Aquaporin-mediated dysregulation of cell migration in disease states

Abstract

Dysregulated cell migration and invasion are hallmarks of many disease states. This dysregulated migratory behavior is influenced by the changes in expression of aquaporins (AQPs) that occur during pathogenesis, including conditions such as cancer, endometriosis, and arthritis. The ubiquitous function of AQPs in migration of diseased cells makes them a crucial target for potential therapeutics; this possibility has led to extensive research into the specific mechanisms underlying AQP-mediated diseased cell migration. The functions of AQPs depend on a diverse set of variables including cell type, AQP isoform, disease state, cell microenvironments, and even the subcellular localization of AQPs. To consolidate the considerable work that has been conducted across these numerous variables, here we summarize and review the last decade's research covering the role of AQPs in the migration and invasion of cells in diseased states.

Keywords: Cancer; Cell signaling; Cell volume; Endometriosis.

Fig. 1

The role of aquaporins in cancer progression. There is substantial evidence that AQPs are an indispensable protein in cancer progression and more specifically tumor cell migration. The influence of AQPs on this process can be broadly broken down into four categories that are depicted in this schematic: (1) AQP influence on cancer cell signaling, leading to direct [23, 75, 108, 151] and indirect [13, 14, 20, 38, 78, 81, 93] activation of signaling cascades associated with migration and overall cancer survival; (2) AQP-mediated epithelial-to-mesenchymal transition [40, 48, 55, 73, 78, 93, 97], resulting in more invasive phenotypes [23, 40, 70, 75] associated with poor prognosis; (3) tumor-associated angiogenesis mediated by AQPs [17, 112, 124, 126], providing the tumor with highways to spread throughout the body and the nutrients needed to proliferate; 4) AQPs involvement in cancer metastasis occurs at key stages [23, 105, 130, 131] (note that the role of AQPs in intravasation still has yet to be investigated)

Fig. 2

Average cell velocity vs. relative AQP4 expression in a range of cell types: Representation of the relationship between cancer cell migration velocity in confined microchannels and their AQP4 expression across more than 20 different cancer cell lines (reproduced with permission from Ref. [100])

Fig. 3

Currently known pathways by which AQPs are capable of inducing tumor cell EMT. Other pathways have been implicated in the progression of cancer, but this figure focuses specifically on EMT-related signaling

Fig. 4

AQPs and their prognostic value. AQP5 expression (the shading) in relation to ERG (prostate cancer prognostic marker) from over 12,000 patient samples (reproduced with permission from Ref. [136])