Primary Glioblastomas Express Mesenchymal Stem-Like Properties

Abstract

Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature in tumors or that glioblastomas activate a series of genes that result in mesenchymal properties of the cancer cells to effect sustained tumor growth and malignant progression. (Mol Cancer Res 2006;4(9):607 -19)

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

“…Mesenchymal GBM initially respond to treatment but often recur rapidly, producing highly chemoresistant tumors with very poor prognosis (6), and recurrent GBM from other subtypes shift toward a mesenchymal phenotype (5,19). Although recent studies indicate that increased miR-218 expression impacts cell viability in nasopharyngeal cancer and GBM cells (20,21), a role for miR-218 in conferring chemoresistance was not known.…”

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

“…Primary tumor tends to be a proneuronal type, however along with the recurrence, GBM becomes mesenchymal type with invasion and angiogenesis (22,23). Recently, STAT3, C/EBP, bHLH-B2, RUNX1, FOSL2, and ZNF238 have been shown to collectively control more than 74% of the mesenchymal gene expression signature gene (24).…”

Glioma cancer stem cells and their role in therapy

“…Further characterization of GCSCs led to conclusions that they are stem-like cells. They express high levels of stem cell genes involved in self-renewal and genes that regulate neural stem proliferation and differentiation commitment, such as Sox2, Notch, Bmi1, Sonic hedgehog, Musashi-1, CD133, endothelin 3 (Hemmati et al, 2003;Chen et al, 2010;Tso et al, 2006;Liu et al, 2011). Obviously, key mechanisms that control the activity of normal neural progenitors are altered in brain tumors.…”

“…Glioblastoma cells produce factors, like growth factors, cytokines and chemokines, which support the growth and the infiltrating character of glioblastoma cells in paracrine and autocrine fashion (Liu, 2011). Tso et al, (2006) observed that high-grade glioblastomas express cellular and molecular markers that are associated with mesenchymal stem cells. It is not known whether glioblastoma cells are derived from transformed stem cells or that activated genes in glioma cells elicit mesenchymal properties of cancer cells.…”