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

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.

Keywords: chemoresistance; epithelial–mesenchymal transition (EMT); glioblastoma; glioma; phenotypic plasticity; proneural-mesenchymal transition (PMT); tumor heterogeneity.

Figure 1

Glioblastoma subtype classification and prevalence of each subclass in all malignant gliomas. Some of the specific molecular and clinical characteristics are indicated on the side. OS, Overall Survival; NL, neural; PN, proneural; MES, mesenchymal; CL, classical.

Figure 2

Signaling pathways in the proneural-mesenchymal transition (PMT). PMT is driven by the activation of a restrict set of master regulators (MRs), among which a key role is exploited by STAT3, C/EBPβ, and TAZ. NF-κB is an upstream regulator of these MRs, and several factors, both intrinsic and from the extracellular environment, can lead to its activation. Beside MRs, the activation of a plethora of factors by several distinct pathways play also a relevant role in driving the PMT.

Figure 3

PMT upon radio- and chemotherapeutic treatment of GBM. A single GBM contains GSCs of both PN and MES phenotype. Upon treatment, most of them pass from the PN to the MES phenotype as a result of different treatment-dependent events, some of which are shown below. In purple: cells with proneural features; in grey: cells with mesenchymal features.

Figure 4

Word cloud image obtained using all published abstracts of the last 5 years searched with GBM, Proneural, and Mesenchymal as keywords. The resulting message highlights the importance of the subtype signature and molecular pathways, especially those involved in GSC regulation, resistance and invasion, for patient’s target therapy.