Signaling pathways and mesenchymal transition in pediatric high-grade glioma

Abstract

Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal types of cancer in children. In recent years, it has become evident that these tumors are driven by epigenetic events, mainly mutations involving genes encoding Histone 3, setting them apart from their adult counterparts. These tumors are exceptionally resistant to chemotherapy and respond only temporarily to radiotherapy. Moreover, their delicate location and diffuse growth pattern make complete surgical resection impossible. In many other forms of cancer, chemo- and radioresistance, in combination with a diffuse, invasive phenotype, are associated with a transcriptional program termed the epithelial-to-mesenchymal transition (EMT). Activation of this program allows cancer cells to survive individually, invade surrounding tissues and metastasize. It also enables them to survive exposure to cytotoxic therapy, including chemotherapeutic drugs and radiation. We here suggest that EMT plays an important, yet poorly understood role in the biology and therapy resistance of pHGG and DIPG. This review summarizes the current knowledge on the major signal transduction pathways and transcription factors involved in the epithelial-to-mesenchymal transition in cancer in general and in pediatric HGG and DIPG in particular. Despite the fact that the mesenchymal transition has not yet been specifically studied in pHGG and DIPG, activation of pathways and high levels of transcription factors involved in EMT have been described. We conclude that the mesenchymal transition is likely to be an important element of the biology of pHGG and DIPG and warrants further investigation for the development of novel therapeutics.

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

“…In line with this, EMT-associated pathways and transcription factors have been found activated in DIPG (41). Moreover, in adult GBM a higher incidence of TP53 mutation was observed in tumors with a diffuse compared to non-diffuse classification (42).…”

“…Indeed, this process has been heavily associated with malignant invasive and migratory behavior for many types of cancer (40). In DIPG, mesenchymal transition of glial cells, including the upregulation of mesenchymal related transcription factors and the induction of a mesenchymal phenotype could contribute to tumor invasion as well (41). Loss of TP53 is relatively common in DIPG (17) and, although not directly studied, could contribute to its invasive nature by promoting mesenchymal transition though SNAI1 (Figure 1B).…”

Elevation of CXCL1 indicates poor prognosis and radioresistance by inducing mesenchymal transition in glioblastoma

“…17 Intriguingly, GBM cells utilize the ability to undergo mesenchymal transition, either spontaneously, 18 or in response to radiotherapy. 19 In this study, we identified that CXCL1 is highly enriched in GBM and the elevation of CXCL1 is associated with radioresistance and poor prognosis in GBM patients. Additionally, knockdown of CXCL1 attenuated the proliferation and enhanced radiosensitivity of GBM cells.…”

“…32 Acquired radioresistance characterizes a major cause of poor prognosis thus promotes tumor recurrence in GBM. 33 Various molecular pathways have been proved to be responsible for the acquisition of radioresistance, including EMT, 19 NF-κB, 34 and Wnt/β-catenin. 35 Accumulating data showed that CXCL1, a small cytokine expressed by macrophages, epithelial cells, and neutrophils, 36,37 was associated with therapy resistance in diverse subtypes of cancers.…”

“…Epithelial‐mesenchymal transition (EMT) is regarded as essential for migratory and invasive features, inducing stem cell properties, preventing apoptosis, and senescence, as well as contributing to immunosuppression and therapy resistance . Intriguingly, GBM cells utilize the ability to undergo mesenchymal transition, either spontaneously, or in response to radiotherapy …”