Endothelial trans-differentiation in glioblastoma recurring after radiotherapy

Abstract

We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7 chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7 amplification, were then assessed by CD31 and α Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7 signal and the total CD31+ cells was 0.23 ± 0.09 (mean ± sem) and 0.63 ± 0.07 in primary tumors and in recurrent ones, respectively (p < 0.002, Student-t test). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7 over the total CD31+ cells lining the capillary lumen was 0.21 ± 0.06 (mean ± sem) and 0.42 ± 0.07 at primary surgery and at recurrence, respectively (p < 0.005, Student-t test). Expression of α Smooth Muscle Actin by cells with EGFR/CEP7 amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization.

Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

“…41 Senescence also occurs in stromal cells 140 , and tumour cells can compensate for endothelial cell senescence by transdifferentiating into endothelial cells enabling angiogenesis. 143 The chemotherapeutic temozolomide (TMZ) increases patient survival but can trigger TME remodelling that promotes a resistant, pro-invasive tumour phenotype. Treatment of cultured GBM cells with radiation and TMZ induces an increase in MMP-2 secretion and abundance of matrix-degrading invadopodia.…”

ADAMTSL4, a Secreted Glycoprotein, Is a Novel Immune-Related Biomarker for Primary Glioblastoma Multiforme

“…Nowadays, although comprehensive treatment of GBM (WHO grade IV) has been carried out to each patient, the prognosis is still poor [1, 2, 31]. With the development of immunotherapy, more and more attention is attracted to the heterogeneous immune status of GBM (WHO grade IV).…”

Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1

“…Four‐μm thick paraffin sections were dewaxed with xylene and rehydrated in ethanol. Combined immunophenotyping with antibody antihuman CD31 (Monoclonal Mouse, clone JC70A, 1:50 dilution, Dako, Milan, Italy) and fluorescence in situ hybridization (FISH) using LSI EGFR Probe (Vysis EGFR/CEP7 FISH Probe Kit, Abbott, Rome, Italy) was performed as described (Supporting Information Methods) . Sections were incubated overnight at 4 °C in PB with 0.3% Triton X‐100 and 0.1% NDS with Lectin from Lycopersicon esculentum (tomato) biotin conjugate (1:500; Sigma‐Aldrich, St. Louis, MO) together with Monoclonal Mouse Anti‐IDH1 (R132H; clone HMab‐1, 1:50, Sigma Aldrich, St. Louis, MO).…”