Based on cells’ ability to respond to physical stimuli, a team of researchers hypothesized that extracellular fluid viscosity (which varies under physiological and pathological conditions, such as cancer) may be a cue that cells respond to. However, the mechanism by which cells sense and respond to changes in viscosity, and the impact that may have on cancer biology, have remained unknown.
In a new study, the researchers uncovered that cancer cells move faster when they are surrounded by thicker fluids, a change that occurs when lymph drainage is compromised by a primary tumor. Revealing this new mechanism, which enables cancer cells to move throughout the body, provides a potential new target to stop metastasis.
The work is published in Nature, in the paper, “Extracellular fluid viscosity enhances cell migration and cancer dissemination.”
“This is really the first time that the viscosity of the extracellular fluid has been looked at in detail,” said John Lewis, PhD, professor and chair in prostate cancer research at the University of Alberta’s Faculty of Medicine and Dentistry. “Now that we know that fluid viscosity signals cancer cells to move in a specific way, we can potentially use drugs to basically short-circuit that signaling pathway and encourage cancer cells to slow down, or even maybe to stop.”
The findings show that elevated viscosity “counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumor spheroids.”
“Our contribution to the work was to very precisely show that cancer cells change their gene expression when they encounter increased viscosity in the surrounding fluid and become more aggressive,” noted Lewis. “And even when you bring the viscosity back down, these cells stay more aggressive.”
“We then went on to show that when this signaling pathway is perturbed in cancer cells it changes their ability to escape the bloodstream and metastasize,” Lewis said.
More specifically, the researchers showed that increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network. This, in turn, enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin.
NHE1, the authors wrote, “promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility.” It is this coordinated action that facilitates enhanced motility at higher viscosities.
Despite the excitement of the findings, Lewis cautions that once a new therapeutic target is identified, it could take 10 to 15 years to develop and test a drug.