Bevacizumab-Induced Hypertension in Glioblastoma Patients and Its Potential as a Modulator of Treatment Response

Abstract

Glioblastoma invasion is the primary mechanism responsible for its dismal prognosis and is the direct result of interactions between glioblastoma cells and the tumor vasculature. The dysregulated microvasculature in glioblastoma tumors and vessels co-opted from surrounding brain tissue support rapid tumor growth and are utilized as pathways for invasive cancer cells. Attempts to target the glioblastoma vasculature with antiangiogenic agents (eg, bevacizumab) have nonetheless shown limited and inconsistent efficacy, and the underlying causes of such heterogeneous responses remain unknown. Several studies have identified that patients with glioblastoma who develop hypertension following treatment with bevacizumab show significant improvement in overall survival compared with normotensive nonresponders. Here we review these findings and discuss the potential of hypertension as a biomarker for glioblastoma treatment response in individual patients and the role of hypertension as a modulator of interactions between tumor cells and cells in the perivascular niche. We suggest that a better understanding of the actions of bevacizumab and hypertension at the cellular level will contribute to developing more effective personalized therapies that address glioblastoma tumor cell invasion.

Keywords: bevacizumab; biomarkers; brain; glioblastoma; hypertension.

Figure 1.

Glioblastoma microvasculature and the correlation between the development of hypertension and survival for glioblastoma patients treated with bevacizumab. A, Glioblastomas commonly feature regions of hypoxia and necrosis. Tumor cells in the hypoxic areas express VEGFA (vascular endothelial growth factor A), inducing the formation of numerous new poorly formed and leaky blood vessels. The blood-brain barrier is often disrupted in the central tumor, causing edema and hemorrhage, while on the tumor periphery, this barrier variably remains intact. B, Roughly 4 of every 10 patients treated with bevacizumab will develop hypertension following treatment. Patients who develop hypertension have improved overall survival. This figure was created using BioRender.com.

Figure 2.

Modulators of vascular tone and endothelial dysfunction in the perivascular niche. Vascular tone is maintained by a careful balance of vasodilators and vasoconstrictors. VEGFA (vascular endothelial growth factor A) induces upregulation and activation of eNOS (endothelial nitric oxide synthase), which generates the key vasodilator NO. Inhibition of VEGFA signaling by bevacizumab reduces NO production. Under conditions of hypertension, angiotensin-II (Ang-II) signaling induces production of superoxide by NOX1 (NADPH oxidase 1), which combines with available NO to form peroxynitrite. This reactive oxygen species (ROS) then destabilizes eNOS by reducing the cofactor tetrahydrobiopterin (BH₄), causing eNOS to switch to production of superoxide, driving endothelial dysfunction through the loss of NO. This figure was created using BioRender.com.

Figure 3.

VEGFA (vascular endothelial growth factor A) inhibition by bevacizumab normalizes vascular tone by reducing endothelial nitric oxide synthase (eNOS) production of NO. Certain patients experience such a change in peripheral resistance due to capillary rarefaction and increase in vascular tone that they develop hypertension following treatment. These patients may experience further endothelial dysfunction due to the compounding effects of hypertension on NO availability. This figure was created using BioRender.com.