Cancer cells "carry weight", Nature research shows that the higher the extracellular viscosity, the faster the tumor spreads

In the manga "Dragon Ball", Goku often uses the "weight training method" to quickly improve his combat effectiveness, from the beginning of the weight bearing on clothes, to the later gravity training ground, so that the body can get used to the intense movements under high weight, and then quickly enhance his combat ability
.

Interestingly, a team of researchers at Johns Hopkins University in the United States showed that weight-bearing training "is equally effective
against cancer cells at the microscopic level.
" The researchers found that the higher the viscosity of the extracellular fluid around the cells and the greater the resistance to flow, the faster
cancer cells undergoing weight-training metastasized from the primary tumor to other parts of the body.

The study was published in Nature on November 2, 2022, in a paper titled: Extracellular fluid viscosity enhances cell migration and cancer dissemination
.

Metastasis and spread are an important manifestation of many advanced cancers, and they are also the most difficult to
cure.
At that time, the patient's cancer cells will have a reduced or even complete loss of attachment ability, and the enhancement of migration ability will cause cancer cells to metastasize from their native site to other body parts with the blood or lymphatic system, and eventually form new tumor lesions
.

Previous studies have shown that on two-dimensional (2D) surfaces, supraphysiological viscosity (≥40 cP) increases the viability
of cancer cells and normal cells.
This is quite counterintuitive, because the higher the viscosity, the slower
the movement of particles in the fluid.
Therefore, this phenomenon also prompted the research team to explore the link between extracellular viscosity and the
spread of cancer metastasis.

Notably, extracellular viscosity increases
with degradation of large proteins secreted by normal and cancer cells and obstruction of lymphatic drainage due to primary tumor growth.
In this latest study, the researchers found that a higher resistance environment drives the formation of a denser actin network, promoting local enrichment of ion transporters, which work with water channels to promote water absorption, which in turn promotes cell expansion and increases membrane tension
.

High extracellular viscosity enhances cell migration

This increase in membrane tension activates a signaling pathway that includes an ion channel called TRPV4, which senses physical signals
.
Liquid viscosity instructs cells to turn on TRPV4 channels and promote calcium intake, thereby enhancing the cell's ability to exert force, ultimately pushing cells to move
faster.

To use a vivid metaphor, this is like cells with high viscosity going to the gym for hard training to produce stronger muscles (actin and myosin), which improves the motility of tumor cells and enhances the speed of
their metastasis and spread.

High extracellular viscosity promotes cell expansion, thereby activating TRPV4, resulting in calcium influx

Previous ideas have suggested that mechanical induction cascades begin with ion channels like TRPV4
.
But now, the research team has found that the perception of extracellular viscosity begins with the formation of a denser and highly branched actin, and that activation of TRPV4 is actually downstream
of actin.
In addition, the researchers found that knocking out TPRV4 blocked the rapid movement of cells, as well as the cells' ability to form memories when pre-exposed to
high-viscosity environments.

Pattern diagram of extracellular viscosity sensing pathway

The research team used a 3-day-old zebrafish embryo model to demonstrate that high-viscosity training leaves "memories" that allow cells to move
faster through living blood vessels.
Not only that, but they also used chicken embryos and mouse models to show that this memory can be enhanced by a process called extravasation, which enhances the spread of cancer cells outside blood vessels and leads to more distant metastases
.

Cells trained with high extracellular viscosity form "memories" that exhibit enhanced migration, extravasation, and lung colonization

Taken together, this Nature study sheds light on how cells sense and respond to highly viscous extracellular fluid and demonstrates that extracellular viscosity is a key physiological feature that has an important impact
on the spread and migration of cancer cells.

These findings will force researchers in fields other than cancer mechanistic biology to consider fluid viscosity as a key physical cue
for regulating cellular responses.
In this regard, the development and optimization of biosensors to enable real-time measurement of extracellular fluid viscosity and imaging live cancer cells will be the key
to solving this problem.
The research team also plans to investigate whether extracellular viscosity affects other physiologically relevant cellular processes
.

Paper link: