Community Research and Development Information Service - CORDIS


CHAMELEON Report Summary

Project ID: 617595
Funded under: FP7-IDEAS-ERC
Country: Belgium

Periodic Report Summary 2 - CHAMELEON (Cellular Hypoxia Alters DNA MEthylation through Loss of Epigenome OxidatioN)

The early causes of cancer are well-known: due to chance or carcinogenic factors, a single cell’s DNA mutates, followed by a rapid expansion of the abnormal cell. These genetic mutations disturb the normal cell function, but are beneficial for the growth and survival of cancer cells. But apart from these genetic changes, tumors cells also differ epigenetically, which has to do with if and how genes are used, rather than the genes themselves. Although such 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 unknown.
We here investigated one frequent epigenetic alteration: hypermethylation, or the excessive addition of methyl groups to DNA. Hypermethylation silences the expression of tumor suppressing genes, thereby enabling aberrant behaviour of cells and the excessive growth of tumors. We show that these epigenetic alterations are caused by the environment of the tumor, more specifically by oxygen shortage – which we call ‘hypoxia’. 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. 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. Uncovering the link between oxygen shortage and tumor growth was the result of the analyses of over 3,000 patient tumors. As a next step, we verified another assumption: would interfering in the tumor oxygen supply affect tumour DNA hypermethylation? Using mice, we proved that normalizing the blood supply is sufficient to stop the epigenetic alterations from occurring.
These understandings can impact cancer management. First of all, we are developing methods to 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, we shed 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 are now testing whether analyzing tumor DNA can be used to predict tumor oxygenation.

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