Aquaporins and Brain Tumors

Abstract

Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs).

AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

“…In fact, glioma cells have to face the complex architecture of the brain parenchyma, which represents an obstacle to their dissemination. Secretion of metalloproteinases by glioma cells is important to break the extracellular matrix; meanwhile, reducing their volume helps them to sneak into the brain interstitial space and to migrate following a water flux l generated by AQP4 (11). Glioma cell shrinkage able to increase cell migration (48) is similarly triggered by an ion extrusion in turn driving water efflux, as in AVD.…”

“…Alteration of brain fluid homeostasis is a common feature of brain tumors. There is extensive literature on the role of aquaporins in tumor biology, including tumor-associated edema, tumor cell migration, tumor proliferation, and tumor angiogenesis, indicating the need for AQP inhibitors as potentially useful anticancer drugs (10)(11)(12). The role for endothelial aquaporin-1 (AQP1) in the context of tumor angiogenesis is welldescribed (13,14).…”

Fluorescein for resection of high-grade gliomas: A safety study control in a single center and review of the literature

“…[24] According to the current WHO grading system, high grades include grade III and IV lesions. One-year survival rate for high-grade gliomas (HGGs) is 53.7%, while 2-year survival rate for these patients is only 14.6%.…”

Aquaporins in the Spinal Cord

“…Strong AQP4 expression at the borders between brain parenchyma and major fluid compartments, e.g., between brain ventricles and glia limitans externa or at the BBB, suggests that AQP4 functions in facilitating water flow into and out of the brain and spinal cord. Moreover, an increased AQP4 expression has been demonstrated in glioblastoma multiforme, suggesting it is also involved in malignant brain tumors [27]. Although water transport can occur to a certain extent through simple diffusion across the plasma membrane [28], studies utilizing AQP4 knockouts demonstrated great importance of this water channel in the pathogenesis of brain water imbalance and CNS injuries.…”