Low-oxygen conditions help breast cancer cells spread

Scientists have discovered that low oxygen conditions, which often persist inside tumours, initiate a molecular chain of events that give breast cancer cells their ability to move.
The study by the Johns Hopkins University underlines the importance of hypoxia-inducible factors in promoting breast cancer metastasis.
"High levels of RhoA and ROCK1 were known to worsen outcomes for breast cancer patients by endowing cancer cells with the ability to move, but the trigger for their production was a mystery," said Gregg Semenza, the C Michael Armstrong Professor of Medicine at the Johns Hopkins University School of Medicine and senior author of the study.

"We now know that the production of these proteins increases dramatically when breast cancer cells are exposed to low oxygen conditions," Semenza said.
To move, cancer cells must make many changes to their internal structures, Semenza said. Thin, parallel filaments form throughout the cells, allowing them to contract and cellular "hands" arise, allowing cells to "grab" external surfaces to pull themselves along.
The proteins RhoA and ROCK1 are known to be central to the formation of these structures.

Moreover, the genes that code for RhoA and ROCK1 were known to be turned on at high levels in human cells from metastatic breast cancers. In a few cases, those increased levels could be traced back to a genetic error in a protein that controls them, but not in most.

This activity, said Semenza, led him and his team to search for another cause for their high levels.
The study found that low oxygen conditions, which are frequently present in breast cancers, serve as the trigger to increase the production of RhoA and ROCK1 through the action of hypoxia-inducible factors.
"As tumour cells multiply, the interior of the tumour begins to run out of oxygen because it isn't being fed by blood vessels," said Semenza.
"The lack of oxygen activates the hypoxia-inducible factors, which are master control proteins that switch on many genes that help cells adapt to the scarcity of oxygen," he said.

He explained that, while these responses are essential for life, hypoxia-inducible factors also turn on genes that help cancer cells escape from the oxygen-starved tumour by invading blood vessels, through which they spread to other parts of the body.
Researchers were also able to successfully decrease the mobility of breast cancer cells in the lab by using genetic tricks to knock the hypoxia-inducible factors down.
"Now that we understand the mechanism at play, we hope that clinical trials will be performed to test whether drugs that inhibit hypoxia-inducible factors will have the double effect of blocking production of RhoA and ROCK1 and preventing metastases in women with breast cancer," said Daniele Gilkes, lead author of the report.

The study was published in Proceedings of the National Academy of Sciences.