Tumors with low oxygen levels prompt spread of breast cancer
Researchers now know what can cause breast cancer to spread. Biologists from Johns Hopkins University have discovered that tumors with low levels of oxygen can trigger the spread of breast cancer, according to a new study published in the Proceedings of the National Academy of Sciences.
The researchers found that low oxygen conditions generate increased amounts of proteins called RhoA and ROCK1, which contribute to the spread of breast cancer cells by enabling them to move and spread during the process known as metastasis.
Senior study author, Dr. Gregg Semenza, a professor of medicine at the Johns Hopkins School of Medicine, says that the internal structures of cancer cells have to undergo numerous changes for metastasis to occur – and the proteins RhoA and ROCK1 both play a crucial role in contributing to these structural changes.
For example, the proteins enable the production of protruding extensions in cancer cells. Referred to as "parallel filaments", these extensions reach out and grab onto surrounding tissue, resulting in the spread of cancer cells.
Dr. Semenza explained that many metastatic breast cancers have high levels of RhoA and ROCK1 present in amounts sufficient to activate the process of metastasis in which cancer cells move and spread.
It’s also quite common in breast cancer for tumors to have low oxygen levels, which can cause cancer cells to multiply because the inside of the cells start to run out of oxygen when the blood vessels are no longer feeding them. This, in turn, activates hypoxia-induced factors, or master control proteins, which switches on several genes that assist the cells as they adjust to the decreased levels of oxygen.
Dr. Semenza further explained that when the switch for these hypoxia-induced factors turns the many genes on, it prompts the cancer cells to “break away” from the oxygen depleted tumor, disrupting blood vessels so the cells can migrate and spread to other parts of the body.
Daniel Gilkes of Johns Hopkins University led the study by conducting a series of lab studies in an effort to further explore how these hypoxia-induced factors “bind” to RhoA and ROCK1.
What Gilkes discovered was that breast cancer cells had a dramatic increase in movement when they were exposed to low oxygen levels, as opposed to the breast cancer cells that were exposed to normal oxygen levels.
Indeed, when breast cancer cells were exposed to low oxygen levels, they clearly had a significantly increased number of protruding extensions – and up to three times as many "parallel filaments". In other words, they had a much greater ability to move and spread.
By the same token, when Gilkes decreased the amount of hypoxia-inducible factors, the breast cancer cells likewise showed decreased movement, including a decreased amount of protruding extensions and parallel filaments.
Accordingly, the research team concluded that hypoxia-inducible factors do indeed bind to and activate the RhoA and ROCK1 genes.
Compared with breast cancer patients who had low levels of RhoA and ROCK1 proteins, breast cancer patients with high levels of these proteins were also found to be at a significantly greater risk of death, especially if the patient had high levels of both proteins.
So what does this discovery mean for women with breast cancer in the future?
According to Gilkes, the researchers for this study have successfully decreased the mobility of breast cancer cells in the laboratory by using “genetic tricks to knock the hypoxia-inducible factors down,” and now that they understand the mechanism at play, they are hopeful that clinical studies will be conducted to further validate 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."
SOURCE: Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells, doi: 10.1073/pnas.1321510111, Daniele M. Gilkes, Lisha Xiang, Sun Joo Lee, Pallavi Chaturvedi, Maimon E. Hubbi, Denis Wirtz, Gregg L. Semenza, published in the Proceedings of the National Academy of Sciences, 9 December 2013.