Arsenic-induced sub-lethal stress reprograms human bronchial epithelial cells to CD61^- cancer stem cells

In the present report, we demonstrate that sub-lethal stress induced by consecutive exposure to 0.25 μM arsenic (As³⁺) for six months can trigger reprogramming of the human bronchial epithelial cell (BEAS-2B) to form cancer stem cells (CSCs) without forced introduction of the stemness transcription factors. These CSCs formed from As³⁺-induced sub-lethal stress featured with an increased expression of the endogenous stemness genes, including Oct4, Sox2, Klf4, Myc, and others that are associated with the pluripotency and self-renewal of the CSCs. Flow cytometry analysis indicated that 90% of the CSC cells are Cd61^-, whereas 100% of the parental cells are CD61⁺. These Cd61^- CSCs are highly tumorigenic and metastatic to the lung in xenotransplantation tests in NOD/SCID Il2rγ^-/- mice. Additional tests also revealed that the Cd61^- CSCs showed a significant decrease in the expression of the genes important for DNA repair and oxidative phosphorylation. To determine the clinical relevance of the above findings, we stratified human lung cancers based on the level of CD61 protein and found that CD61^low cancer correlates with poorer survival of the patients. Such a correlation was also observed in human breast cancer and ovarian cancer. Taken together, our findings suggest that in addition to the traditional approaches of enforced introduction of the exogenous stemness circuit transcription factors, sub-lethal stress induced by consecutive low dose As³⁺ is also able to convert non-stem cells to the CSCs.