Dynamics of expression patterns of AQP4, dystroglycan, agrin and matrix metalloproteinases in human glioblastoma

Abstract

In human glioblastoma, the blood-brain barrier (BBB) is disturbed. According to our concept, the glio-vascular relationships and thus the control of the BBB are essentially dependent on the polarity of astroglial cells. This polarity is characterized by the uneven distribution of the water channel protein aquaporin-4 (AQP4), dystroglycan and other molecules. Recently, we were able to show that the extracellular matrix component agrin is important for the construction and localization of the so-called orthogonal arrays of particles (OAPs), which consist in AQP4. Here, combining freeze-fracture electron microscopy, immunohistochemistry and Western blotting, we describe alterations of expression and distribution of AQP4, dystroglycan, agrin and the matrix metalloproteinases (MMP) 2, 3 and 9 in human primary glioblastomas (eight primary tumours, six recurrent tumours). Increase of MMP3- and MMP2/9 immunoreactivities went along with loss of agrin and dystroglycan respectively. On the protein level, AQP4 expression was increased in glioblastoma compared to control tissue. This was not accompanied by an increase of OAPs, suggesting that AQP4 can also occur without forming OAPs. The results underline our concept of the loss of glioma cell polarity as one of the factors responsible for the disturbance of the neurovascular unit and as an explanation for the formation of edemas in the glioblastoma.

Molecular scaffolds underpinning macroglial polarization: An analysis of retinal Müller cells and brain astrocytes in mouse

“…Loss of macroglial polarization – characterized by depletion of molecules that normally are enriched in macroglial endfoot membranes - emerges as a prominent feature of a number of diseases and disease models, including temporal lobe epilepsy, Alzheimer’s disease, stroke, injury, and glioblastoma (Eid et al, 2005; Yang et al, 2011; Noell et al, 2012; Zeynalov et al, 2008; Robel et al, 2011). Losing polarity implies loss of normal function.…”

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

“…Thus, the blood-tumor barrier is leaky compared to the healthy, intact bloodbrain barrier, which helps supply the tumor with an increasing demand of nutrients. 284,285 Noell et al 286 showed increased MMP-2, -3, and -9 immunoreactivity in brain slices of human primary glioblastomas compared to non-tumor brain tissue and assumed blood-brain barrier leakage in this area. Studies from other groups detected increased proMMP-2 and proMMP-9 levels in the CSF of dogs with intracranial tumors compared to healthy dogs.…”

Physiological Roles of Aquaporin-4 in Brain

“…Increased expression of AQP4 or Aqp4 mRNA has been found in numerous conditions, including bacterial meningitis (141), inflammation secondary to intraparenchymal injection of lipopolysaccharides (LPS) (187) or lysolecithin (190), subarachnoid hemorrhage (198), intracerebral hemorrhage (182), brain tumors (32,135,164), and hydrocephalus (100,144,168,170,189). It is still not known whether changes in surface expression of AQP4 occur under physiological conditions.…”