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Single-cell clones of liver cancer stem cells have the potential of differentiating into different types of tumor cells.

Liu H, Zhang W, Jia Y, Yu Q, Grau GE, Peng L, Ran Y, Yang Z, Deng H, Lou J - Cell Death Dis (2013)

Bottom Line: 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.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).Simultaneously, Oct4 in CSCs is indispensable in this process.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, PR China.

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.

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Related in: MedlinePlus

Origin and characteristics of T3A. (a) Microvascular endothelial cells derived from human liver cancer. (b) A cell subpopulation (T3A) was observed in cultured human liver cancer microvascular endothelial cells in the eighth generation. (c) The T3A cells rapidly proliferated. (d) T3A cells were purified by subcloning. (e, f) T3A cells formed a solid tumor after a subcutaneous injection into nude mice and the pathological type of tumor tissue was poorly differentiated carcinoma
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fig1: Origin and characteristics of T3A. (a) Microvascular endothelial cells derived from human liver cancer. (b) A cell subpopulation (T3A) was observed in cultured human liver cancer microvascular endothelial cells in the eighth generation. (c) The T3A cells rapidly proliferated. (d) T3A cells were purified by subcloning. (e, f) T3A cells formed a solid tumor after a subcutaneous injection into nude mice and the pathological type of tumor tissue was poorly differentiated carcinoma

Mentions: Recent evidence indicates that endothelial cells interact closely with CSCs, and CSCs are maintained within vascular niches.12, 13, 14 In agreement, in the cultured eighth generation of microvascular endothelial cells (Figure 1a) derived from a human primary liver cancer tissue, we accidently found a cell population morphologically different from endothelial cells, which is small, oval-like or polygonal-like (Figure 1b), and grows fast (Figure 1c). The cells were purified by subcloning and named T3A (Figure 1d). T3A cells express stem cell markers and are able to form a solid tumor after a subcutaneous injection into nude mice (Figure 1e), and the histopathological type appeared to be poorly differentiated adenocarcinoma (Figure 1f).


Single-cell clones of liver cancer stem cells have the potential of differentiating into different types of tumor cells.

Liu H, Zhang W, Jia Y, Yu Q, Grau GE, Peng L, Ran Y, Yang Z, Deng H, Lou J - Cell Death Dis (2013)

Origin and characteristics of T3A. (a) Microvascular endothelial cells derived from human liver cancer. (b) A cell subpopulation (T3A) was observed in cultured human liver cancer microvascular endothelial cells in the eighth generation. (c) The T3A cells rapidly proliferated. (d) T3A cells were purified by subcloning. (e, f) T3A cells formed a solid tumor after a subcutaneous injection into nude mice and the pathological type of tumor tissue was poorly differentiated carcinoma
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824650&req=5

fig1: Origin and characteristics of T3A. (a) Microvascular endothelial cells derived from human liver cancer. (b) A cell subpopulation (T3A) was observed in cultured human liver cancer microvascular endothelial cells in the eighth generation. (c) The T3A cells rapidly proliferated. (d) T3A cells were purified by subcloning. (e, f) T3A cells formed a solid tumor after a subcutaneous injection into nude mice and the pathological type of tumor tissue was poorly differentiated carcinoma
Mentions: Recent evidence indicates that endothelial cells interact closely with CSCs, and CSCs are maintained within vascular niches.12, 13, 14 In agreement, in the cultured eighth generation of microvascular endothelial cells (Figure 1a) derived from a human primary liver cancer tissue, we accidently found a cell population morphologically different from endothelial cells, which is small, oval-like or polygonal-like (Figure 1b), and grows fast (Figure 1c). The cells were purified by subcloning and named T3A (Figure 1d). T3A cells express stem cell markers and are able to form a solid tumor after a subcutaneous injection into nude mice (Figure 1e), and the histopathological type appeared to be poorly differentiated adenocarcinoma (Figure 1f).

Bottom Line: 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.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).Simultaneously, Oct4 in CSCs is indispensable in this process.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, PR China.

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.

Show MeSH
Related in: MedlinePlus