Kluiver T A, Alieva M, van Vuurden D G, Wehrens Ellen J, Rios Anne C
Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
Department of Cancer Research, Oncode Institute, Hubrecht Institute, KNAW Utrecht, Utrecht, Netherlands.
Front Oncol. 2020 Feb 7;10:92. doi: 10.3389/fonc.2020.00092. eCollection 2020.
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.
弥漫性脑桥内在型胶质瘤（DIPG）是一种罕见的、具有高度侵袭性的儿科脑肿瘤，起源于脑桥。DIPG无法治疗，且无一例外都会导致死亡，中位预期寿命不到一年。由于肿瘤的解剖位置，手术切除不是一种选择，放射治疗效果有限，且尚无化疗或靶向治疗方法被证明是成功的。这种不良预后部分归因于肿瘤高度浸润性的弥漫性和侵袭性扩散。因此，针对DIPG的侵袭行为具有潜在的治疗价值。为了成功靶向DIPG的侵袭，需要对其潜在驱动因素有详细的机制性了解。在这里，我们综述了促成DIPG侵袭的DIPG肿瘤细胞内在分子过程和外在环境因素。重要的是，DIPG是一种异质性疾病，随着全基因组测序技术的进步，现在已经认识到基于潜在驱动基因突变的不同疾病亚型。最近的证据还表明，肿瘤在侵袭性方面存在瘤内异质性，这意味着高度浸润性的肿瘤亚克隆可以增强邻近细胞的迁移行为。这可能部分是由“肿瘤微管”介导的，肿瘤细胞通过这种长的膜状延伸相互连接和通讯，同时也通过细胞外囊泡的分泌来实现。一些描述的侵袭相关过程已经在临床试验中成为靶点。然而，迫切需要对DIPG侵袭机制进行更多研究，这可能会为患有这种毁灭性疾病的儿童开发出有效的治疗方法。我们讨论了新发现的侵袭机制对治疗靶向的意义，以及鉴于发育中的大脑中的疾病，治疗开发所面临的挑战。
