Proneural-Mesenchymal Transition: Comparison
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Please note this is a comparison between Version 1 by Monica Fedele and Version 2 by Catherine Yang.

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. GBM has been classified into four molecular subgroups namely proneural, neural, classical and mesenchymal. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift from the proneural toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with aggressive carcinomas. 

  • glioma
  • proneural-mesenchymal transition (PMT)
  • multitherapy resistance
  • gliobalstoma
  • phenotipic plasticity

1. 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. Consequently, GBM exhibits a diffused infiltration throughout the brain rendering it incurable by surgery [1]. 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). Unfortunately, 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]. Therefore, despite therapeutic strategies and supportive care having been improved, GBM remains characterized by a very poor quality of life and prognosis, with a mean median survival time of 15 months [2]. The poor outcome of GBM has been ascribed to the high degree of intra-tumor heterogeneity that occurs at multiple levels, including histopathological, transcriptional and genomic [4][5][6][7]. In the effort to facilitate the development of more effective target therapies, large-scale genomic projects on patient specimens have adopted to identify GBM molecular subtypes associated with prognostic values [8][9]. Ultimately, GBM has been classified into at least four molecular subgroups namely proneural (PN), neural (NL), classical (CL) and mesenchymal (MES) [9]. Since typical molecular alterations, sensitivity to therapy and prognosis are associated with each subgroup, this classification has implications in selecting target therapy strategies. The MES subtype is the most aggressive and strongly associated with a poor prognosis compared to PN subtype, in addition, a shift from PN to MES subtype, namely the PMT, can occur in patients following radiation therapy and chemotherapy [10]. The molecular events driving this transition are similar to those driving the epithelial-mesenchymal transition (EMT) in carcinomas cells. EMT has been described as a crucial mechanism by which carcinoma cells enhance their invasive capacity by losing cell polarity and intercellular adhesions acquiring a mesenchymal and more motile phenotype, thus promoting cancer metastasis [11]. The molecular mechanisms driving EMT have been investigated and highlight the down-regulation of E-cadherin together with other epithelial specification genes paralleled by the up-regulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin [11][12]. Expression of mesenchymal markers by primary tumors correlates with enhanced invasiveness and poorer clinical prognosis. Moreover, mounting evidence associates EMT to chemotherapy resistance [13][14][15][16]. In general, cancer cell lines with epithelial features are more sensitive to chemotherapy drugs compared to those displaying a mesenchymal phenotype; on the contrary, the acquisition of resistance to several drugs is accompanied by the expression of mesenchymal markers [17][18]. Many signals that unleash EMT are involved in triggering and maintaining the mesenchymal state and converge in the activation of a network of master transcriptional regulators (EMT-TF) that drive the EMT process. Among these, a major role is played by ZEB 1/2, Snail 1/2/3, and Twist 1/2 [12][19]. The same EMT-TF network is also active in PMT and there is evidence, both in vitro and in vivo, supporting a critical role for these factors in the acquisition of the MES phenotype [20][21][22]. As for EMT, PMT has been shown to have a role in conferring an unfavorable prognosis. Specifically, radiation and chemotherapy induced resistance by promoting a PN to MES phenotypic shift, therefore investigation of PMT mechanisms is critical for improving therapy selection and patient outcomes.

2. PMT in Multitherapy Resistance

Current treatments for GBM, consisting of radiotherapy and concomitant adjuvant chemotherapy with TMZ, are still ineffective, since the tumor inevitably relapses and the prognosis is extremely poor, being fatal in 90% of patients 5 years after initial diagnosis [2][23]. A sub-population of tumor cells with stem-like properties, the glioma stem cells (GSCs) or glioma-initiating cells (GICs), which are responsible for tumor initiation, is specifically endowed to resist or adapt to the standard therapies, leading to therapy resistance [23]. It has been recently proposed that GSCs can be sub-divided into two main groups, characterized by either a PN or a MES phenotype [24]. Segerman et al. have shown that a single GBM gives rise to many GIC clones with different resistance to therapies. However, they observed that, upon treatment with radiotherapy and different drugs, all clones become resistant to the same treatments acquiring a multitherapy resistance phenotype with different degrees of resistance along a continuous distribution, suggestive of a dynamic process in the GIC population [10]. The gene set enrichment analysis (GSEA) of these clones showed a clear connection of multitherapy resistance to MES signature on one side, and sensitivity to PN signature on the other side. Therefore, it is likely that a primary GBM contains both PN and MES GSCs, but the treatment pushes PMT in GSCs, resulting in a prevalence of MES GSCs in the recurrent tumor (Figure 1). The passage from PN to MES upon radio- and chemotherapy is governed by epigenetic changes, specifically DNA methylation, on regulatory elements of master regulators of the MES GBM subtype, such as FOSL2 [10][14]24]. It is likely that the inflammatory microenvironment consequent to the exposure to the therapeutic agents could be responsible for such dynamicity. More recently, Minata et al. reported that, upon exposure to IR, CD109 is highly induced, while CD133 is downregulated, in PN GSCs present at the invading edge of the tumor, which is often unresectable upon surgery. The resulting switch from PN to MES phenotype could explain the IR-dependent tumor recurrence. Mechanistically, IR activates NF-κB via ATM, which in turn induces CD109 via C/EBPβ. They also showed that CD109 acts upstream of the YAP/TAZ signaling pathway, which could contribute to the PMT of the CD109+ tumor cells [25]. However, due to the reversible nature of the process, elucidating the mechanisms of PMT may help to identify new strategies to sensitize GBM to treatment. Consistently, the blockage of STAT3 activation inhibits radiation-induced PMT, resulting in prolonged survival of mice with PN GBM [26]. Also, silencing of LncRNA-H19 decreases chemoresistance of human glioma cells to TMZ by suppressing PMT via the Wnt/β-catenin pathway [27].
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Figure 1. 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.
Another therapy experimented for GBM is the antiangiogenic therapy (e.g., bevacizumab/anti-VEGF) that, by reducing vascular permeability is thought to reduce the tumor burn of a highly vascularized cancer such as GBM. However, after an initial delay in tumor progression, chronic exposure to antiangiogenic therapy ultimately provoked an aggressive treatment-resistant phenotype [28]. Also, in this case, gene expression and GSEA of resistant clones showed an increase in genes associated with the MES GBM subtype, thus identifying a PMT in tumors resistant to antiangiogenic therapy [29]. Upregulation of MES markers with concomitant downregulation of the PN phenotype, consequent to increased intracellular levels of reactive oxygen species (ROS), was also observed in primary GSCs treated with the cannabinoid and redox modulator cannabidiol (CBD), thus suggesting a combinatorial approach consisting of CBD and small molecule inhibitors of ROS for a more successful treatment of GBM [23].

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