Abstract
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.
Highlights
A new cancer therapy using cancer stem cells (CSCs) as target will be a promising approach in the future
Recent evidence indicates that endothelial cells interact closely with CSCs, and CSCs are maintained within vascular niches.[12,13,14]
We provide evidence to support an important aspect of the cancer stem cell hypothesis, which claims that single-cell-cloned liver CSCs can self-renew and initiate a carcinoma
Summary
A new cancer therapy using CSCs as target will be a promising approach in the future. We must answer a question as to whether the multilineage differentiation potential of CSCs is derived from a single-clonal cell population or depends on multiple different CSCs. whether certain CSCs can differentiate into a variety of distinct types of tumor cells and what the key determinants in this process are is unclear. Whether certain CSCs can differentiate into a variety of distinct types of tumor cells and what the key determinants in this process are is unclear It is necessary for investigating the multilineage differentiation potential to establish a stable and singlecell-cloned CSC line. Tumor microenvironment makes iPS cells turn into malignant cells too.[11] All these data imply that the microenvironment is a critical factor for deciding differentiation fate Based on these studies, we ascertained whether CSCs are able to differentiate into different types of tumor cells after exposure to the corresponding tumor microenvironment.
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