Increased migration and metastatic potential of tumor cells expressing aquaporin water channels

Abstract

Aquaporin (AQP) water channels are expressed in high-grade tumor cells of different tissue origins. Based on the involvement of AQPs in angiogenesis and cell migration, we tested whether AQP expression in tumor cells might enhance their migration and metastatic potential. Transfection of B16F10 and 4T1 tumor cells with AQP1 did not affect their appearance, size, growth, or substrate adherence but increased their plasma membrane osmotic water permeability by 5- to 10-fold. In vitro analysis of cell migration by transwell assay, wound healing and video microscopy showed a 2- to 3-fold accelerated migration of the AQP1-expressing tumor cells compared to control cells. In mice, AQP1 expression increased tumor cell extravasation by >1.5-fold as quantified by counting tumor cells in lung at 6 h after tail vein injection of a mixture of fluorescently tagged AQP1-expressing and control tumor cells. AQP1 expression also increased by 3-fold the number of lung metastases 14 days after tail vein injection of tumor cells, with alveolar wall infiltration seen with AQP1-expressing tumor cells. Our results provide evidence for AQP-facilitated tumor cell migration and spread, suggesting a novel function for AQP expression in high-grade tumors. AQP inhibition may thus reduce the metastatic potential of some tumors.

Aquaporins—new players in cancer biology

“…AQP1 and AQP4 accelerate the migration of cultured Chinese Hamster Ovary and Fisher Rat Thyroid cells [14]; AQP4 facilitates astrocyte cell migration [12,13]; and AQP1 facilitates the migration of cultured renal proximal tubule cells [10], B16F10 melanoma, and 4T1 breast cancer cells [16]. Two mechanisms have been proposed to explain how AQPs facilitate cell migration [17]: According to the first theory, AQPs facilitate rapid water flow across the plasma membrane into the front end of migrating cells (Fig.…”

“…To test this possibility, tumor cell migration, invasiveness, and metastatic potential were evaluated using two established mouse cell lines (B16F10 melanoma and 4T1 breast tumor) without vs with AQP1 expression [16]. AQP1 expression did not affect the appearance, size, growth, or substrate adherence of the tumor cells in culture, but it increased their plasma membrane osmotic water permeability by 5-to 10-fold.…”

Aquaporin-1-Expression bei invasiven Mammakarzinomen

“…Unterstützt wird diese Ver mutung durch eine gesteigerte Expres sion von Stammzellregulatorgenen wie CD133, Bmi1 und SLUG [23]. In Zelllinien von malignen Melanomen und Mamma karzinomen wurde eine gesteigerte Migra tions und Ausbreitungsfähigkeit von AQP1 exprimierenden Zellen nachge wiesen, was auf eine neue zellbiologische Funktion von AQP1 in malignen Tumo ren hinweist [9].…”

“…AQPs werden in verschiedenen Epithel und Endothelzel len in flüssigkeitstransportierenden Ge weben, wie Nierentubulusepithelien, und exokrinen Drüsenepithelien gefunden. Sie werden aber auch von epidermalen Plat tenepithelzellen, Adipozyten, Urothelzel len und Astrogliazellen exprimiert, wor aus sich die Frage nach anderen biolo gischen Funktionen als dem Wassertrans port ergibt [9,13].…”

“…Bei AQP1 Knock out Mäusen wurde ein verlangsamtes Tumorwachstum mit einer reduzierten Tumorangiogenese beobach tet [21]. Zellkulturstudien weisen auf ei nen Einfluss der AQP1 Expression auf die Migration, Invasion und Metastasierungs fähigkeit von Tumorzellen hin [9]. …”