Tag Archives: 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.

Boosting physical activity/curbing sitting time likely to lower breast cancer risk:Mendelian randomisation study reveals

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Boosting physical activity levels and curbing sitting time are highly likely to lower breast cancer risk, finds research designed to strengthen proof of causation and published online in the British Journal of Sports Medicine.

The findings were generally consistent across all types and stages of the disease, reveals the Mendelian randomisation study, prompting the researchers to recommend a stronger focus on exercise as a way of warding off breast cancer.

Mendelian randomisation is a technique that uses genetic variants as proxies for a particular risk factor—in this case lifelong physical activity levels/sedentary behaviour—to obtain genetic evidence in support of a causal relationship.

Exercise/Photo:en.wikipedia.org

Observational studies show that physical inactivity and sedentary behaviour are linked to higher breast cancer risk, but proving they cause breast cancer is another matter.

The researchers therefore used Mendelian randomisation to assess whether lifelong physical activity and sitting time might be causally related to breast cancer risk in general, and specifically to different types of tumour.

They included data from 130,957 women of European ancestry: 69, 838 of them had tumours that had spread locally (invasive); 6667 had tumours that hadn’t yet done so (in situ); and a comparison group of 54,452 women who didn’t have breast cancer.

Exercise-Yoga/Photo:en.wikipedia.org

The researchers then drew on previously published studies that had used the vast repository of UK Biobank data on potential genetic explanations for overall predisposition to physical activity, vigorous physical activity, or sitting time—as measured by wrist-worn activity trackers—to genetically predict how physically active or inactive their own study participants were.

Next, the researchers estimated overall breast cancer risk, according to whether the women had or hadn’t gone through the menopause; and by cancer type,stage (size and extent of tumour spread), and grade (degree of tumour cell abnormality).

Analysis of the data showed that a higher overall level of genetically predicted physical activity was associated with a 41% lower risk of invasive breast cancer, and this was largely irrespective of menopausal status, tumour type, stage, or grade.

Similarly, genetically predicted vigorous physical activity on 3 or more days of the week was associated with a 38% lower risk of breast cancer, compared with no self-reported vigorous activity. These findings were consistent across most of the case groups.

cancer cells/photo:en.wikipedia.org

Finally, a greater level of genetically predicted sitting time was associated with a 104% higher risk of triple negative breast cancer. These findings were consistent across hormone-negative tumour types.

The findings were unchanged after factoring in the production by a single gene of two or more apparently unrelated effects (pleiotropy), such as smoking and overweight, for example.

There are plausible biological explanations for their findings, say the researchers, who point to a reasonable body of evidence indicating numerous causal pathways between physical activity and breast cancer risk, such as overweight/obesity, disordered metabolism, sex hormones, and inflammation.

“Mechanisms linking sedentary time and cancer are likely to at least partially overlap with those underpinning the physical activity relationship,” suggest the researchers.

Their findings provide “strong evidence” that more overall physical activity and less sitting time are likely to reduce breast cancer risk, they say.

And they conclude: “Increasing physical activity and reducing sedentary time are already recommended for cancer prevention. Our study adds further evidence that such behavioural changes are likely to lower the incidence of future breast cancer rates.

“A stronger cancer-control focus on physical activity and sedentary time as modifiable cancer risk factors is warranted, given the heavy burden of disease attributed to the most common cancer in women.”

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