Clinical Relevance of Tumor Cells with Stem-Like Properties in Pediatric Brain Tumors

Abstract

BackgroundPrimitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined.Methodology/Principal FindingsTumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting.Conclusions/SignificanceIn brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

Intracellular glycine receptor function facilitates glioma formation in vivo

“…We next analyzed expression of GlyR a1 and a3 subunits in established and well-characterized human stem-cell-like glioma cells (Galan-Moya et al, 2011;Silvestre et al, 2011;Thirant et al, 2011) (supplementary material Table S2). mRNA coding for the GlyR a1ins RNA splice variant was detected in three out of six stem-cell-like cell samples from adult oligoastrocytoma and glioblastoma multiforme (Galan-Moya et al, 2011;Silvestre et al, 2011), whereas GlyR a1-encoding mRNA in stem-cell-like cells from pediatric glioma lacked the RNA splice insert (supplementary material Table S2).…”

Links Between Injury-Induced Brain Remodeling and Oncogenesis

“…In addition, GSCs respond to short-term exposure to serum with downregulation of their stemlike markers and loss of their tumor-initiating property. A growing body of evidence supports that these self-renewing tumor cells determine a tumor's behavior, including proliferation, progression, invasion, and-most importantly-a great part of resistance to therapies (Bao et al 2006 ;Bleau et al 2009 ;Murat et al 2008 ;Thirant et al 2011 ). Whether or not these glioma cells with stemlike properties correspond to the progeny of NSCs or NPCs that were the initial targets of the oncogenic hits remains an open question.…”

A new era for children with diffuse intrinsic pontine glioma: hope for cure?

“…This addresses the second key issue; preclinical models for DIPG are still very rare. To date, only two groups have published on DIPG in vitro models [17,22]. With the lack of DIPG cell lines, in vivo models have been developed using adult glioma cell lines, but these lack the DIPG genotype.…”

“…Moreover, only few animal models show the diffuse growth typical for DIPG [21]. From the few existing DIPG cell cultures, only two groups have reported the development of xenografts thus far [17,22].…”