Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus.

In existing mouse models for malignant brain tumors, genes with no proven pathogenical relevance for humans have been used. Coexpression of platelet-derived growth factor (PDGF) and PDGF receptors suggests an autocrine mechanism of growth factor stimulation in the development of brain tumors in man. A murine retrovirus coding for the PDGF B-chain was, therefore, used to induce brain tumors in mice. Of 35 mice who received injections, 15 developed brain tumors of oligo- or monoclonal origin. They coexpressed PDGF B-chain and alpha-receptor mRNA, as expected, from an autocrine mechanism of transformation. Most tumors displayed characteristics of glioblastoma multiforme or of a primitive neuroectodermal tumor, and the consistent expression of nestin suggested that they were all derived from an immature neuroglial progenitor. The results show that an autocrine mechanism of transformation may be an initial or early event in neuro-oncogenesis. The present model provides an ideal system for studies of genetic mechanisms involved in the development of brain tumors.

[1]  T. Mapstone.  Expression of platelet-derived growth factor and transforming growth factor and their correlation with cellular morphology in glial tumors. , 1991, Journal of neurosurgery.

[2]  C. Heldin,et al.  Platelet-derived growth factor (PDGF) in neoplastic and non-neoplastic cystic lesions of the central nervous system and in the cerebrospinal fluid. , 1994, British Journal of Cancer.

[3]  C. Heldin,et al.  Antibodies against platelet-derived growth factor inhibit acute transformation by simian sarcoma virus , 1985, Nature.

[4]  C. Heldin,et al.  Efficient reversion of simian sarcoma virus-transformation and inhibition of growth factor-induced mitogenesis by suramin. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[5]  E. Oldfield,et al.  Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. , 1992, Cancer research.

[6]  Todd R. Golub,et al.  Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation , 1994, Cell.

[7]  C. Stiles,et al.  Selective expression of PDGF A and its receptor during early mouse embryogenesis. , 1990, Developmental biology.

[8]  J. Dumanski,et al.  Deregulation of the platelet-derived growth factor β-chain gene via fusion with collagen gene COL1A1 in dermatof ibrosarcoma protuberans and giant-cell fibroblastoma , 1997, Nature Genetics.

[9]  T. Golub,et al.  The TEL/platelet-derived growth factor β receptor (PDGFβR) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGFβR kinase-dependent signaling pathways , 1996 .

[10]  Paul Stroobant,et al.  Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus , 1983, Nature.

[11]  Lingzhi Fan,et al.  The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system , 1988, Neuroscience Letters.

[12]  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.

[13]  R. McKay,et al.  Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. , 1996, Genes & development.

[14]  W. Richardson,et al.  Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture , 1988, Nature.

[15]  M. Waterfield,et al.  Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor ceil , 1988, Nature.

[16]  R F Doolittle,et al.  Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. , 1983, Science.

[17]  U. Lendahl,et al.  Expression of the class VI intermediate filament nestin in human central nervous system tumors. , 1992, Cancer research.

[18]  J. Murphy,et al.  The Parodi-Irgens feline sarcoma virus and simian sarcoma virus have homologous oncogenes, but in different contexts of the viral genomes , 1983, Journal of virology.

[19]  D. Turner,et al.  Reactive astrocytes express the embryonic intermediate neurofilament nestin. , 1994, Neuroreport.

[20]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[21]  V. Gallo,et al.  Developmental and growth factor-induced regulation of nestin in oligodendrocyte lineage cells , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  C. Heldin,et al.  Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[23]  U. Lendahl,et al.  Coexpression of PDGF alpha and beta-receptors on medulloblastomas and other primitive neuroectodermal tumors (PNET) is consistent with an immature stem cell and neuronal derivation , 1996 .

[24]  J. Trojanowski,et al.  Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. , 1992, Laboratory investigation; a journal of technical methods and pathology.

[25]  D. Schiffer,et al.  Control of meningioma cell growth by platelet-derived growth factor (PDGF) , 1995, Journal of the Neurological Sciences.

[26]  R. McKay,et al.  CNS stem cells express a new class of intermediate filament protein , 1990, Cell.

[27]  C. Heldin,et al.  Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. , 1992, Cancer research.

[28]  O. Bogler,et al.  Cooperation between two growth factors promotes extended self-renewal and inhibits differentiation of oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Aguzzi,et al.  Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice , 1997, Oncogene.