Intratumoral heterogeneity in glioblastoma: don't forget the peritumoral brain zone

Abstract

Glioblastoma (GB) is the most frequent and aggressive primary tumor of the central nervous system. Prognosis remains poor despite ongoing progress. In cases where the gadolinium-enhanced portion of the GB is completely resected, 90% of recurrences occur at the margin of surgical resection in the macroscopically normal peritumoral brain zone (PBZ). Intratumoral heterogeneity in GB is currently a hot topic in neuro-oncology, and the GB PBZ may be involved in this phenomenon. Indeed, this region, which possesses specific properties, has been less studied than the core of the GB tumor. The high rate of local recurrence in the PBZ and the limited success of targeted therapies against GB demonstrate the need for a better understanding of the PBZ. We present here a review of the literature on the GB PBZ, focusing on its radiological, cellular, and molecular characteristics. We discuss how intraoperative analysis of the PBZ is important for the optimization of surgical resection and the development of targeted therapies against GB.

Keywords: glioblastoma; histology; omics; peritumoral brain zone; radiology; targeted therapies.

Fig. 1.

Graphical representation of the radiological, cellular and molecular characteristics of the glioblastoma peritumoral brain zone (GB PBZ).

Fig. 2.

Nano-biotechnological approaches to target the glioblastoma peritumoral brain zone (GB PBZ). Lipid nanocapsules are promising nanoscale systems for delivering therapeutic molecules to the GB PBZ. They can encapsulate many compounds including drugs, radionuclides, DNA, siRNA, and nuclease-resistant locked nucleic acids. Their association with antibodies against molecular components overexpressed in the PBZ such as αVβ3 integrin, KCa3.1, CD146, and CSPG4/NG2 can be used to specifically target the tumor cells and/or GASCs present in the PBZ. Their combination with mesenchymal stem cells, which have endogenous tumor-homing activity and are targeted to the peritumoral region, is another strategy to improve the delivery of therapeutic agents to the PBZ. Abbreviations: Ca-AMPA, Ca²⁺ permeable AMPA receptor; CSF-1R, colony stimulating factor 1 receptor; CSPG4, chondroitin sulfate proteoglycan; GASC, GB-associated stromal cells; GFAP, glial fibrillary acidic protein; KCa3.1, Ca²⁺-activated K⁺ channel.