Tumor Heterogeneity in Glioblastomas: From Light Microscopy to Molecular Pathology

Abstract

One of the main reasons for the aggressive behavior of glioblastoma (GBM) is its intrinsic intra-tumor heterogeneity, characterized by the presence of clonal and subclonal differentiated tumor cell populations, glioma stem cells, and components of the tumor microenvironment, which affect multiple hallmark cellular functions in cancer. “Tumor Heterogeneity” usually encompasses both inter-tumor heterogeneity (population-level differences); and intra-tumor heterogeneity (differences within individual tumors). Tumor heterogeneity may be assessed in a single time point (spatial heterogeneity) or along the clinical evolution of GBM (longitudinal heterogeneity). Molecular methods may detect clonal and subclonal alterations to describe tumor evolution, even when samples from multiple areas are collected in the same time point (spatial-temporal heterogeneity). In GBM, although the inter-tumor mutational landscape is relatively homogeneous, intra-tumor heterogeneity is a striking feature of this tumor. In this review, we will address briefly the inter-tumor heterogeneity of the CNS tumors that yielded the current glioma classification. Next, we will take a deeper dive in the intra-tumor heterogeneity of GBMs, which directly affects prognosis and response to treatment. Our approach aims to follow technological developments, allowing for characterization of intra-tumor heterogeneity, beginning with differences on histomorphology of GBM and ending with molecular alterations observed at single-cell level.

A novel therapeutic strategy of multimodal nanoconjugates for state-of-the-art brain tumor phototherapy

“…Secondly, GBM is characterized by high heterogeneity between intra-tumor and inter-tumor regions at cellular and histological level. This peculiarity of GBM containing tissues induces different responses to therapeutic agents, leading to failure of targeted therapy [ 5 , 6 ]. Lastly, the central nervous system (CNS) has a distinct microenvironment that is protected by the blood brain barrier (BBB), restricting systemically delivered drugs from accessing the brain.…”

Classification of potential pathways affecting the VEGF pathway in glioblastoma multiforme (GBM) recurrent: A bioinformatics study based on differentially expressed- microRNAs

“…The mechanisms underlying cancer drug resistance is still not fully understood. Therefore, it is critical to discover the mechanisms of drug resistance to increase the success rate of GBM treatment, which is a recurrent disease [20,21] . In recurrent GBM, chromosomal instability (CIN) is considered an important mechanism leading to tumor heterogeneity.…”

Mesenchymal and Proneural Subtypes of Glioblastoma Disclose Branching Based on GSC Associated Signature

“…Even after maximal gross-total resection at surgery of well-demarcated tumors and subsequent combined irradiation and chemotherapy, the vast majority of tumors are recurring and resulting in a dismal outcome, since recurred GBMs are resistant to therapy. The main factor previously indicated to be at least partially responsible for poor patient outcome was inter- and intra-heterogeneity of GBMs which does not allow for proper treatment [ 2 ]. Genome-wide transcriptome analysis led to classify GBM into four more homogenous subtypes: mesenchymal (MES), classical (CL), proneural (PN) and neural (NE) based on bulk tumor transcription profile [ 3 ], nevertheless the clinical relevance of subtyping is still debatable [ 4 , 5 ].…”