A cell inside a tumor is a suffocating cell, but it doesn’t react by gasping and writhing. It alters its gene expression. The oxygen-deprived cells suffer an excess of DNA methylation, which silences the expression of tumor-suppressing genes, thereby enabling aberrant cellular behavior and enhancing tumor growth.

This finding appeared August 17 in the journal Nature, in an article entitled, “Tumour Hypoxia Causes DNA Hypermethylation by Reducing TET Activity.” The article, which was contributed by scientists based at VIB (the Flanders Institute for Biotechnology)-KU Leuven, suggests that maintaining a proper oxygen supply within tumors could inhibit epigenetic aberrations that favor tumor growth. For example, new drugs could be developed that target blood vessels and enhance circulation. Alternatively, drugs could target the epigenetic aberrations directly.

“The activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells,” wrote the article’s authors. “TET enzymes catalyse DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor activity or reactive oxygen species, and depends directly on oxygen shortage.”

Uncovering the link between oxygen shortage and tumor growth was the result of the analysis of over 3000 patient tumors. As a next step, the researchers verified another assumption: Would interfering with tumor 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 the epigenetic alterations from occurring.

“Our data suggest that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage,” detailed the authors. “Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect.”

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.

“Our study shows that these epigenetic alterations are caused by the environment of the tumor, and more specifically by oxygen shortage, which we call ‘hypoxia,’” said the VIB’s Diether Lambrechts, who was a co-senior author of the current study “Oxygen is required by the enzymes that normally remove the methyl groups from the DNA. When there is oxygen shortage, too much methylation is retained, causing hypermethylation. Even more, hypoxia explains up to half of the hypermethylation in tumors. While we dedicated much of our efforts to breast tumors, we also demonstrated that this mechanism has a similarly broad impact in bladder, colorectal, head and neck, kidney, lung, and uterine tumors.”

The VIB lab is now testing whether analyzing tumor DNA can be used to predict tumor oxygenation. It is also engaged in new research that focuses on blood vessel–normalizing therapies.

“Our new insights can have a potentially huge impact on cancer management,” explained the VIB’s Bernard Thienpont, the other co-senior author of the current study. “First of all, we could use epigenetic aberrations to monitor the oxygen supply to a tumor, allowing us to better predict tumor behavior and make more informed treatment decisions. Secondly, it sheds new light on existing blood vessel targeting therapies. They don't only help deliver chemotherapy to the tumor, but also inhibit new epigenetic aberrations. This could in turn help make relapses less aggressive, and thus prove to be therapeutically beneficial.”

“We want to know whether it's not just possible to inhibit, but maybe even to reverse some of these epigenetic aberrations,” added Lambrechts. “Following through on these and other new research avenues gives us great faith in the future of cancer research.”

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