Mouse Models of Pediatric Supratentorial High-grade Glioma Reveal How Cell-of-Origin Influences Tumor Development and Phenotype.

Smitha Sreedharan,Anders Sundström,Naga Prathyusha Maturi,Yuan Xie,Malin Jarvius,Lene Uhrbom,Rolf Larsson,Mårten Fryknäs,Irina Alafuzoff,Sylwia Libard,Holger Weishaupt,Fredrik J Swartling

doi:10.1158/0008-5472.can-16-2482

Smitha Sreedharan, Anders Sundström + Show 10 more

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https://doi.org/10.1158/0008-5472.can-16-2482

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Abstract

High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease. Cancer Res; 77(3); 802-12. ©2016 AACR.

Highlights

IntroductionPediatric high-grade glioma (HGG) is a group of aggressive primary central nervous system (CNS) tumors diagnosed in children (age 0–19 years) that comprises astrocytomas of WHO grade III (anaplastic astrocytoma) and IV (glioblastoma; ref. 1)
Pediatric high-grade glioma (HGG) is a group of aggressive primary central nervous system (CNS) tumors diagnosed in children that comprises astrocytomas of WHO grade III and IV
As mouse modeling and glioma cells (GC) culturing had showed a role of the cell-of-origin for tumor development and tumor cell phenotype, we investigated this further by performing functional analyses on four GCGFAP cultures and one GCCNP culture

Summary

Introduction

Pediatric high-grade glioma (HGG) is a group of aggressive primary central nervous system (CNS) tumors diagnosed in children (age 0–19 years) that comprises astrocytomas of WHO grade III (anaplastic astrocytoma) and IV (glioblastoma; ref. 1). Pediatric high-grade glioma (HGG) is a group of aggressive primary central nervous system (CNS) tumors diagnosed in children (age 0–19 years) that comprises astrocytomas of WHO grade III (anaplastic astrocytoma) and IV Astrocytomas are diffusely growing tumors of presumable glial origin and are the most common primary malignant brain tumors of adults. Pediatric HGGs are, relatively rare and represent around 8%–16% of all CNS tumors in children [2,3,4]. A majority of pediatric HGGs arise in the brainstem and are called diffuse intrinsic pontine glioma (DIPG), but a large fraction of these tumors are supratentorial and located in the cerebral hemispheres. We refer to these tumors as pediatric HGGs. Similar to adult HGGs there is no efficient treatment available. Standard treatment of care for pediatric supratentorial HGG

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