Inhibition of telomerase in the endothelial cells disrupts tumor angiogenesis in glioblastoma xenografts.
Tumor angiogenesis is a complex process that involves a series of interactions between tumor cells and endothelial cells (ECs). In vitro, glioblastoma multiforme (GBM) cells are known to induce an increase in proliferation, migration and tube formation by the ECs. We have previously shown that in human GBM specimens the proliferating ECs of the tumor vasculature express the catalytic component of telomerase, hTERT, and that telomerase can be upregulated in human ECs by exposing these cells to GBM in vitro. Here, we developed a controlled in vivo assay of tumor angiogenesis in which primary human umbilical vascular endothelial cells (HUVECs) were subcutaneously grafted with or without human GBM cells in immunocompromised mice as Matrigel implants. We found that primary HUVECs did not survive in Matrigel implants, and that telomerase upregulation had little effect on HUVEC survival. In the presence of GBM cells, however, the grafted HUVECs not only survived in Matrigel implants but developed tubule structures that integrated with murine microvessels. Telomerase upregulation in HUVECs enhanced such effect. More importantly, inhibition of telomerase in HUVECs completely abolished tubule formation and greatly reduced survival of these cells in the tumor xenografts. Our data demonstrate that telomerase upregulation by the ECs is a key requisite for GBM tumor angiogenesis.
Falchetti
Maria Laura
ML
Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy. marialaura.falchetti@inmm.cnr.it
Mongiardi
Maria Patrizia
MP
Fiorenzo
Paolo
P
Petrucci
Giovanna
G
Pierconti
Francesco
F
D'Agnano
Igea
I
D'Alessandris
Giorgio
G
Alessandri
Giulio
G
Gelati
Maurizio
M
Ricci-Vitiani
Lucia
L
Maira
Giulio
G
Larocca
Luigi Maria
LM
Levi
Andrea
A
Pallini
Roberto
R
D001932:Brain Neoplasms / Q000098:blood supply* / Q000201:enzymology; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000201:enzymology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000098:blood supply* / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors*
D019098:Telomerase