Tumor Microenvironment in the Brain

Abstract

In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context.

Perivascular niches as points of the utmost expression of tumor microenvironment

“…The cell components would be tumor cells, normal and reactive astrocytes, glioblastoma stem cells (GSCs)/progenitors, pericytes, microglia/ macrophages, fibroblasts [2][3][4].…”

“…Since tumor progression largely depends on the exchange between endothelial cells and GSCs through Notch signaling, nitric oxide (NO) and vascular endothelial growth factor (VEGF) [2,3], perivascular niches (PVN) have been considered as the propulsion centers of the tumor. Their prototype in gliomas was the simple association of Nestin+ and CD133+ cells, as representatives of GSCs, with endothelial cells [5], in analogy with the sub-ventricular zone (SVZ) niche, where vasculature is strictly connected with normal neural stem cells [6,7].…”

The Role of Astrocytes in Tumor Growth and Progression

“…This is accomplished by downregulating the pro-inflammatory cytokine TNF-α in surrounding microglia, and suppressing the antigen presenting abilities of various immune cells by downregulating their expression of MHCII and CD80 [152,153]. Additionally, activated astrocytes can co-localize and induce apoptosis in T-cells attempting to infiltrate the brain parenchyma by expression of the "death ligand," CD95L, which binds the receptor on T-cells [152,154].…”

Microenvironment–A Role in Tumour Progression and Prognosis

“…The ECM in the tumour stroma is composed of extra-vasated plasma proteins, due to the leaky vasculature, but also dense collagen scaffolds are present, due to the fibrotic reaction. However, when treating the brain carcinoma it shows uptake of drugs Paclitaxel and Doxorubicin by tumour lesions was lower in brain carcinoma because of leaky vasculature [6]. These features of the tumour stroma profoundly contribute to the nature of the neoplastic disease, and many aspects of the progression and treatment of cancers are dependent on the non-malignant cell component of the tumour [7].…”