Normalizing Tumour Oxygen Supply Could Be Key Factor in the Fight Against Cancer

A lack of oxygen in tumour cells contributes to the growth of cancer. That is the main conclusion of a study by Professor Diether Lambrechts and Dr Bernard Thienpont (VIB/KU Leuven). Maintaining a proper oxygen supply in tumours could inhibit the excessive growth of the cancer cells. These insights may eventually lead to new anti-cancer drugs.

These are four images of the same cells, each time with a different staining. From left to right: the nuclei of the cancer cells (in blue), the nuclei with a high degree of hydroxymethylation (in red), and the cells with oxygen shortage (in green). Image 4 combines the first three images and shows that hydroxymethylation is lower in the area with oxygen shortage. This, in turn, triggers DNA methylation (hypermethylation), which may be at the basis of the aberrant behaviour of tumour cells.

Cancer onset is generally well-understood: due to chance or carcinogenic factors, a single cell’s DNA mutates, followed by the rapid expansion of the abnormal cell. These genetic mutations disturb normal cell function, but are beneficial for the growth and survival of cancer cells. But apart from these genetic changes, tumour cells also differ in terms of epigenetics, which has to do with how genes are expressed rather than with the genes themselves. Although epigenetic changes don’t affect the genetic code, they can strongly disturb gene function in a similar way, to the benefit of cancer cells. But until now, the origins of these epigenetic changes mostly remained a mystery.

Professor Lambrechts and his lab investigated a common epigenetic alteration: hypermethylation, a process that enables the excessive growth of cancer cells. By analysing 3,000 tumours, the scientists uncovered the link between oxygen shortage and tumour growth. “Our study shows that hypermethylation is caused by oxygen shortage or hypoxia. In fact, oxygen shortage explains up to half of the hypermethylation in tumours. While we dedicated much of our efforts to breast tumours, we also demonstrated that this mechanism has a similarly broad impact in bladder, colorectal, head and neck, kidney, lung and uterine tumours.”

Breathing new life into cancer research

As a next step, the researchers verified another assumption: would interfering with tumour oxygen supply strike a blow against the progression of cancer? They were pleased to see this hypothesis confirmed: using mice, they proved that normalizing the blood supply is sufficient to stop hypermethylation.

The researchers are convinced that their findings can have a potentially huge impact on cancer management. “Monitoring the oxygen supply to a tumour may help us predict tumour behaviour and make more informed treatment decisions,” says Bernard Thienpont. “Our study also sheds new light on existing blood vessel targeting therapies. After all, blood vessels help deliver chemotherapy to the tumour, but they also deliver oxygen. This may help make relapses less aggressive.”

The first ambition is already in full swing: the lab is currently testing whether analysing tumour DNA can be used to predict tumour oxygenation. The scientists are also engaged in new research that focuses on blood vessel normalizing therapies. “We want to know whether it’s not just possible to inhibit, but maybe even to reverse some of these epigenetic aberrations. Following through on these and other new research avenues gives us great faith in the future of cancer research,” concludes prof. Lambrechts.