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Cancer can affect anyone regardless of age, gender or social status. It causes a tremendous burden for patients, families and societies at large. The EU Cancer Mission has defined clear and ambitious objectives to reverse these trends, using research and innovation to identify better prevention and cures, and thus improve the lives of more than 3 million Europeans affected by cancer.
One of the key challenges is to improve our ability to quantify the malignancy of tumours. Knowing which tumours are likely to develop into life-threating cancers can help clinicians design appropriate treatment plans.
According to Pawel Swietach, a professor of physiology at the University of Oxford, the difference can come down to the tumour’s micro-environment, the complex ecosystem of cells, molecules and blood vessels that surround and support a tumour.
“Whether a tumour results in malignant disease depends on whether this micro-environment offers certain advantages that allow the cancer cells to outcompete normal cells and ultimately evade the body’s immune surveillance system,” he explains. One such factor is a resistance to acidity.
A crucible for cancer
An acidic micro-environment is a fundamental signature of cancer, with pH driven down by a build-up of metabolic waste products released from rapidly dividing cells. Most normal cells do not thrive in acidic conditions, so cancerous cells that are able to resist this harsh environment can power the aggressive growth of tumours.
“The acidic micro-environment was described a century ago as the first chemical feature of tumours, but it was quickly considered a passive end product of cancer activity rather than a meaningful influence that shapes the trajectory of the disease,” says Swietach.
Researchers now believe that understanding the physiology of this acidic resistance could open the door to more effective cancer treatments. “How cancers produce their acidic milieu, how such an environment triggers a specific type of cellular behaviour, and what can be done to derail this malignant trajectory are all questions that have long vexed cancer research,” adds Swietach.
With the support of the Survive project, Swietach and a team of researchers have shed new light on the acid resistance of cancer. Focusing on colorectal and pancreatic cancers, the Survive project developed innovative new ways of understanding cellular responses to acid. These included refined methods to culture cells, new tests to characterise cells, and a more complete model of how cells adapt and thrive in acidic environments.
“Our approach allows us to stratify cells according to their acid sensitivity to gain a better understanding of disease mechanisms, to give more confidence in predicting disease outcomes and to provide direction for improving drug responses,” notes Swietach.
New targets for treatment
The project was able to describe molecular adaptations that enable some cells to become acid-resistant. Researchers identified certain genes that are essential for surviving acidosis – which could potentially be blocked as a means of weakening aggressive cancers.
The project also identified proteins that appear on the surface of acid-resistant cells, and that could be used by cancer-targeting drugs. Last but not least, Survive’s studies provided new insights into how acidity blocks the activity of immune cells, how cells work together to stimulate growth and how acidity interacts with other pathways that are critical for cancer.
According to Swietach, these findings have had a broad impact. “Essentially, all aspects of biology are sensitive to acidity, thus the impact of regulating acidity – whether it is by cancer cells or therapeutically – is substantial,” he explains. Beyond cancer, the project’s work could also benefit other areas of medicine, including heart disease. For instance, its research on how gas is transported in blood can improve the outcome of blood transfusions and transplants.
“We have made the case for making acidity – and how it can be regulated – a key consideration in cancer diagnostic and therapeutic research,” concludes Swietach.
The research team has secured follow-up funding for specific projects on pancreatic and colorectal cancer that will build on the Survive project’s groundbreaking work. The team has also launched the process of commercialising some of its findings, including devices for assessing gas transport by blood, supported by two European Research Council proof of concept grants.