Glioma-associated endothelial cells show evidence of replicative senescence.
The innately programmed process of replicative senescence has been studied extensively with respect to cancer, but primarily from the perspective of tumor cells overcoming this stringent innate barrier and acquiring the capacity for unlimited proliferation. In this study, we focus on the potential role of replicative senescence affecting the non-transformed endothelial cells of the blood vessels within the tumor microenvironment. Based on the well-documented aberrant structural and functional features of blood vessels within solid tumors, we hypothesized that tumor-derived factors may lead to premature replicative senescence in tumor-associated brain endothelial cells (TuBEC). We show here that glioma tissue, but not normal brain tissue, contains cells that express the signature of replicative senescence, senescence-associated beta-galactosidase (SA-beta-gal), on CD31-positive endothelial cells. Primary cultures of human TuBEC stain for SA-beta-gal and exhibit characteristics of replicative senescence, including increased levels of the cell cycle inhibitors p21 and p27, increased resistance to cytotoxic drugs, increased growth factor production, and inability to proliferate. These data provide the first demonstration that tumor-derived brain endothelial cells may have reached an end-stage of differentiation known as replicative senescence and underscore the need for anti-angiogenic therapies to target this unique tumor-associated endothelial cell population.
Charalambous
Christiana
C
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Virrey
Jenilyn
J
Kardosh
Adel
A
Jabbour
Mark N
MN
Qazi-Abdullah
Lubna
L
Pen
Ligaya
L
Zidovetzki
Raphael
R
Schönthal
Axel H
AH
Chen
Thomas C
TC
Hofman
Florence M
FM
D001932:Brain Neoplasms / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D016207:Cytokines / Q000494:pharmacology; D004358:Drug Therapy; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000378:metabolism
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D001616:beta-Galactosidase