Tag Archives: cancer tumours

How being squeezed contributes to risk of breast cancer cells

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A recent study conducted by scientists working in Adelaide University and published in the journal Science Advances has shown the reason as to why certain cancers may grow and survive the body, whereas others do not. It happens that the hard mechanical stress to which the early cancer cells undergo as they are squeezed into a narrow area, causes some of the cancer cells to grow quicker, not to grow, as would otherwise be supposed.

This squeeze worked to the favor of the early breast cancer cells as scientists discovered.

The key point that was explained by the lead researcher, Professor Michael Samuel, of the Centre of Cancer Biology at Adelaide University and the Basil Hetzel Institute is that these breast cancer cells steal a particular sensor – one that our bodies rely on to sense touch – and use it to divide quickly and aid them in making their escape off the major tumour.

The process creates an indefinitely lasting mechanical memory in the breast cancer cells and it still contributes towards aggressive behaviour even after the pressure itself has been removed, Professor Samuel said.

The tumours which are solid are exposed to a lot of physical pressure when the disease is at its early stage of development, as the cancer cells grow in tissues that are limited in space, e.g. the milk ducts of the breast. Up to this day, the mechanism by which these cancer cells detect this pressure and whether or not it impacts the progression of the disease is unknown.

We have a tendency to believe that cancer is a genetic disease, but through this work we know that there is the same importance of physical forces within the tumours as the cause of cancer as there are genetic changes that cause cancer.

The researchers discovered that cancer cells respond to pressure via a molecule named PIEZO1, which is a hole in the cell that relates the interior of a cell to the exterior environment. Upon pressure stimulation, PIEZO1 enables the movement of calcium ions into the cell and subsequent signal transduction containing the Rho-ROCK pathway – a central regulator of cell movement, shape and growth.

The team demonstrated that mechanical pressure of a short duration that is obtained through compressing cancer tissue was sufficient to cause tumour growth to increase significantly. Mechanically compressed tumours in laboratory models of breast cancer became larger and the cancer cells in them fragmented faster than control groups.

In addition to promoting growth, compression was also identified to drive cancer cells into a more aggressive, invasive, state in a process known as epithelial-mesenchymal transition. When either of the PIEZO1 or the Rho-ROCK pathway had, however, been inhibited with the help of suitable drugs, compression did not propel cancer aggressiveness, making their role in this process definite.

Co-lead author Dr Sarah Boyle mentioned that one of the most significant findings was that the cancer aggressiveness effects of compression remained even after removal of the force itself.

According to Dr Boyle, even relatively short durations of pressure can lead to a mechanical memory by altering the way the DNA is packed into the cell, by chemically modifying the histone proteins.

These changes, which are called epigenetic changes, are modifications of the interpretation of the DNA code by the cell, which enables the process of switching on some genes that promote tumour growth and aggressiveness.

This type of epigenetic mechanical memory offers a molecular basis to the long term effects of short term mechanical forces on the cell level of the behaviour of tumours.

Notably, the research established that PIEZO1 is over-expressed in human breast cancers compared to normal breast tissue, and that the level of PIEZO1 differs among the patients. The high PIEZO1 levels have been linked to low patient survival implying that the identical pressure-detecting system found in test animals would probably be applicable in human cancer.

The results indicate a little-known role of mechanical pressure in the development of cancer aggressiveness and represent the PIEZO1 -Rho-ROCK pathway as a possible new therapeutic objective that can be used as an early intervention.

According to the researchers, future therapies can restrict tumour growth and invasiveness by interfering with the sensory and response of cancer cells to mechanical pressure. The results can also be applied in diagnosing the patients who are susceptible to aggressive breast cancers due to excessively high concentrations of PIEZO1.

That work has opened up a whole new field of so-called mechanotherapy – the use of treatments that disrupt the mechanical signals that tumours are dependent on to develop and spread out, as cancers grow to be mechanically responsive diseases, said Professor Samuel.

