Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and evolution

Abstract

Glioma is the most common lethal tumor of the human brain. The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months. The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas. Unlike primary glioblastoma that usually develop de novo in the elderly, secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5–10 years from the time of diagnosis. Based on various evolutional trajectories brought on by clonal and subclonal alterations, the evolution patterns of glioma vary according to different theories. Some important features distinguish the normal brain from other tissues, e.g., the composition of the microenvironment around the tumor cells, the presence of the blood-brain barrier, and others. The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer. Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment. However, the detailed reasons for the progression and recurrence of glioma remain controversial. In this review, we introduce the different mechanisms involved in glioma progression, including tumor heterogeneity, the tumor microenvironment and drug resistance, and their pre-clinical implements in clinical trials. This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.

Keywords

glioma / evolution mechanism / strategies / tumor heterogeneity / secondary glioma

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Acknowledgements

This study was funded by National Natural Science Foundation of China (Nos. 81972337 and 81773208); Beijing Natural Science Foundation (No. JQ20030); Beijing Talents Foundation from Organization Department of Municipal Committee of the CPC (No. 2017000021223ZK32); Beijing Nova Program (No. Z171100001117022); the National Key Research and Development Plan (No. 2016YFC0902500); Beijing Science and Technology Plan (No. Z141100000214009); Capital Medical Development Research Fund (No. 2016-1-1072); Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (No. ZYLX201708); National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) Joint Research Scheme (No. 81761168038 to Tao Jiang and No. N_HKUST606/17 to Jiguang Wang); Beijing Municipal Administration of Hospitals’ Mission Plan (No. SML20180501); and Beijing Tiantan Hospital Young Scientist Program (No. YSP201701). Jiguang Wang was also supported by Collaborative Research Fund, Hong Kong (No. C6002-17GF); Hong Kong Epigenomics Project (No. LKCCFL18SC01-E); and HKUST start-up and initiation grants, and received substantial support from BDBI Laboratory.

Compliance with ethics guidelines

Zhaoshi Bao, Yongzhi Wang, Qiangwei Wang, Shengyu Fang, Xia Shan, Jiguang Wang, and Tao Jiang declare no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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