PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo.

By Chengkai Dai, J. Celestino, Yoshifumi Okada, David N. Louis, G. Fuller, Eric C. Holland. Genes & Development, 2001

734 citations recorded by the source corpus.

We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a-Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-B into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-B caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.

Subfields: Genetics, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/a65dbe8252ee1adf58578489a03b27be8a46b0fe

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Angelo Luigi Vescovi
2. R. Galli
3. B. Reynolds
4. William C. Hahn
5. Eric C. Holland
6. R. DePinho

In Immunology

1. Johanna Andrae
2. C. Betsholtz
3. R. DePinho
4. R. Gallini

In Neurology

1. R. Galli
2. B. Reynolds
3. Angelo Luigi Vescovi
4. C. Betsholtz
5. R. DePinho

Citations in the corpus

• Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. (2006, background): “…on glioma-associated endothelium; however , PDGF overexpression tends to occur in low-grade gliomas and higher-grade gliomas that have transformed from low-grade gliomas rather than in the more common primary glioblastomas (Westermark et al., 1995; Ribom et al., 2002; Dai et al., 2001).”
• PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells (2009, background): “Unlike the high-grade gliomas formed in the Ntv-a/ Ink4a / Arf / mice, RCAS-PDGF induces low-grade gliomas in Ntv-a/wt mouse background (Ink4a/Arf intact) (Dai et al., 2001).”
• Brain tumour stem cells (2006, background): “Likewise, overexpression of platelet-derived growth factor-β ( PDGFβ ) in either nestin-expressing progenitors or GFAP-expressing astrocytes caused a significant increase in the rate of glioma formation, with the highest frequency observed following nestin-directed targetin”
• Gli and hedgehog in cancer: tumours, embryos and stem cells (2002, neutral): “cgi?Q=pdgfa%20or%20pdgfb%20or%20pdgfc&ORG=Mm"> Pdgf”
• Malignant astrocytic glioma: genetics, biology, and paths to treatment. (2007, background): “Given the tumoral coexpression of PDGF and PDGFR, autocrine and paracrine loops may be the primary means by which this growth factor axis exerts its effects.”
• MEF promotes stemness in the pathogenesis of gliomas (2012, positive): “The cells were then filtered through a 70 mm Nylon strainer and plated in 10 cm culture dishes (with the procedure derived with minor modifications from a previously described experimental method) (Dai et al., 2001).”
• Roles of PDGF in animal development (2003, background): “In these mouse models, it was recently shown that Ink4a-Arf, a tumor suppressor gene that is commonly mutated in high-grade human gliomas, cooperates with PDGF in the development and malignant progression of gliomas (Dai et al., 2001).”
• Role of platelet-derived growth factors in physiology and medicine. (2008, positive): “In various experimental systems, overexpression of PDGFs has been shown to cause the formation of glioma-like tumors (Uhrbom et al. 1998; Dai et al. 2001).”