Non-invasive ‘FAST device’ measures the changing size of tumors below the skin

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Engineers at the Georgia Institute of Technology and Stanford University have created a small, autonomous device with a stretchable/flexible sensor that can be adhered to the skin to measure the changing size of tumors below. The non-invasive, battery-operated device is sensitive to one-hundredth of a millimeter (10 micrometers) and can beam results to a smartphone app wirelessly in real-time with the press of a button.

In practical terms, the researchers say, their device—dubbed FAST for “Flexible Autonomous Sensor measuring Tumors”—represents a wholly new, fast, inexpensive, hands-free, and accurate way to test the efficacy of cancer drugs. On a grander scale, it could lead to promising new directions in cancer treatment.

Each year researchers test thousands of potential cancer drugs on mice with subcutaneous tumors. Few make it to human patients, and the process for finding new therapies is slow because technologies for measuring tumor regression from drug treatment take weeks to read out a response. The inherent biological variation of tumors, the shortcomings of existing measuring approaches, and the relatively small sample sizes make drug screenings difficult and labor-intensive.

“FAST” sensor/Photo:Stanford University

“In some cases, the tumors under observation must be measured by hand with calipers,” says Alex Abramson, first author of the study and a recent post-doc in the lab of Zhenan Bao at the Stanford School of Engineering and now an assistant professor at Georgia Tech. The use of metal pincer-like calipers to measure soft tissues is not ideal, and radiological approaches cannot deliver the sort of continuous data needed for real-time assessment. FAST can detect changes in tumor volume on the minute-timescale, while caliper and bioluminescence measurements often require weeks-long observation periods to read out changes in tumor size.

FAST’s sensor is composed of a flexible and stretchable skin-like polymer that includes an embedded layer of gold circuitry. This sensor is connected to a small electronic backpack designed by former post-docs and co-authors Yasser Khan and Naoji Matsuhisa. The device measures the strain on the membrane—how much it stretches or shrinks—and transmits that data to a smartphone. Using the FAST backpack, potential therapies that are linked to tumor size regression can quickly and confidently be excluded as ineffective or fast-tracked for further study.

The researchers say that the new device offers few significant advances.

  1. It provides continuous monitoring, as the sensor is physically connected to the mouse/human patients and remains in place over the entire experimental period.
  2. FAST can detect changes in tumor volume on the minute-timescale, while caliper and bioluminescence measurements often require weeks-long observation periods to read out changes in tumor size.
  3. FAST is both autonomous and non-invasive. It is connected to the skin, not unlike a band-aid, battery operated and connected wirelessly. The mouse/human patients are free to move unencumbered by the device or wires, and scientists do not need to actively handle the mice following sensor placement.
  4. FAST packs are also reusable, cost just $60 or so to assemble and can be attached to the mouse/human patients in minutes.
  5. FAST could significantly expedite, automate and lower the cost of the process of screening cancer therapies.

FAST’s sensor is composed of a flexible and stretchable skin-like polymer that includes an embedded layer of gold circuitry.\/Photo:Alex Abramson, Bao Group, Stanford University

The breakthrough is in FAST’s flexible electronic material. Coated on top of the skin-like polymer is a layer of gold, which, when stretched, develops small cracks that change the electrical conductivity of the material. Stretch the material and number of cracks increases, causing the electronic resistance in the sensor to increase as well. When the material contracts, the cracks come back into contact and conductivity improves.

Both Abramson and co-author Naoji Matsuhisa, an associate professor at the University of Tokyo, characterized how these crack propagation and exponential changes in conductivity can be mathematically equated with changes in dimension and volume.

One hurdle the researchers had to overcome was the concern that the sensor itself might compromise measurements by applying undue pressure to the tumor, effectively squeezing it. To circumvent that risk, they carefully matched the mechanical properties of the flexible material to skin itself to make the sensor as pliant and as supple as real skin.

“It is a deceptively simple design,” Abramson says, “But these inherent advantages should be very interesting to the pharmaceutical and oncological communities. FAST could significantly expedite, automate and lower the cost of the process of screening cancer therapies.”