Cancer stem cells (CSCs) are believed to be a promising target for
cancer therapy because these cells are responsible for
tumor development, maintenance and
chemotherapy resistance. Finding out the critical factors regulating CSC fate is the key for target
therapy of CSCs. Just as normal stem cells are regulated by their microenvironment (niche), CSCs are also regulated by cells in the tumor microenvironment. However, whether various tumor microenvironments can induce CSCs to differentiate into different
cancer cells is not clear. Here, we show that single-cell-cloned CSCs, accidentally obtained from a human
liver cancer microvascular endothelial cells, express classic stem cell markers, genes associated with self-renewal and pluripotent factors and possess colony-forming ability in vitro and the ability of serial
transplantation in vivo. The single-cell-cloned CSCs treated with the different
tumor cell/tissue-derived
conditioned culture medium, which is a mimic of
carcinoma microenvironment, could differentiate into corresponding
tumor cells and express specific markers of the respective type of
tumor cells at the gene,
protein and cell levels, respectively. Interestingly, this multilineage differentiation potential of single-cell-cloned liver CSCs sharply declined after the specific knockdown of octamer-binding
transcription factor 4 (Oct4) alone, even though they were under the same induction conditions (
carcinoma microenvironments). These data support the hypothesis that single-cell-cloned liver CSCs have the potential of differentiating into different types of
tumor cells, and the tumor microenvironment does play a crucial role in deciding differentiation directions. Simultaneously, Oct4 in CSCs is indispensable in this process. These factors are promising targets for liver CSC-specific
therapy.