Mechanisms of Aquaporin-Facilitated Cancer Invasion and Metastasis

Abstract

Cancer is a leading cause of death worldwide, and its incidence is rising with numbers expected to increase 70% in the next two decades. The fact that current mainline treatments for cancer patients are accompanied by debilitating side effects prompts a growing demand for new therapies that not only inhibit growth and proliferation of cancer cells, but also control invasion and metastasis. One class of targets gaining international attention is the aquaporins, a family of membrane-spanning water channels with diverse physiological functions and extensive tissue-specific distributions in humans. Aquaporins-1,-2,-3,-4,-5,-8, and-9 have been linked to roles in cancer invasion, and metastasis, but their mechanisms of action remain to be fully defined. Aquaporins are implicated in the metastatic cascade in processes of angiogenesis, cellular dissociation, migration, and invasion. Cancer invasion and metastasis are proposed to be potentiated by aquaporins in boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with actin cytoskeleton, regulating proteases and extracellular-matrix degrading molecules, contributing to the regulation of epithelial-mesenchymal transitions, and interacting with signaling pathways enabling motility and invasion. Pharmacological modulators of aquaporin channels are being identified and tested for therapeutic potential, including compounds derived from loop diuretics, metal-containing organic compounds, plant natural products, and other small molecules. Further studies on aquaporin-dependent functions in cancer metastasis are needed to define the differential contributions of different classes of aquaporin channels to regulation of fluid balance, cell volume, small solute transport, signal transduction, their possible relevance as rate limiting steps, and potential values as therapeutic targets for invasion and metastasis.

Keywords: aquaporin; cancer; cell migration; drug; invasion; metastasis; pharmacology.

Figure 1

Flow diagram summarizing the steps in cancer metastasis. Metastasis involves the migration of cells from the primary tumor to distant organs. Large tumors with tissue hypoxia rely on angiogenesis for vascular exchange of nutrients and waste. Primary tumor cells undergo phenotypic changes including loss of cell-cell adhesions which enables cells to dissociate from primary tumor, invade the adjacent extracellular matrix (ECM), and intravasate into the blood or lymph systems. Circulating tumor cells extravasate to seed secondary sites at which the process can reoccur.

Figure 2

Key contributions of aquaporins in cell migration. (A) Forward movement is preceded by establishing specialized loci within the cell, with redistribution of aquaporins, ion transporters/exchangers, and actin polymerization machinery to the leading edge. AQP-1,−4,−5, or−9 can be found on leading edges of migrating cancer cells. (B) Protrusions of the membrane might use water influx (down an osmotic gradient established by ion transporters/exchangers) and actin polymerization beneath the plasma membrane to dynamically push the membrane forward. AQP-1,−4, and−5 are implicated in water influx for protrusion extension in cancer cells; AQPs-1 and−4 also appear to interact with actin cytoskeleton. (C) Protrusions adhere to the ECM using integrin to generate “traction” for cellular movement. AQP2 might modulate turnover of integrin at adhesion sites, enabling forward cellular movement. (D) ECM degradation by enzymes can widen gaps through which the cell body can penetrate. AQP-1,−3,−4 and−9 are suggested to interact with ECM-degrading enzymes. (E) The final step is retraction of the cell trailing edge, thought to use aquaporins for water efflux following by K⁺ export.