Current Knowledge about the Peritumoral Microenvironment in Glioblastoma

SIMPLE SUMMARY: In this manuscript, we review the most relevant biological findings on glioblastoma peritumoral tissue. This area, which is beyond frank tumoral tissue, presents a unique microenvironment with a peculiar cellular landscape and genomic and transcriptomic alterations that ultimately lead to glioblastoma progression or recurrence after treatment. Indeed, while some infiltrating tumor cells are found in about one third of cases, these alterations are seen even in non-infiltrated cases. This is of utmost translational interest, as the peritumoral brain zone (PBZ) is the real target of post-operative adjuvant treatment. ABSTRACT: Glioblastoma is a deadly disease, with a mean overall survival of less than 2 years from diagnosis. Recurrence after gross total surgical resection and adjuvant chemo-radiotherapy almost invariably occurs within the so-called peritumoral brain zone (PBZ). The aim of this narrative review is to summarize the most relevant findings about the biological characteristics of the PBZ currently available in the medical literature. The PBZ presents several peculiar biological characteristics. The cellular landscape of this area is different from that of healthy brain tissue and is characterized by a mixture of cell types, including tumor cells (seen in about 30% of cases), angiogenesis-related endothelial cells, reactive astrocytes, glioma-associated microglia/macrophages (GAMs) with anti-inflammatory polarization, tumor-infiltrating lymphocytes (TILs) with an “exhausted” phenotype, and glioma-associated stromal cells (GASCs). From a genomic and transcriptomic point of view, compared with the tumor core and healthy brain tissue, the PBZ presents a “half-way” pattern with upregulation of genes related to angiogenesis, the extracellular matrix, and cellular senescence and with stemness features and downregulation in tumor suppressor genes. This review illustrates that the PBZ is a transition zone with a pre-malignant microenvironment that constitutes the base for GBM progression/recurrence. Understanding of the PBZ could be relevant to developing more effective treatments to prevent GBM development and recurrence.