Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment

Abstract

Malignant nervous system cancers in children are the most devastating and worrisome diseases, specifically due to their aggressive nature and, in some cases, inoperable location in critical regions of the brain and spinal cord, and the impermeable blood-brain barrier that hinders delivery of pharmaco-therapeutic compounds into the tumor site. Moreover, the delicate developmental processes of the nervous system throughout the childhood years adds another limitation to the therapeutic modalities and doses used to treat these malignant cancers. Therefore, pediatric oncologists are charged with the daunting responsibility of attempting to deliver effective cures to these children, yet with limited doses of the currently available therapeutic options in order to mitigate the imminent neurotoxicity of radio- and chemotherapy on the developing nervous system. Various studies reported that c-Met/HGF signaling is affiliated with increased malignancy and stem cell enrichment in various cancers such as high-grade gliomas, high-risk medulloblastomas, and MYCN-amplified, high-risk neuroblastomas. Therapeutic interventions that are utilized to target c-Met signaling in these malignant nervous system cancers have shown benefits in basic translational studies and preclinical trials, but failed to yield significant clinical benefits in patients. While numerous pre-clinical data reported promising results with the use of combinatorial therapy that targets c-Met with other tumorigenic pathways, therapeutic resistance remains a problem, and long-term cures are rare. The possible mechanisms, including the overexpression and activation of compensatory tumorigenic mechanisms within the tumors or ineffective drug delivery methods that may contribute to therapeutic resistance observed in clinical trials are elaborated in this review.

Keywords: cancer stem cells; hepatocyte growth factor/scatter factor; mesenchymal epithelial transition factor signaling; pediatric nervous system tumors; therapeutic resistance.

Figure 1

c-MET interacts with various tumorigenic processes to drive malignancy. The interplay between c-MET and various tumorigenic pathways promotes cancer invasion, migration, proliferation, stem cell enrichment, and therapeutic evasion. Abbreviations: c-MET, mesenchymal epithelial transition factor; WNT/β-catenin, wwingless-related integration site/β-catenin pathway; Oct 4, octamer-binding transcription factor 4; Nanog, transcription factor that is involved in the self-renewal of embryonic stem cells; Klf 4, Krüppel-like factor; JARID 1B, Jumonji C-domain-containing histone demethylase 1B; HGF/SF, hepatocyte growth factor/scatter factor; VEGFR, vascular endothelial growth factor receptor; IGF 1R, insulin-like growth factor 1 receptor; EGFR, epidermal growth factor receptor; PI3K-AKT, phosphoinositide 3-kinase-AK strain transforming; MAPK, mitogen-activated protein kinase; TrKA-B, tropomyosin receptor kinase A-B; PDRX1, peroxiredoxin 1; TNF-α, tumor necrosis factor α; MEK/ERK, MAPK/ERK kinase/extracellular receptor kinase; ATM kinase, ataxia-telangiectasia-mutated (ATM) protein kinase; CSCs, cancer stem cells; p-38α, p38 MAPK family (MAPK14); SOX2, sex-determining region Y-box 2.

Figure 2

c-MET involvement with pediatric NS tumors. Various reports have demonstrated the involvement of c-MET/HGF signaling in pediatric nervous system tumors leading to enhanced malignancy and metastatic potential, therapeutic evasion, and poor survival. Abbreviations: c-MET, mesenchymal epithelial transition factor; HGF, hepatocyte growth factor; DIPG, diffuse intrinsic pontine glioma; SHH, Sonic Hedgehog; STAT3, signal transducer and activator of transcription 3.

Figure 3

Protein-protein interactions between MET and tumorigenic markers in brain CSCs. String functional association networks reveal known interactions between MET and other tumorigenic players identified in brain CSCs. Known interactions were identified experimentally (pink lines), from curated databases (blue lines), and predicted interactions were identified as co-expressed proteins (black lines) and from text mining (green lines). Abbreviations: EZH2, enhancer of zeste homolog 2; SOX2, sex-determining region Y-box 2; PDGFRA, platelet-derived growth factor receptor A; GLI 1, glioma-associated oncogene homolog 1; FOXG 1, forkhead box protein G1; STAT 3, signal transducer and activator of transcription 3; BMI 1, B lymphoma Mo-MLV insertion region 1 homolog; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; NANOG, transcription factor that is involved in the self-renewal of embryonic stem cells; LAMC 1, laminin subunit gamma-1 precursor; AKT 1, AK strain transforming 1; MYC, proto-oncogene, bHLH transcription factor; MYCN, v-myc myelocytomatosis viral-related oncogene, neuroblastoma-derived; FOXM 1, forkhead box M1; LAMB 1, laminin subunit beta-1; TNF, tumor necrosis factor.

Figure 4

Stimulation of c-Met leads to enhanced cancer stem cell (CSC) properties. Within the bulk tumor resides a sub-population of stem-like tumor cells termed CSCs. Enhanced c-Met signal transduction leads to enrichment of the CSC sub-population within the bulk tumor. Abbreviations: c-Met: mesenchymal epithelial transition factor.