Glioblastoma (GBM) is the most aggressive and invasive primary brain tumor. Current therapies are not curative, and patients' outcomes remain poor with an overall survival of 20.9 months after surgery. The typical growing pattern of GBM develops by infiltrating the surrounding apparent normal brain tissue within which the recurrence is expected to appear in the majority of cases. Thus, in the last decades, an increased interest has developed to investigate the cellular and molecular interactions between GBM and the peritumoral brain zone (PBZ) bordering the tumor tissue. The aim of this review is to provide up‐to‐date knowledge about the oncogenic properties of the PBZ to highlight possible druggable targets for more effective treatment of GBM by limiting the formation of recurrence, which is almost inevitable in the majority of patients. Starting from the description of the cellular components, passing through the illustration of the molecular profiles, we finally focused on more clinical aspects, represented by imaging and radiological details. The complete picture that emerges from this review could provide new input for future investigations aimed at identifying new effective strategies to eradicate this still incurable tumor.

The peritumoral brain zone in glioblastoma: where we are and where we are going

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.

Current Knowledge about the Peritumoral Microenvironment in Glioblastoma

Treating malignant glioma is challenging owing to its highly invasive potential in healthy brain tissue and the formation of intense surrounding edema. Peritumoral edema in gliomas can lead to severe symptoms including neurological dysfunction and brain herniation. For the past 50 years, the standard treatment for peritumoral edema has been steroid therapy. However, the discovery of cerebral lymphatic vessels a decade ago prompted a re-evaluation of the mechanisms involved in brain fluid regulation and the formation of cerebral edema. This review aimed to describe the clinical features of peritumoral edema in gliomas. The mechanisms currently known to cause glioma-related edema are summarized, the limitations in current cerebral edema therapies are discussed, and the prospects for future cerebral edema therapies are presented. Further research concerning edema surrounding gliomas is needed to enhance patient prognosis and improve treatment efficacy.

Peritumoral Edema in Gliomas: A Review of Mechanisms and Management

Glioblastoma is a highly aggressive and invasive tumor that affects the central nervous system (CNS). With a five-year survival rate of only 6.9% and a median survival time of eight months, it has the lowest survival rate among CNS tumors. Its treatment consists of surgical resection, subsequent fractionated radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Despite the implementation of clinical interventions, recurrence is a common occurrence, with over 80% of cases arising at the edge of the resection cavity a few months after treatment. The high recurrence rate and location of glioblastoma indicate the need for a better understanding of the peritumor brain zone (PBZ). In this review, we first describe the main radiological, cellular, molecular and biomechanical tissue features of PBZ; and subsequently, we discuss its current clinical management, potential local therapeutic approaches and future prospects.

Peritumoral brain zone in glioblastoma: biological, clinical and mechanical features

Despite the efforts made in recent decades, glioblastoma is still the deadliest primary brain cancer without cure. The potential role in tumour maintenance and progression of the peritumoural brain zone (PBZ), the apparently normal area surrounding the tumour, has emerged. Little is known about this area due to a lack of common definition and due to difficult sampling related to the functional role of peritumoural healthy brain. The aim of this work was to better characterize the PBZ and to identify genes that may have role in its malignant transformation. Starting from our previous study on the comparison of the genomic profiles of matched tumour core and PBZ biopsies, we selected CDK4 and EXT2 as putative malignant drivers of PBZ. The gene expression analysis confirmed their over-expression in PBZ, similarly to what happens in low-grade glioma and glioblastoma, and CDK4 high levels seem to negatively influence patient overall survival. The prognostic role of CDK4 and EXT2 was further confirmed by analysing the TCGA cohort and bioinformatics prediction on their gene networks and protein–protein interactions. These preliminary data constitute a good premise for future investigations on the possible role of CDK4 and EXT2 in the malignant transformation of PBZ.

https://www.mdpi.com/1422-0067/24/3/2835/pdf?version=1675304518

Insights into the Peritumoural Brain Zone of Glioblastoma: CDK4 and EXT2 May Be Potential Drivers of Malignancy

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The peritumoral brain zone in glioblastoma: where we are and where we are going