Dataset Information

Expression of Alpha-type Platelet-derived Growth Factor Receptor-influenced Genes Predicts Clinical Outcome in Glioma.

ABSTRACT:

Background

Alpha-type platelet-derived growth factor receptor (PDGFRα) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRα plays an important role in the regulation of several biological processes and contributes to the pathophysiology of a broad range of human cancers, including glioma. Here, we hypothesize that the genes directly or indirectly influenced by PDGFRα might be useful for prognosis in glioma.

Methods

By comparing the genome-wide gene expression pattern between PDGFRα⁺ and PDGFRα^- cells from human oligodendrocyte progenitor, we defined the genes potentially influenced by PDGFRα.

Results

The PDGFRα-influenced genes are strongly associated with cancer-related pathways. We subsequently developed a prognostic gene signature derived from the PDGFRα-influenced genes. This gene signature is able to predict clinical outcome of glioma. This signature is also independent of traditional prognostic factors of glioma. Resampling tests indicate that the prognostic power of this gene signature outperforms random gene sets selected from human genome. More importantly, this signature is superior to the random gene signatures selected from glioma related genes.

Conclusions

Despite the absence of clear elucidation of molecular mechanisms, this study suggests the vital role of PDGFRα in carcinogenesis. Furthermore, the PDGFRα-based gene signature provides a promising prognostic tool for glioma and validates PDGFRα as a novel and effective therapeutic target in human cancers.

SUBMITTER: Ko EA

PROVIDER: S-EPMC6933209 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Expression of Alpha-type Platelet-derived Growth Factor Receptor-influenced Genes Predicts Clinical Outcome in Glioma.

Ko Eun-A EA Lee Haeyeong H Sanders Kenton M KM Koh Sang Don SD Zhou Tong T

Translational oncology 20191221 2

<h4>Background</h4>Alpha-type platelet-derived growth factor receptor (PDGFRα) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRα plays an important role in the regulation of several biological processes and contributes to the pathophysiology of a broad range of human cancers, including glioma. Here, we hypothesize that the genes directly or indirectly influenced by PDGFRα might be useful for prognosis in glioma.<h4>Methods</h4>By comparin ...[more]

PMID: 31869747

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Project description:Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.

Dataset Information

Expression of Alpha-type Platelet-derived Growth Factor Receptor-influenced Genes Predicts Clinical Outcome in Glioma.

Background

Methods

Results

Conclusions

Publications

Expression of Alpha-type Platelet-derived Growth Factor Receptor-influenced Genes Predicts Clinical Outcome in Glioma.

Similar Datasets

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