Abstract
For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too.
Highlights
Alongside the definition of cancer as a genetic disease, in recent years, the key role of the relation between tumor epithelium and tissue microenvironment in the tumorigenesis has been outlined: the dynamic interaction between microenvironment and cancer cells promotes the growth, proliferation and protection of the tumor from immune surveillance and therapy [1].It has emerged that tumor progression takes place by a Darwinian selection of the favorite clones [2], and mutator phenotypes allow greater adaptations to the microenvironment [3]
The authors showed that in an inflammatory microenvironment, Caspase 8, a protein implicated in apoptosis, promotes NF-κB transcription factor activation with consequent increase of vascular endothelial growth factor (VEGF), IL-6, IL-8, IL-1β and MCP-1 secretion, enhancing neovascularization and resistance to temozolomide (TMZ), an alkylating agent widely used in glioblastoma treatment
The phenomenon of chemoresistance developed in glioblastoma to conventional treatments is related to its biological complexity and to different cellular and molecular mechanisms activated during tumorigenesis and progression
Summary
Alongside the definition of cancer as a genetic disease, in recent years, the key role of the relation between tumor epithelium and tissue microenvironment in the tumorigenesis has been outlined: the dynamic interaction between microenvironment and cancer cells promotes the growth, proliferation and protection of the tumor from immune surveillance and therapy [1]. It has emerged that tumor progression takes place by a Darwinian selection of the favorite clones [2], and mutator phenotypes allow greater adaptations to the microenvironment [3]. Cancer cells can acquire a resistant phenotype in response to therapy, or they can be intrinsically resistant due to genetic aberrations underlying tumor development [9]. In both cases, the altered expression of multi-drug resistance (MDR)-related genes is associated with a reduced responsiveness to therapy [10]. The immunosuppressive feature of the tumor microenvironment (TME) allows cancer cells to sidestep immune surveillance, progressing [12]. This review provides an overview on how microenvironment affects glioblastoma response to therapy, on the direct pharmacological modulation of BBB drugs’ permeability, on involvement of genetic pathways in the chemoresistant phenotype of glioblastoma, and on how the brain’s microenvironment could offer the opportunity to implement treatment of glioblastoma patients
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