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Review
. 2020 Feb 7;10:92.
doi: 10.3389/fonc.2020.00092. eCollection 2020.

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

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Free PMC article
Review

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

T A Kluiver et al. Front Oncol. .
Free PMC article

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.

Keywords: diffuse intrinsic pontine glioma (DIPG); driver mutations; invasion; microenvironment; therapeutic targeting; tumor subclones.

Figures

Figure 1
Figure 1
Tumor cell-intrinsic alterations that can contribute to DIPG invasion and strategies for their therapeutic targeting. The majority of DIPG tumors harbor a H3K27M mutation resulting in epigenetic dysregulation that might contribute to invasion and can be targeted therapeutically by Panobinostat (A). Loss of function mutations in TP53 are common in DIPG and can enhance migratory cell behavior by inducing the mesenchymal transcription factor SNAI1 (B). Gain of function mutations in AVCR1 (C) and PDGFRA (D) activate downstream RAS/MAPK, PI3K/Akt, and JAK/STAT signaling, which can induce invasion associated mesenchymal transition through SNAI1/2, ZEB1/2, and TWIST1 transcription factors. Enhanced PI3K/Akt signaling can be therapeutically targeted by Sirolimus and Everolimus and PDGFRA signaling by Dasatinib. EPH-ephrin signaling and GSK-3 have been implicated in migratory behavior in DIPG cell cultures and can be targeted therapeutically by LDN-211904 and LiCL, respectively (E).
Figure 2
Figure 2
Cell-extrinsic factors that can promote the invasive behavior of DIPG cells. DIPG tumors consist of a cooperative network of cellular subclones in which highly migratory clones can enhance the invasive behavior of less motile cells (A). Cellular communication via both TMs (B) and EVs (C) could play a role in this clonal synergy in invasive behavior. Neuron progenitor cells promote DIPG invasion into the SVZ through the production of PTN (D). Secretion of NLGN3 by activated neurons could contribute to DIPG invasion by inducing the formation of TMs and by activating the PI3K/Akt pathway (E). The immune cell infiltrate in DIPG mainly consist of microglia/macrophages with a low inflammatory phenotype and it is still unclear how this impacts invasion (F).

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References

    1. Buczkowicz P, Hawkins C. Pathology, molecular genetics, and epigenetics of diffuse intrinsic pontine glioma. Front Oncol. (2015) 5:147. 10.3389/fonc.2015.00147 - DOI - PMC - PubMed
    1. Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, Baugh J, Chaney B, Hoffmann M, et al. . Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the international and european society for pediatric oncology DIPG registries. J Clin Oncol. (2018) 36:1963–72. 10.1200/JCO.2017.75.9308 - DOI - PMC - PubMed
    1. Jansen MH, Veldhuijzen van Zanten SE, Sanchez Aliaga E, Heymans MW, Warmuth-Metz M, Hargrave D, et al. . Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria. Neuro Oncol. (2015) 17:160–6. 10.1093/neuonc/nou104 - DOI - PMC - PubMed
    1. Valvi S, Gottardo NG. Diffuse intrinsic pontine glioma. In: Agrawal A, Moscote-Salazar LR, editors. , editors. Brain Tumors - An Update. London: IntechOpen; (2018). p. 35–70. 10.5772/intechopen.78578 - DOI
    1. Johung TB, Monje M. Diffuse intrinsic pontine glioma: new pathophysiological insights and emerging therapeutic targets. Curr Neuropharmacol. (2017) 15:88–97. 10.2174/1570159X14666160509123229 - DOI - PMC - PubMed

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