Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues.

Takahashi, J.; Mori, Haruo; Fukumoto, Manabu; Igarashi, Koichi; Jaye, Michael; Oda, Yoshifumi; Kikuchi, Hiroe; Hatanaka, Masakazu

doi:10.1073/pnas.87.15.5710

Cited by 246 publications

(104 citation statements)

References 24 publications

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“…This lesion was sufficiently large to obtain numerous sections for immunohistochemical staining for other gene products. Similar to what has been reported for high-grade human gliomas (Takahashi et al 1990;Plate et al 1994), cells in the implicated region overexpress endogenous bFGF and vascular endothelial growth factor (VEGF). The cells comprising this lesion also stain with antibodies to GFAP and nestin, indicating an immature astrocytic cell type.…”

Section: Features Of Gliomas Are Induced By Egfr* Gene Transfer In Insupporting

confidence: 50%

A constitutively active epidermal growth factor receptor cooperates with disruption of G₁ cell-cycle arrest pathways to induce glioma-like lesions in mice

et al. 1998

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The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30%-50% of human gliobastoma multiforme (GBM). These mutations are associated usually with deletions of the INK4a-ARF locus, which encodes two gene products (p16 INK4a and p19 ARF ) involved in cell-cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis, using avian retroviral vectors to transfer a mutant EGFR gene to glial precursors and astrocytes in transgenic mice expressing tv-a, a gene encoding the retrovirus receptor. TVA, under control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGFR in cells in the glial lineage can induce lesions with many similarities to human gliomas. These lesions occur more frequently with gene transfer to mice expressing tv-a from the progenitor-specific nestin promoter than to mice expressing tv-a from the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, suggesting that tumors arise more efficiently from immature cells in the glial lineage. Furthermore, EGFR-induced gliomagenesis appears to require additional mutations in genes encoding proteins involved in cell-cycle arrest pathways. We have produced these combinations by simultaneously infecting tv-a transgenic mice with vectors carrying cdk4 and EGFR or by infecting tv-a transgenic mice bearing a disrupted INK4a-ARF locus with the EGFR-carrying vector alone. Moreover, EGFR-induced gliomagenesis does not occur in conjunction with p53 deficiency, unless the mice are also infected with a vector carrying cdk4. The gliomagenic combinations of genetic lesions required in mice are similar to those found in human gliomas.[Key Words: EGFR; gliomagenesis; cell cycle arrest] Received July 29, 1998; accepted in revised form October 14, 1998. Gliomas are the most common forms of primary brain tumors and are classified into four clinical grades (Kleihues et al. 1993). The most aggressive tumors, grade 4, also known as glioblastoma multiforme (GBM), appear to arise either de novo as GBMs or present initially as lower grade tumors that progress to higher grades over time . Certain mutations and other properties are highly correlated with one or the other of these two pathogenic pathways. Gliomas that are first detected as grade 4 tumors usually lack an intact INK4a-ARF tumor suppressor locus (Schmidt et al. 1994;He et al. 1995;Ichimura et al. 1996); and they are thus unable to make the two INK4a-ARF gene products, p16 INK4a and p19 ARF , which arrest the cell cycle by different pathways in G 1 and in both G 1 and G 2 , respectively ( Fig. 1; Serrano et al. 1993;Quelle et al. 1995). In addition, these tumors occur frequently in older patients, contain mutations or amplification of the EGFR gene, tend to be more aggressive, and are generally diploid He et al. 1994;Schlegel et al. 1994;Ono et al. 1996;Hayashi et al. 1997). In contrast, gliomas that progress from lower to higher grade lesions are usually wild type for INK4a-ARF , but have an ampl...

