Abstract
Elevated extracellular fluid viscosity increases cell motility and dissemination in 2D, 3D, and in vivo tumor models.
Major Finding: Elevated extracellular fluid viscosity increases cell motility and dissemination in 2D, 3D, and in vivo tumor models.
Concept: Increased viscosity induces NHE1-mediated cell swelling, which triggers TRPV4-mediated calcium influx leading to increased RHOA-induced cell contractility.
Impact: These results identify viscosity as a novel physical cue and propose a mechanism that induces metastasis, which provides potential targets for its mitigation.
Cell migration can be controlled by mechanical forces that arise from cell-substrate interactions and the surrounding fluid, with extracellular fluid viscosity typically being increased in the presence of tumors. However, the impact of increased viscosity on cancer cells themselves, including their ability to sense and respond to these changes, is not yet known. Bera and colleagues investigated the effects of altered extracellular fluid viscosity on cancer cells and showed that an increase in extracellular fluid viscosity enhances cell motility on 2D surfaces as well as cell dissemination from 3D tumor spheroids. This elevated viscosity induced a switch from the amoeboid/blebbing phenotype to the protrusive/mesenchymal phenotype, with a denser and more highly branched actin structure being observed at the front or growing cell edge, which is mediated by ARP2/3. Moreover, elevated fluid viscosity increased Na+/H+ exchanger 1 (NHE1) polarization at the cell leading edge through ARP2/3-mediated enrichment of the actin-binding protein ezrin, which anchors NHE1 to the cell membrane. NHE1 mediates cell swelling, which in turn, leads to increased membrane tension, and transient receptor potential cation vanilloid 4 (TRPV4)–mediated calcium influx, ultimately increasing RHOA-dependent cell contractility. Together, this pathway facilitates the observed enhancement of cell motility. Additionally, cells were shown to be able to imprint memory of extracellular viscosity via TRPV4. The TRPV4-dependent mechanical memory of preexposed cells was mediated through transcriptional control of the Hippo pathway. Faster cell migration was also observed in zebrafish and with breast cancer cells preconditioned at elevated viscosity. Preconditioned cells also exhibited enhanced extravasation and tissue colonization in chick embryo and mouse tail-vein injection models. In summary, this study shows that extracellular fluid viscosity enhances 2D and 3D cancer cell motility and dissemination and elucidates the underlying mechanism of this phenomenon, providing a potentially targetable pathway to mitigate cancer metastasis.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
RSS Feeds