18q11.2

MIWC,WCH4

Melanoma

Melanoma cells implanted into the striatum of wild type and AQP4-null mice produce peritumoral edema and comparable sized-tumors in both groups after a week. However, the AQP4-null mice have a higher intracerebral pressure and water content (Manley et al., 2004).

Astrocytoma

AQP4 expression has also been demonstrated to be up-regulated in edematous astrocytomas and metastatic tumors (Saadoun et al., 2002). An increased AQP4 expression has been demonstrated in glioblastoma multiforme (GBM) together with loss of polarized expression around the vessels and an AQP4 redistribution in glioma cells (Warth et al., 2004; Warth et al., 2005; Warth et al., 2007). Warth et al. (2007) investigated grade I-IV glioma by immunohistochemistry and the prognostic significance for patients survival. In gliomas, a remarkable de novo AQP4 redistribution was observed in comparison with normal central nervous system tissue. Moreover, the highest membranous staining levels were seen in pilocytic astrocytomas WHO grade I and grade IV glioblastomas, both significantly higher than in WHO grade II. AQP4 up-regulation was associated with brain edema formation and no association between survival and WHO grade-dependent AQP4 expression was seen. Moreover, in glioma cells co-localization of AQP4 with K+ channel protein Kir 4.1 is abolished and a mislocation of both Kir channels and AQP4 has been reported (Warth et al., 2007), suggesting that this molecular rearrangement occurs as a reaction to BBB damages, facilitating edema fluid flow. Mou et al. (2010) investigated changes of AQP4 protein expression in normal brain and in brain glioma tumor and peritumoral edematous tissues and analyzed the relationship of AQP-4 protein with edema index, VEGF and hypoxia inducible factor 1 alpha (HIF-1α) protein. They demonstrated that expression of AQP-4 was higher in the tumor and highest in the peritumor tissue. Moreover, AQP-4 protein in tumor tissue of gliomas of different grades was not statistically different. In normal brain tissues, AQP-4 was mainly expressed in the foot processes of astrocytes, but rare in the parenchyma. Finally, the degree of peritumoral edema positively correlated with the expression level of AQP-4 protein and this latter correlated with VEGF and HIF-1α expression. Nico et al. (2009) evaluated AQP4 expression and content in GBM and correlated with VEGF-VEGFR-2 expression. They demonstrated that in the relapse after chemotherapy and radiotherapy, AQP4 reduced in parallel with VEGF-VEGFR-2 expression as compared with primary tumors, and in the peripheral areas of relapsed tumors AQP4 mimicked normal findings of perivascular rearrangements. These data indicate that in GBM chemotherapy and radiotherapy induce a down-regulation in AQP4 expression restoring its perivascular rearrangement and suggest its potential role in the resolution of brain edema. Moreover, the normally polarized rearrangement of AQP4 in peripheral areas in tumor specimens obtained after combined chemotherapy and radiotherapy could be expression of a process of normalization of tumor blood vessels. Tumor implantation experiments into AQP4-null mice have demonstrated that these mice have an increased intracranial pressure than wild-type controls (Papadopoulos et al., 2004a; Papadopoulos et al., 2004b). McCoy et al. (2010) using D54MG glioma cells stably transfected with either AQP1 or AQP4 demonstrated that protein kinase C (PKC) activity regulates water permeability through phosphorylation of AQP4. Activation of PKC with either phorbol 12-myristate 13-acetate or thrombin enhanced AQP4 phosphorylation, reduced water permeability and significantly decreased tumor cell invasion. Conversely, inhibition of PKC activity with chlerythrine reduced AQP4 phosphorylation, enhanced water permeability and tumor cell invasion.

Meningioma

Ng et al. (2009) demonstrated that overexpression of AQP4 in meningiomas was associated with significant peritumoral edema.

Therapeutic perspectives

Inhibition of AQPs expression and/or AQP-mediated water influx by acetozolamide, cyclophosphamide, topiramate, thiopenthal, phenobarbital and propofol, affects cancer cell proliferation, migration, metastasis and angiogenic potential (Monzani et al., 2007).
Inhibition of AQP-4 expression (by small interference RNA technology) or their function (with a blocking antibody or a small inhibitory molecule) may result in increased intracellular acidosis and cytotoxicity and reduced invasive potential of glioma cells. Ding et al. (2011), using small interference RNA and a pharmaceutical inhibitor to knock down the expression of AQP-4, demonstrated a specific and massive impairment of glioblastoma cell migration and invasion in vitro and in vivo. Moreover, they showed that down-regulation of matrix metalloproteinase-2 (MMP-2) expression coincides with decreased cell invasive ability. Accordingly, Badaut et al. (2011) using RNA interference have demonstrated that brain water motility decreases after astrocyte AQP-4 inhibition.
Corticosteroids are largely used in combination with chemotherapy and contribute to significantly reduce peritumoral brain edema by decreasing the permeability of tumor vessels and/or enhance the clearance of extracellular water (Sinha et al., 2004). Animal experiments showed a decrease of cerebral AQP-4 protein expression upon dexamethasone treatment (Ron et al., 2005), suggesting that AQP-4 may be considered one of the major molecular targets of the well-functioning steroid treatment in brain edema formation. Moreover, corticosteroids reduced AQP-4 mRNA level in experimental brain tumor model and after intracerebral hemorrhage in rats (Heiss et al., 1996; Gu et al., 2007). The evidence that AQP-4 facilitates the migration of reactive astrocytes towards an injury site and the infiltration of malignant astrocytes in glioblastoma (Verkman et al., 2008) suggests that AQP-4 inhibitors may reduce reactive gliosis and infiltration of astrocytes.