Bowel cancers can grow very quickly into large tumour masses, eventually becoming invasive and deadly. This expansion is powered by metabolism, a biological process that produces major changes in the chemical environment of cancer cells. The harsh conditions brewing inside a tumour are typically toxic to normal cells, which is a factor stopping their excessive growth. Somehow cancer cells find a way to thrive in these conditions and out-compete normal cells. Bowel Research UK (BRUK)-funded researchers in Oxford are working out how this happens. Understanding the mechanisms by which cancer cells adapt to harsh conditions can unravel vulnerabilities to target with new drugs.
Among the key features of the tumour chemical environment, two stand out because of their powerful effect on cell survival: the depletion of oxygen (hypoxia) and build-up of acid (acidosis). Hypoxia arises when cancer cells use up oxygen faster than its delivery from the blood. Similarly, acidosis arises when cancer cells produce acids faster than their removal with blood. Oxygen is essential for respiration, a process that is critical for harnessing energy. Acids, on the other hand, are the end-products of metabolism and often considered to be wastes. The 2019 Nobel Prize in Physiology or Medicine was awarded to scientists who discovered how cells respond to hypoxia. Today, knowledge of this mechanism is exploited in the treatment and diagnosis of cancers. However, one missing piece of the puzzle concerned the response to hypoxia when conditions are also acidic. Such an interaction is highly relevant to tumours where the combination of acidosis and hypoxia is typically present. BRUK-funded research has helped in understanding this interaction.
Findings published in the Journal of Cell Biology describe how acidic conditions reduce the cellular response to hypoxia in colorectal cancer cells by making hypoxic responses more transient. This is a significant observation because it means that at least some adaptive responses to hypoxia may not become fully engaged in bowel cancers. It also means that treatments and tests that exploit responses to hypoxia may not be as effective as we would hope. Encouragingly, the study shows how interrupting the interaction could make cancer cells even more vulnerable. It also identifies new molecules that can inform us about the conditions experienced by tumours, which is helpful in guiding better treatments. In light of this publication, future studies must consider hypoxia and acidosis concurrently. For example, it is critical to carefully replicate the conditions found in tumours when designing scientific experiments.
Pawel Swietach, the lead researcher at the University of Oxford, said: “Malignant growths emerge when cancer cells find ways of overcoming checks and controls on growth. A strong cue for acquiring aggressive properties is provided by the chemical environment in which cancer cells grow. We think that a good way of derailing malignant growth is by disabling the mechanisms that facilitate growth under harsh conditions. Our recent findings provide new insights into how this could be achieved. We are particularly excited about the prospects of specifically targeting adapted cancer cells while sparing healthy tissue. This could make cancer treatment more effective with fewer side effects.”