Precancerous stem cells have the potential for both benign and malignant differentiation

Cancer stem cells (CSCs) may be derived from normal stem cells through a precancerous stage, during which stem cells are hierarchically disturbed in their genetic program of self‐renewal by environmental insults. While the CSCs have been identified in hematopoietic and solid cancers, their precancerous precursor stem cells (pCSCs) have not yet been characterized. Here we report that the pCSCs have bi‐potency for benign and malignant differentiation. We have cloned several lines of pCSCs from the spleen of a mouse with dendritic cell‐like lymphoma. Although these cell lines show genomic instability, they retain the stem cell capacity of self‐renewal and multipotency for differentiation in vitro and in vivo. In fact, they differentiated into hematopoietic and somatic cells, like monocyte/macrophages, neutrophils, endothelia, tubular epithelia, adipocytes and hepatocytes in immunocompetent recipients without developing into cancer. However, they also developed into a variety of malignant tumors when injected into immunocompromised mice. Mechanistically, we found that, the self‐renewal of pCSCs appears to be regulated by ectopic expression of mili, a gene normally exclusively expressed in testis germline stem cells. Thus, our results provide an evidence for the first time that various types of cancer can develop from a single clone of pCSCs. We anticipate that the pCSCs can be a useful tool for the identification of genes (e.g. mili) that hierarchically controls tumorigenesis, and they may also serve as target for anti‐cancer drug development and, perhaps, cancer prevention.