Study sheds light on how cancer stem cells thrive when oxygen is scarce

Scientists have known for a while that low oxygen can encourage cancer stem cells to multiply within a tumor. But a research team at Johns Hopkins University recently zeroed in on exactly how that happens.

The researchers looked at the similarities between embryonic stem cells and cancer stem cells, ultimately focusing on a specific protein that increases the numbers of cancer stem cells in low-oxygen conditions.

The team's findings, published March 21 in the Proceedings of the National Academy of Sciences, could help clear a major roadblock in cancer treatments, given that cancer cells that thrive in low oxygen are particularly likely to metastasize and resist chemotherapy.

"There are still many questions left to answer, but we now know that oxygen-poor environments, like those often found in advanced human breast cancers, serve as nurseries for the birth of cancer stem cells," says study leader Gregg Semenza, a professor at the Johns Hopkins Institute for Cell Engineering. "While chemotherapy is often successful at killing cancer cells that are located in oxygen-rich parts of the tumor, we need new treatments that will target cancer stem cells located in oxygen-poor tumor environments."

The researchers started by asking whether cancer stem cells behaved similarly to embryonic stem cells. All stem cells are immature cells that can multiply indefinitely as they mature, in the embryo, into specific cell types that populate the body's tissues. Stem cells also replenish tissues throughout the life of an organism. The stem cells found in tumors, however, twist these attributes to maintain and enhance the survival of cancers.

"The search has been intense to find these cells' Achilles' heel," Semenza says. "If we could get cancer stem cells to abandon their stem cell state, they would no longer have the power to keep repopulating tumors."

The team conducted its study using human breast cancer cells and mice.

Graduate student Chuanzhao Zhang narrowed in on a protein called NANOG, which instructs cells to become stem cells. Previous studies of embryonic stem cells have shown that a process called methylation halts production of NANOG protein—in turn, causing the cells to abandon their stem cell state and mature into different cell types.

Applying this knowledge to cancer cells, the researchers found that low-oxygen conditions turned on a specific protein called ALKBH5, which decreased the methylation. When the researchers prevented the cells from making ALKBH5, they saw a decrease in the production of NANOG and a decrease in the number of breast cancer stem cells. Vice versa, when they increased ALKBH5 production, they saw increased numbers of breast cancer stem cells, even under oxygen-rich conditions.

Tests with mice helped the scientists confirm that ALKBH5 was critical to preserve cancer stem cells and their tumor-forming abilities.

"When we prevented human breast cancer cells from making ALKBH5, we reduced their ability to form tumors in mice by more than 50 percent," Semenza says.

Semenza says his team is now studying how the relationship between low oxygen, ALKBH5, and NANOG affects metastasis, the spread of cancer from its original tumor.

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