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Section: Features Of Gliomas Are Induced By Egfr* Gene Transfer In Insupporting

confidence: 50%

A constitutively active epidermal growth factor receptor cooperates with disruption of G₁ cell-cycle arrest pathways to induce glioma-like lesions in mice

et al. 1998

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“…Schweigerer et al (1987b) reported that basic FGF is an autocrine growth factor for human embryonal rhabdomyosarcoma cells. In addition, human gastric cancers, gliomas, meningiomas and renal cell carcinomas have been reported to express basic FGF mRNA (Takahashi et al, 1990;Zagzag et al, 1990;Tanimoto et al, 1991;Eguchi et al, 1992), and Kaposi's sarcoma cells have been reported to release basic FGF into their medium (Ensoli et al, 1989). However, basic FGF lacks a typical signal peptide region which facilitates secretion (Gospodarowicz et al, 1987) and its release mechanism remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Basic FGF is thought to induce fibrosis, angiogenesis, and tumour progression in human gastric carcinomas, renal cell carcinomas, brain tumours, and malignant melanoma through an autocrine mechanism (Becker et al, 1989;Takahashi et al, 1990;Zagzag et al, 1990;Tanimoto et al, 1991;Eguchi et al, 1992). Pancreatic carcinomas exhibit strong stromal reactions, or desmoplasia, and have an aggressive behaviour and poor prognosis .…”

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confidence: 99%

Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas

Ohta

Yamamoto²,

Numata³

et al. 1995

Br J Cancer

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“…Overexpression of FGF-2 in certain gliomas correlates with the grade of the tumor and the extent of anaplasia (Zagzag et al, 1990). Proliferation of glioma cells is inhibited by FGF-2-speci®c antisense oligonucleotides (Liberman et al, 1987;Takahashi et al, 1990;Morrison, 1991;Morrison et al, 1994a).…”

Section: Introductionmentioning

confidence: 99%

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

et al. 1997

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FGF-2 has been implicated in the neoplastic transformation of glioma cells and in the transition of normal quiescent astrocytes to a proliferating, reactive state. In the present study we have observed that in human glial cells, levels and subcellular localization of FGF-2 are di erent in quiescent and proliferating cells. FGF-2 was detected in the cytoplasm of non-reactive astrocytes in human brain sections. In contrast FGF-2 was located within the cytoplasm and nuclei of reactive astrocytes in gliotic brain tissue and in neoplastic cells of glioma tumors. In vitro, FGF-2 was found predominantly in the nucleus of subcon¯uent proliferating astrocytes, but was detected only in the cytoplasm of density arrested quiescent astrocytes. Our results suggest that reduced cell contact stimulates nuclear accumulation of FGF-2, accompanying mitotic activation of reactive human astrocytes. FGF-2 was constitutively localized to the nucleus of continuously proliferating glioma cells independent of cell density. A role for intracellular FGF-2 was further suggested by the observation that glioma cells that are not stimulated to proliferate by extracellular FGF-2 proliferated faster when transfected with FGF-2 expressing vectors. This increased proliferation correlated with nuclear accumulation of FGF-2. Cell proliferation was attenuated by 5'-deoxy-5'-methylthioadenosine, a FGF-2 receptor tyrosine kinase inhibitor that acts within the cell, but was una ected by myo-inositol hexakis [dihydrogen phosphate] that disrupts FGF-2 binding to plasma membrane receptors. Our results indicate that FGF-2 serves as a nuclear regulator of proliferation in astrocytic cells. In glioma cells, the constitutive presence of FGF-2 in the nucleus may promote proliferation that is insensitive to cell contact inhibition.

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Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues.

Cited by 246 publications

References 24 publications

A constitutively active epidermal growth factor receptor cooperates with disruption of G₁ cell-cycle arrest pathways to induce glioma-like lesions in mice

A constitutively active epidermal growth factor receptor cooperates with disruption of G₁ cell-cycle arrest pathways to induce glioma-like lesions in mice

Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

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Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues.

Cited by 246 publications

References 24 publications

A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice

A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice

Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

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A constitutively active epidermal growth factor receptor cooperates with disruption of G₁ cell-cycle arrest pathways to induce glioma-like lesions in mice

A constitutively active epidermal growth factor receptor cooperates with disruption of G₁ cell-cycle arrest pathways to induce glioma-like lesions in mice