Brain Microenvironment-Secreted Cytokines Facilitate Glioblastoma Proliferation And Invasion

Introduction

Glioblastoma is the most common and lethal type of brain cancer with a median survival of under fifteen months. It is a highly angiogenic tumor exhibiting an extremely invasive nature. It is well-known that the brain microenvironment plays a crucial role in glioblastoma progression although the large multitude of interactions between the cancer cells and their microenvironment are yet to be fully unraveled. Astrocytes are the most abundant glial cells in the brain and have been shown to be involved in many types of brain pathologies as well as metastatic colonization in the brain. Microglia are macrophages-like cells which possess antigen-presenting and phagocytic abilities that serve as the brain immune system. Hence, we investigated the influence of astrocytes and microglia on the migratory and infiltrative abilities of glioblastoma cells.

Methods

In order to evaluate the influence of brain microenvironment on glioblastoma progression, we co-cultured glioblastoma and stromal cells and determined their proliferation and migration abilites. Using protein profiler we assessed the level of cytokines secreted following interaction of glioblastoma cells and their microenvironment. Candidate cytokines were evaluated and validated by immunohistochemistry of sections from our mouse models and patient-derived samples.

Results

Using in vitro and ex vivo assays, we found that in the presence of either astrocytes or their conditioned media, the migration rate of glioblastoma cells is significantly increased.
In a co-culture proliferation assay, we observed that microglia increased glioblastoma cells proliferation at a concentration-dependent manner. Co-culture of glioblastoma cells with either astrocytes, microglia or brain endothelial cells resulted in elevated levels of several common cytokines. Moreover, immunohistochemistry analysis of several brain tumor samples inoculated orthotopically in mice revealed an increased level of activated astrocytes and microglia and high microvessel density within the tumor site.

Conclusions

Our findings indicate that the brain microenvironment facilitates glioblastoma proliferation and invasion by cytokines secretion paving the way for investigation of their use as targets for glioblastoma therapy.