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The video shows how tumor cells composed of breast cancer cells separate faster and move more at high viscosity (8 cP) than at low viscosity (0.
7 cP).
The human body is made up of more than 1 billion cells that combine to form the tissues and organs
of our body.
However, cells are dynamic structures that, through different technologies, move through the body to fulfill various functions, such as healing wounds or transporting nutrients to other tissues
.
Understanding how cancer cells move and make decisions in these restricted environments is important because 90% of cancer-related deaths are related to
metastasis.
Konstantinos Konstantopoulos and Miguel A.
Valverde have spent the past 6 years studying how cancer cells use ion movement to adapt to different mechanical stresses and environments by mechanically activating ion channels (stimulating membrane deformation
).
The results of the study were published in
the journal Nature and Nature Communications.
In the two new studies, the scientists ask questions:
1) how cancer cells polarize the ion transport mechanisms at the front and trail edges of cells in order to move in a narrow space;
2) How cancer cells optimize movement
when the viscosity of the liquid is high.
To address these important questions, they studied the movement of cells in a three-dimensional medium generated by bioengineering techniques, similar
to the path that cells normally move in our bodies.
They used high-resolution microscopy to locate key proteins within cells, record cell volume, ion motility, and electrical activity, and assess how the expression of different genes important for cancer progression changed
.
In the first study, published in Nature Communications, the international team found that cancer cells can move
through confined spaces by absorbing water at the front edge of the cell and releasing it at the posterior edge of the cell.
They do not require molecular interactions
with surrounding tissue walls.
Dr Valverde explains: "It works like a hydraulic propeller, similar to the device
that Tom Clancy fictionalized in the novel Hunting Red October to drive a submarine.
"
"By simply transferring water from the front edge of the cell to the back edge, cancer cells can move in a limited space"
In real life, this is possible because at their leading edge, cells accumulate an ion transport system, the sodium/proton exchanger (NHE1), which recharges the cells with sodium, increasing osmotic pressure in favor of water entering the cell
.
At the same time, cancer cells concentrate the SWELL1 protein at the posterior edge
.
SWELL1 (also known as LRRC8A) is a chloride channel that activates when cell water content increases, facilitating chloride and water excretion
.
The end result of the synergy of these two ion transport systems at the leading and trailing edges makes cell movement possible
.
What's more, the study shows that the activity of these two systems is essential
for the development of cancer cell movement and metastasis outside blood vessels.
In a second study, published in the journal Nature, scientists question how changes in the viscosity of the cell's
environment affect the movement and behavior of cancer cells.
Viscosity measures the resistance
exerted by a fluid to any object that enters or moves with the fluid.
Therefore, common sense and basic engineering show that inert particles move more slowly
in highly viscous media.
Scientists have now demonstrated an effect that seems inherently counterintuitive: high viscosity promotes tumor cell migration, invasion, extravasation (outflow from blood vessels) and lung colonization
.
"Unlike inert particles, cells exposed to high viscosity move faster"
"The cells of our body are constantly exposed to liquids of different viscosities," Valverde
continues.
"In certain pathological situations, such as tumor growth, the local viscosity around the initial tumor increases
due to abnormal protein degradation or compression of normal drainage channels (lymphatic vessels).
In addition, as the cancer spreads to other parts of the body, cells must travel through spaces filled with interstitial fluid and blood, which is more viscous than water
.
”
In previous research, Valverde's team demonstrated that cells adapt to a high-viscosity environment
by activating a protein called TRPV4.
TRPV4 is an ion channel that promotes calcium entry into cells that would otherwise be impossible because lipid membranes divide cells and ions are impermeable
.
Calcium is an element that, when increased within cells, controls various cellular functions
.
Given this background, the international team of scientists hypothesized that cancer cells exposed to high viscosity might use a similar mechanism to enhance their motility and spread
.
And they're right.
.
.
This brings a fun surprise!!
By exposing cancer cells to a high-viscosity environment, they observed that the first cellular element to respond to this stimulus was the protein actin, which is part of the cytoskeleton that shapes the cell's body
.
This sets off a cascade of molecular events that eventually ends with the activation of the TRPV4 channel, which in turn activates a cascade of intracellular events leading to the enhancement of the cytoskeleton and activation
of motilin proteins.
Interestingly, with all these changes, cells change the way they migrate and no longer use the movement of
water.
In this case, they use the "skeleton and muscles" of the cells, as well as their interactions with the surrounding walls, to propel themselves faster
.
In the words of UPF's Dr.
Seruma Serra, "It's as if the cells are training hard in the gym under a highly viscous load, and they perform better
when they are physically challenged on their way from the primary tumor to their final destination in distant metastases.
" ”
The study's authors also found that cells moved faster not only when surrounded by a high-viscosity liquid, but also when they were removed after being exposed to that liquid before
.
In other words, cells can not only detect and react to increased viscosity, but also form memories
of their exposure to the situation.
"Cells develop mechanobiological memory and enhance the spread of cancer"
How important is this finding?The vast majority of
cell biology research is performed in cell culture media with a viscosity close to water.
Researcher Dr.
Konstantopoulos explains: "In our work, we determined for the first time how cells detect and respond to viscosity levels
of physiologically relevant fluids common in healthy and patient bodies.
The definition of the molecular mechanisms that cells use to adapt to changes in the viscosity of the medium is a stunt that we must change our preconceived notions about which cellular elements respond
to this mechanical stimulus first.
”
The tremendous coordination between the structural elements of cells—their actin and myoctinin cytoskeletons—and the mechanisms that regulate cell volume ion and water marks a major breakthrough
in our understanding of cellular mechanistic biology.
Dr.
Valverde explained this major breakthrough, demonstrating the ability of cancer cells to form memories of pre-exposure/pre-adaptation in a high-viscosity environment, and emphasized the importance of
teamwork.
"Our paper is also a great example of the need for multidisciplinary collaboration—bioengineers, geneticists, theoretical biophysicists, cell biologists, and physiologists—each with a different but complementary approach that allows us to seek answers to complex questions," he concludes
.
It will be useful to study how primary tumors and cancer cells that have spread from primary tumors respond to local changes in the viscosity of extracellular fluid in vivo during disease progression and invasion of the tissue microenvironment
.
Developing and optimizing biosensors to enable real-time measurement of extracellular fluid viscosity and imaging of cancer cells in live animals will be key
to solving this problem.
"At this stage, we cannot propose a specific molecular intervention to combat cancer metastasis, but we believe that the molecules and pathways we found in our study can be used as pharmacological targets for possible cancer treatments," Valverde explained
.
Extracellular fluid viscosity enhances cell migration and cancer dissemination
