Down‐regulation of caveolin‐1 in glioma vasculature: Modulation by radiotherapy

Abstract

Primary brain tumors, particularly glioblastomas (GB), remain a challenge for oncology. An element of the malignant brain tumors' aggressive behavior is the fact that GB are among the most densely vascularized tumors. To determine some of the molecular regulations occuring at the brain tumor endothelium level during tumoral progression would be an asset in understanding brain tumor biology. Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling, oncogenesis, and angiogenesis. In this work we investigated regulation of caveolin-1 expression in brain endothelial cells (ECs) under angiogenic conditions. In vitro, brain EC caveolin-1 is down-regulated by angiogenic factors treament and by hypoxia. Coculture of brain ECs with tumoral cells induced a similar down-regulation. In addition, activation of the p42/44 MAP kinase is demonstrated. By using an in vivo brain tumor model, we purified ECs from gliomas as well as from normal brain to investigate possible regulation of caveolin-1 expression in tumoral brain vasculature. We show that caveolin-1 expression is strikingly down-regulated in glioma ECs, whereas an increase of phosphorylated caveolin-1 is observed. Whole-brain radiation treatment, a classical way in which GB is currently being treated, resulted in increased caveolin-1 expression in tumor isolated ECs. The level of tumor cells spreading around newly formed blood vessels was also elevated. The regulation of caveolin-1 expression in tumoral ECs may reflect the tumoral vasculature state and correlates with angiogenesis kinetics.

Caveolin-1 Is Critical for the Maturation of Tumor Blood Vessels through the Regulation of Both Endothelial Tube Formation and Mural Cell Recruitment

“…Furthermore, our data underscore how caveolin deficiency contributes through an early increase in tumor vessel permeability to build up an extravascular matrix network that promotes angiogenesis. Thus, the previously reported angiogenic growth factor-driven decrease in caveolin abundance 16,17 supports the advantages of an increased endothelium permeability, the stimulation of EC proliferation/migration and the prevention of the angiogenic process termination by mural cell recruitment. Caveolin-1 has therefore the potential to be an important prognostic indicator in delineating the degree of tumor vessel maturity and thereby the therapeutic efficacy of anti-angiogenic drugs.…”

“…14,15 Interestingly, endogenous (native) caveolin has been reported to be down-regulated in the tumor vasculature 16 and in endothelial cells exposed to angiogenic growth factors including VEGF and basic fibroblast growth factor 17,18 or when co-cultured with tumor cells. 16 Angiogenic mediators such as nitric oxide 19 or proangiogenic stresses such as ionizing radiation 20 and hypoxia 16 have also been associated with a decrease in endothelial caveolin abundance. Conversely, angiogenesis inhibitors including angiostatin, fumagillin, and thalidomide were reported to block VEGF-induced down-regulation of caveolin-1.…”

Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1

“…Expression of Cav-1 is also dysregulated in normal cells adjacent to tumors. In endothelial cells isolated from glioblastomas, Cav-1 is downregulated, and expression returns to the levels observed in normal brain endothelial cells after irradiation (Regina et al, 2004).…”

Overexpression of Caveolin-1 Inhibits Endothelial Cell Proliferation by Arresting the Cell Cycle at G0/G1 Phase

“…Overexpression of caveolin-1 inhibited the 16 and a stable association of caveolin-1 with VEGFR-2 that is rapidly dissociated upon VEGF stimulation. 11 However, whether caveolin-1 expression affects endothelial cell proliferation is not clear.…”