Low Oxygen Environments in Tumors Lead to Dangerous Epigenetic Changes

Researchers have discovered that the low oxygen conditions in a tumor contribute to the spread of cancer. The hypoxic environment changes gene expression, leading to more mutations. The findings may help scientists predict cancer behavior and develop new treatments. The details are in a paper just published in the journal Nature.

Cancer arises when a cell develops mutations and then replicates. The proliferation of these abnormal cells leads to even more mutations and the cancer then spreads. Further uncontrolled growth of cancer cells causes the development of tumors. Very little oxygen can reach the tumor cells, resulting in an oxygen shortage (hypoxia). While the genetic mutations involved in tumor growth have been studied extensively, changes arising from the hypoxic environment are poorly understood.

Researchers from Belgium investigated the effect of a low oxygen environment on tumor cells by studying thousands of preserved tumors. They discovered that the hypoxic conditions were leading to epigenetic changes, alterations that affect gene expression without actually modifying the genetic code. Specifically, the researchers noticed a phenomenon called hypermethylation. Hypermethylation is the addition of methyl groups to DNA, changing the chemistry of the bases that make up genes. The methyl groups interfere with normal cell processes and prevent the expression of tumor suppressing genes, allowing the tumor to continue growing. The enzymes normally responsible for removing methyl groups can’t function in low oxygen environments, explaining the connection between hypoxia and hypermethylation.

To test their theory, the research team increased oxygen levels in mouse tumors. After restoring the oxygen supply to the tumors, hypermethylation stopped. The opposite was also true; decreasing oxygen concentrations led to increased hypermethylation in the tumors. This shows that normalizing the oxygen supply to a tumor can stop certain epigenetic changes, slowing the growth of cancer.

The researchers were able to halt hypermethylation in mouse tumors by restoring oxygen concentrations to normal levels. The authors believe that this information can be used to predict tumor behavior by monitoring the oxygen supply. The team is now testing possible treatments for tumor hypoxia. This would allow doctors to prevent or even reverse epigenetic changes such as hypermethylation.

REFERENCE

Bernard Thienpont et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature (2016).

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