Work on human breast cancer cells and mice has helped researchers at Johns Hopkins University explain how some cancer stem cells (CSCs) thrive when oxygen supply is limited. CSCs are a major source for chemotherapy resistance and tumors spreading, and this research highlights a potential pathway that may be blocked to prevent their proliferation.
Gregg Semenza and his team published their work in the Proceedings of the National Academy of Sciences earlier this month.
They found that an environment low in oxygen initiates the growth of both embryonic stem cells and breast cancer stem cells. So even when chemotherapy kills more than 99% of cancer cells, the remaining cancer stem cells can resist their harsh environment, proliferate and initiate cancer relapse.
"Aggressive cancers contain regions where the cancer cells are starved for oxygen and die off, yet patients with these tumors generally have the worst outcome," Semenza said in a release. "Our new findings tell us that low oxygen conditions actually encourage certain cancer stem cells to multiply through the same mechanism used by embryonic stem cells."
One of the genes responsible for initiating a stem cell fate under low oxygen conditions is called NANOG. This gene is one of many turned on in oxygen-poor conditions by proteins called hypoxia-inducible factors, or HIFs. NANOG in turn instructs cells to become stem cells to resist the poor conditions and help survival.
NANOG levels can be artificially lowered in embryonic stem cells by experimentally methylating the respective mRNA transcript at the sixth position of its adenine nucleotide. Since this methylation is otherwise thought to stabilize the transcript from degradation, this may help NANOG abandon its proposed stem cell fate for the cell.
When the researchers added ALKBH5--a protein that removes methyl groups from mRNAs--to two breast cancer cell lines, they found there was a decrease in NANOG levels, and the number of cancer stem cells, in cells exposed to low oxygen.
They did further experiments showing that in mice injected with triple negative breast cancer cells with and without the ALKBH5 gene, those receiving the ALKBH5-null cancer cells had less tumor formation, demonstrating ALKBH5 helps to preserve cancer stem cell function and only poses a threat when conditions are unfavorable--such as low oxygen perfusion.
They will next see whether metastasis of the cancer is affected in the same mice injected with the ALKBH5-null cancer cells when the oxygen levels are reduced. And they will explore whether other proteins and mRNAs are involved in the low oxygen/ALKBH5/NANOG relationship trio.