Modulating microenvironments for treating glioblastoma

Abstract

Purpose of review: This review focuses on the development and progression of glioblastoma through the brain and glioma microenvironment. Specifically we highlight how the tumor microenvironment contributes to the hallmarks of cancer in hopes of offering novel therapeutic options and tools to target this microenvironment.

Recent findings: The hallmarks of cancer, which represent elements of cancers that contribute to the disease's malignancy, yet elements within the brain tumor microenvironment, such as other cellular types as well as biochemical and biophysical cues that can each uniquely affect tumor cells, have not been well-described in this context and serve as potential targets for modulation.

Summary: Here, we highlight how the brain tumor microenvironment contributes to the progression and therapeutic response of tumor cells. Specifically, we examine these contributions through the lens of Hanahan & Weinberg's Hallmarks of Cancer in order to identify potential novel targets within the brain that may offer a means to treat brain cancers, including the deadliest brain cancer, glioblastoma.

Keywords: Glioblastoma; brain microenvironment; cancer hallmarks; tumor microenvironment.

Figure 1.. Tumor microenvironment contributors to cancer hallmarks in glioblastoma.

Each boxed schematic corresponds to a specific cancer hallmark that occurs and the key players that are involved in GBM. The top left box represents metabolic reprogramming where oxidative phosphorylation and glycolysis can be utilized for metabolism based on GBM-TME influenced phenotype. The top middle image corresponds to the evasion of growth suppressors, which can be promoted through mutations and mitogens based on conditions within the GBM-TME. The top right box represents common genetic reprogramming that promotes mutations and leads to both sustained proliferative signaling and tumoral heterogeneity. The middle right image represents tumor cells avoiding immune destruction. The bottom right image represents how GSCs possess plasticity to self-replicate or acquire other fates, such as tumor cells, endothelial cells, and pericytes, often influenced by the GBM-TME, and support tumor progression. The bottom middle image represents invasion and migration, which can be induced through autologous chemotaxis in glioblastoma as well as tumor-associated astrocytes and microglia among other mechanisms. The bottom left image represents angiogenesis, which occurs based on the tumor microenvironment influencing the sprouting of blood vessels. The middle left image represents tumor-promoting inflammation which can be induced by myeloid derived suppressor cells or tumor-associated macrophages. Boxed items correspond respectively with the colors within the cancer hallmark graphic circle. The figure was created with Biorender.com (The circular hallmark graphic was modified under the Copyright Clearance Center’s RightsLink service and reprinted from Cancer Cell, Volume 21(3), Douglas Hanahan & Lisa M. Coussens, Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment, Pages 309–322, 2012 with permission from Elsevier.) TAM=Tumor-associated macrophage; MDSC=Myeloid derived suppressor cell.