Study Offers New Insights Into How Cancer Metastasis Occurs

New research suggests that higher viscosity of the extracellular fluid enables cancer cells to migrate more rapidly from a primary tumor to other sites in the body. These findings could ultimately help to combat cancer metastasis.

The study, published in the peer-reviewed journal Nature, looked at how high viscosity, or resistance to flow, of extracellular fluid affects the dissemination of cancer cells in animal models. Extracellular fluid is a body fluid outside the cells. It is found in blood, lymph, brain, spinal cord channels, and other tissues.

“We clarified how cells sense and respond to physiologically relevant levels of fluid viscosity that are commonly found in the body of healthy and diseased patients,” says Konstantinos Konstantopoulos, Ph.D., lead investigator of the study, the William H. Schwarz Professor of Chemical and Biomolecular Engineering with appointments in Biomedical Engineering and Oncology, and member of the Johns Hopkins Kimmel Cancer Center Invasion and Metastasis Program.

“We also showed that cells have the ability to form memory when preexposed to elevated fluid viscosities. We believe these findings will compel researchers in other fields, beyond cancer mechanobiology, to consider fluid viscosity as a key physical cue that regulates cell responses.”

Authors of the study note that although deregulated viscosity of bodily fluids has been linked to many diseases for decades, studies on cancer cell dissemination to date were primarily performed using fluids of low viscosity.

“The expectation was that since there is more resistance in more viscous fluids, cancer cells wouldn’t move or metastasize efficiently, but we showed that the opposite is true,” says Kaustav Bera, Ph.D., a recent graduate from the Konstantopoulos lab and first author of the study.

The researchers found that a higher resistance environment drives the formation of a denser actin — an intracellular protein — network, which promotes local enrichment of ion transporters that cooperate with water channels to facilitate water uptake, promote cell swelling, and increase membrane tension.

At the cell’s leading edge, this increased membrane tension activates a signaling pathway, which includes an ion channel called TRPV4 that senses physical cues. Fluid viscosity instructs the cell to open its TRPV4 channels, facilitating the intake of calcium, which enhances the force-generating capacity of cells and ultimately drives faster cell movement.

When the researchers knocked down TRPV4, they blocked the faster movement of cells and their ability to form memory in response to preexposure to elevated viscosities.

Application to a targeted therapy

Milda Alksnė, PhD, a junior researcher at Vilnius University Life Sciences Center, who is not involved in the study, says that TRPV4 is a marker that could be possibly blocked in cancer cells.

“In a targeted therapy, researchers are looking for markers, blocking of which would stop cancer spreading in various ways. For example, if a specific protein which is responsible for a new blood vessel formation is blocked, the newly dividing cancer cells will die because they do not receive the necessary amount of nutrients,” she explains.

If TRPV4 was blocked, cells would not be able to sense the changes in the viscosity of fluid; therefore, they would not be able to sense the changes in the environment and learn how to migrate and metastasize, Alksnė explains.

According to the researcher, certain diseases may cause changes in the viscosity of the extracellular fluid.

“Cancer often spreads to lymph nodes and causes them to decrease significantly. When the function of lymph nodes is deregulated, the viscosity of the extracellular fluid begins increasing,” she said.

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