Yibin Kang, Warner-Lambert/Parke-Davis Professor of Molecular Biology, and colleagues at the Department of Molecular Biology at Princeton University have identified a microRNA molecule that protects breast cancer stem cells from the immune system.
Stem cells have the ability to renew themselves and differentiate into the different cell types present in the body. That process continues through adulthood and allows the body to renew tissues during adult life.
Cancer stem cells have also been found that have the ability to differentiate into all cancer cells found in a sample and generate tumors through stem cell processes. It is these cancer cells that are believed to be involved in relapses and metastasis. Some cancers contain high numbers of these cancer stem cells, such as triple negative breast cancers – those that lack estrogen, progesterone and HER2 receptors.
The researchers looked at non-cancerous mammary gland stem cells (MaSCs) and tried to identify factors that allowed them to resist differentiation and retain the ability to self-renew. The researchers were specifically looking at microRNA molecules. These molecules can inhibit messenger RNA molecules, thereby reducing the levels of specific proteins.
The team identified a microRNA named miR-199a that suppresses a protein called LCOR. LCOR regulates gene expression by binding to DNA. The team found that this microRNA molecule helped cancer stem cells retain their stem cell activity.
Increasing levels of miR-199a in mice MaSCs resulted in suppression of LCOR production and increased stem cell function. By increasing levels of LCOR, stem cell activity was reduced. The team also found that increasing miR-199a levels enhanced the ability of cancer stem cells to form tumors and vice versa with increased levels of LCOR. The researchers also found that human patients with tumors that expressed high levels of miR-199a had poor survival rates, while those with tumors with high levels of LCOR fared better.
The researchers discovered that during normal development, epithelial cells and macrophages release interferon-signaling molecules to promote differentiation and inhibit cell division. LCOR sensitizes cells to those interferon-signaling molecules. miR-199a therefore protects MaSCs from interferon signaling allowing them to remain undifferentiated and capable of self-renewal. The researchers found the microRNA molecules protect breast cancer stem cells from the effects of interferons secreted by immune cells in tumors during tumorigenesis.
First author of the study, Toni Celià-Terrassa, said “This study unveils a new property of breast cancer stem cells that give them advantages in their interactions with the immune system, and therefore it represents an excellent opportunity to exploit for improving immunotherapy of cancer.”
Interferons have been used in the treatment of certain types of cancers. Kang said, “[Interferon] treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway.”
The study will be published in the journal Nature Cell Biology next month.