Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma.

Monica Fedele,Riccardo Sgarra,Silvia Pegoraro,Laura Cerchia,Guidalberto Manfioletti

doi:10.3390/ijms20112746

Abstract

Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12–15 months and just 3–5% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with other aggressive cancers. In this review we frame this process in the high degree of phenotypic inter- and intra-tumor heterogeneity of GBM, which exists in different subtypes, each one characterized by further phenotypic variability in its stem-cell compartment. Under the selective pressure of different treatment agents PMT is induced. The mechanisms involved, as well as the significance of such event in the acquisition of a multitherapy resistance phenotype, are taken in consideration for future perspectives in new anti-GBM therapeutic options.

Highlights

Glioblastoma (GBM) is the most common intrinsic and aggressive primary brain tumor in adults
Since the 1970s, the first-line adjuvant treatment after surgery is represented by radiotherapy that has been recently been combined with targeted chemotherapy approaches involving DNA alkylating agents, such as temozolomide (TMZ)
Always related to the NF-κB pathway is the work by the Park group [44]. In this study they demonstrated that the perinecrotic regions of GBM display an upregulation of transglutaminase 2 (TGM2) expression, providing evidence that TGM2 is involved in the transition towards a MES phenotype; they demonstrated that, upon TGM2 silencing in MES GSCs, both MES master regulators (MRs) and MES markers were downregulated, while the contrary occurred in PN GSCs by TGM2 overexpression

Summary

Introduction

Glioblastoma (GBM) is the most common intrinsic and aggressive primary brain tumor in adults It is characterized by alteration in crucial signaling pathways that results in the acquisition of hallmarks properties of cancer. Since the 1970s, the first-line adjuvant treatment after surgery is represented by radiotherapy that has been recently been combined with targeted chemotherapy approaches involving DNA alkylating agents, such as temozolomide (TMZ) This therapeutic option shows many limitations in its efficacy and almost all patients present the progression of the disease after a mean progression-free survival of 7–10 months [2,3]. Radiation and chemotherapy induced resistance by promoting a PN to MES phenotypic shift, investigation of PMT mechanisms is critical for improving therapy selection and patient outcomes

Phenotypic Heterogeneity and Plasticity in Glioblastoma

Signaling Mechanisms in PMT

The Extracellular Environment and the NF-κB Pathway

Multiple Routes to Drive the MES Phenotype

Findings

Conclusions and Therapeutic Perspectives