Aquaporins in Brain Tumor-Related Edema: A Narrative Review.

BACKGROUND

Brain tumor-related edema is a major contributor to morbidity in patients with intracranial neoplasms, arising from interactions between blood-brain barrier (BBB) dysfunction, tumor biology, and dysregulated water transport. Aquaporins (AQPs), and particularly AQP4, are central to cerebral water homeostasis, and alterations in their expression and spatial polarization within and around brain tumors influence both cytotoxic and vasogenic edema. This narrative review synthesizes contemporary evidence on AQP biology in the tumor-bearing brain and critically appraises the translational maturity of AQP-directed therapy.

SUMMARY: AQP4 is the predominant central nervous system AQP, concentrated at astrocytic end-feet and essential for water flux across the BBB and along glymphatic pathways. In high-grade gliomas, AQP4 is upregulated and loses perivascular polarity, a pattern that accompanies extensive vasogenic edema, impaired perivascular clearance, and enhanced tumor cell invasion. Low-grade gliomas and meningiomas show more restricted or vascular-predominant AQP expression, including AQP1 in meningioma vasculature, and comparatively less peritumoral edema. Experimental work demonstrates a bidirectional, context-dependent role for AQP4: it promotes astrocytic swelling when the BBB is intact, yet facilitates reabsorption of extracellular fluid once the barrier is disrupted. This duality has not been resolved in human tumor tissue and constrains any single-direction therapeutic strategy. Candidate interventions, including small-molecule inhibitors (AER-270/AER-271), monoclonal antibodies, SUR1-TRPM4 modulation, RNA interference, and CRISPR/Cas9-based editing, have shown activity in rodent injury models but have not been evaluated in brain tumor populations.

KEY MESSAGES: (1) AQP4 is not uniformly pro-edematous; its net effect depends on BBB integrity, edema phase, and preservation of perivascular polarity, so undifferentiated inhibition risks impairing fluid clearance in precisely the tumors that most need it. (2) The evidence base remains dominated by rodent injury models and small immunohistochemical series rather than human tumor tissue, and no AQP-targeted agent has entered a brain tumor trial. (3) Meaningful progress will require human-tissue studies that quantify AQP4 polarity rather than total expression, prospective imaging biomarkers such as diffusion tensor image analysis along the perivascular space capable of stratifying patients before treatment, and astrocyte-targeted, temporally controlled gene-editing approaches rather than constitutive gene deletion.