Oxygen-Scarce Environments Provoke Growth of Breast Cancer Stem Cells

An investigation performed at John Hopkins University depicts new data on how low-oxygen conditions stimulate breast cancer stem cell progression. The study lead by Gregg Semenza was published in the Proceedings of the National Academy of Sciences. It’s known that poor oxygen environments affect cancer growth, however its vice-versa in case of advanced tumors.

In aggressive cancer, the tumor cells flourish more in low-oxygen state, resist chemotherapy; and cause metastasis, relapse and eventual death. Working on breast cancer cell lines and mice, Semenza observed that breast cancer stem cells proliferate through the same biochemical mechanism as embryonic stem cells. During embryogenesis, healthy stem cells (immature cells) multiply and develop into mature specific cell types. Chemotherapy wipes out 99% of cancer cells missing about 1% cancer stem cells. These cancer stem cells mimic the same mechanism to preserve cancer progression. It is thus crucial to identify such cells and abandon their stem cell state.

According to recent studies, of the 21% oxygen we breathe, 9% resides in healthy human breast tissue while only 1.4% in breast tumors. Low-oxygen conditions trigger production of a family of proteins–HIFs (hypoxia-inducible factors) which turn on various genes including NANOG that instructs cells to become stem cells. In embryonic stem cells, NANOG protein synthesis may be dropped by methylating NANOG’s mRNA and thereby aborting their stem cell state.

In the present study, exposure of human breast cancer cell lines to low-oxygen state induced production of protein ALKBH5 (which removed methyl groups from NANOG mRNAs) and subsequent cancer stem cell proliferation. Even in zero NANOG levels, low-oxygen state prompted HIFs production which turned on genes for NANOG and ALKBH5. Genetic manipulation of cells to spur ALKBH5 levels without low-oxygen exposure also showed similar results, whereas averting ALKBH5 synthesis lowered NANOG levels and number of cancer stem cells.

Experimentation on live mice also produced similar findings concluding that ALKBH5 protein retains cancer stem cells and their tumor-forming skills.