction.

AB - Malignant astrocytomas are common human primary brain tumors that result from neoplastic transformation of astroglia or their progenitors. Here we show that deregulation of the c-Myc pathway in developing astroglia predisposes mice to malignant astrocytomas within 2-3 weeks of age. The genetically engineered murine (GEM) gliomas harbor a molecular signature resembling that of human primary glioblastoma multiforme, including up-regulation of epidermal growth factor receptor and Mdm2. The GEM gliomas seem to originate in an abnormal population of glial fibrillary acidic protein-expressing cells in the ventricular zone and, analogous to human glioblastomas, exhibit molecular and morphological heterogeneity. Levels of connexin 43 in the majority of the tumors are unaltered from normal tissue, indicating that GEM tumors have retained the capacity to establish syncytial networks. In line with this, individual glioma foci are composed of a mixture of actively proliferating cells expressing c-Myc and proliferating cell nuclear antigen and less dividing bystander cells that express glial fibrillary acidic protein and the broad complex tramtrack bric-a-brac/poxvirus and zinc finger domain protein HOF. A subset of the transgenic mice harbored, in addition to brain tumors, vestigial cerebellums in which granule cell migration and radial Bergman glial cell differentiation were disturbed. These observations argue for a window of vulnerability during astrocyte development where c-Myc overexpression is sufficient to trigger the neoplastic process, presumably by inducing the sustained growth of early astroglial cells. This is in contrast to most other transgenic studies in which c-Myc overexpression requires co-operating transgenes for rapid tumor induction.

KW - Animals

KW - Base Sequence

KW - Brain Neoplasms

KW - DNA Primers

KW - Glioma

KW - Immunohistochemistry

KW - Mice

KW - Proto-Oncogene Proteins c-myc

U2 - 10.1074/jbc.M211195200

DO - 10.1074/jbc.M211195200

M3 - Journal article

VL - 278

SP - 8300

EP - 8308

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 10

ER -

Jensen NA, Pedersen KM, Lihme F, Rask L, Nielsen JV, Rasmussen TE et al. Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas. Journal of Biological Chemistry. 2003;278(10):8300-8. https://doi.org/10.1074/jbc.M211195200