The aquaporin‐4 water channel and brain tumour oedema

Abstract

Aquaporin‐4 (AQP4) is a water channel protein that is expressed by perimicrovessel astrocyte foot processes in normal brain. There is up‐regulation of astrocyte AQP4 mRNA in areas of the rat brain where the blood brain barrier is disrupted following focal brain ischaemia or physical injury. In contrast AQP4 knockout mice show less brain swelling and improved survival rates after water intoxication or focal cerebral ischaemia compared to wild type mice. However little is known about the expression of AQP4 in aggressive human brain tumours, even though they result in peritumoural oedema. Therefore formalin fixed samples of morphologically normal human brain (n = 5), astrocytomas (n = 10) and adenocarcinoma metastases to brain (n = 5) were embedded in paraffin wax, sections cut and investigated by AQP4 immunocytochemistry. These samples were obtained from patients who underwent craniotomy at Atkinson Morley’s Hospital during 1998–9. Immunolabelling was performed using a polyclonal AQP4 antibody (AB3068, Chemicon), visualised with immunoperoxidase and diaminobenzidine hydrochloride. Blood–brain barrier opening was visualised preoperatively, using contrast enhancement on computed tomography. AQP4 immunolabelling was confined to astrocyte foot processes surrounding microvessels in the 5 samples of normal brain and 5 low grade (Daumas‐Duport I or II) astrocytomas. In 4/5 high grade (Daumas‐Duport III or IV) astrocytomas there was strong immunolabelling over the cytoplasm of most tumour cells and/or reactive astrocytes that was not restricted to the perimicrovessel region. Up‐regulation of AQP4 immunoreactivity was also found in astrocytes adjacent to the 5 metastatic adenocarcinomas investigated. There was a significant correlation between up‐regulation of AQP4 immunolabelling and contrast enhancement on computed tomographs (P < 0.0001 Fisher exact). Therefore oedematous aggressive brain tumours and surrounding tissues demonstrate massive up‐regulation of expression of the water channel protein AQP4. The strong correlation between the presence of brain oedema and AQP4 expression suggests that AQP4 expression is intimately involved in the pathophysiology of tumour related brain oedema. However, it is not clear whether AQP4 is involved in the accumulation or clearance of brain oedema fluid.