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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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Effect of Oct4 knockdown on the multi-differentiation potential of T3A-A3 cells. After Oct4 knockdown in T3A-A3 cells, the committed inductions were repeated using melanoma, lymphoma and prostate cancer tissue-derived conditioned culture medium. The tumor-specific markers were detected by RT-PCR, western blot, immunofluorescence staining in vitro and immunohistochemistry staining on graft tumor tissue in vivo. (a) Detection of the expressions of gp100 in shOct4-T3A-A3 cells induced by melanoma tissue-derived conditioned culture medium. (b) Detection of CD10 in shOct4-T3A-A3 cells induced by lymphoma tissue-derived conditioned culture medium. (c) Detection of PSA in shOct4-T3A-A3 induced by prostate cancer tissue-derived conditioned culture medium. 1: Positive control (corresponding cancer cell line); 2: shNC-T3A-A3 cells; 3: induced shNC-T3A-A3 cells; 4: shOct4-T3A-A3 cells; 5: induced shOct4-T3A-A3 cells)
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fig6: Effect of Oct4 knockdown on the multi-differentiation potential of T3A-A3 cells. After Oct4 knockdown in T3A-A3 cells, the committed inductions were repeated using melanoma, lymphoma and prostate cancer tissue-derived conditioned culture medium. The tumor-specific markers were detected by RT-PCR, western blot, immunofluorescence staining in vitro and immunohistochemistry staining on graft tumor tissue in vivo. (a) Detection of the expressions of gp100 in shOct4-T3A-A3 cells induced by melanoma tissue-derived conditioned culture medium. (b) Detection of CD10 in shOct4-T3A-A3 cells induced by lymphoma tissue-derived conditioned culture medium. (c) Detection of PSA in shOct4-T3A-A3 induced by prostate cancer tissue-derived conditioned culture medium. 1: Positive control (corresponding cancer cell line); 2: shNC-T3A-A3 cells; 3: induced shNC-T3A-A3 cells; 4: shOct4-T3A-A3 cells; 5: induced shOct4-T3A-A3 cells)

Mentions: After Oct4 knockdown, T3A-A3 cells cannot differentiate into different cancer cells, and the specific markers of three kinds of tumors cannot be detected both in vitro and in vivo even if under the corresponding tumor microenvironments as in the previous differentiation experiments (Figure 6).


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)

Effect of Oct4 knockdown on the multi-differentiation potential of T3A-A3 cells. After Oct4 knockdown in T3A-A3 cells, the committed inductions were repeated using melanoma, lymphoma and prostate cancer tissue-derived conditioned culture medium. The tumor-specific markers were detected by RT-PCR, western blot, immunofluorescence staining in vitro and immunohistochemistry staining on graft tumor tissue in vivo. (a) Detection of the expressions of gp100 in shOct4-T3A-A3 cells induced by melanoma tissue-derived conditioned culture medium. (b) Detection of CD10 in shOct4-T3A-A3 cells induced by lymphoma tissue-derived conditioned culture medium. (c) Detection of PSA in shOct4-T3A-A3 induced by prostate cancer tissue-derived conditioned culture medium. 1: Positive control (corresponding cancer cell line); 2: shNC-T3A-A3 cells; 3: induced shNC-T3A-A3 cells; 4: shOct4-T3A-A3 cells; 5: induced shOct4-T3A-A3 cells)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Effect of Oct4 knockdown on the multi-differentiation potential of T3A-A3 cells. After Oct4 knockdown in T3A-A3 cells, the committed inductions were repeated using melanoma, lymphoma and prostate cancer tissue-derived conditioned culture medium. The tumor-specific markers were detected by RT-PCR, western blot, immunofluorescence staining in vitro and immunohistochemistry staining on graft tumor tissue in vivo. (a) Detection of the expressions of gp100 in shOct4-T3A-A3 cells induced by melanoma tissue-derived conditioned culture medium. (b) Detection of CD10 in shOct4-T3A-A3 cells induced by lymphoma tissue-derived conditioned culture medium. (c) Detection of PSA in shOct4-T3A-A3 induced by prostate cancer tissue-derived conditioned culture medium. 1: Positive control (corresponding cancer cell line); 2: shNC-T3A-A3 cells; 3: induced shNC-T3A-A3 cells; 4: shOct4-T3A-A3 cells; 5: induced shOct4-T3A-A3 cells)
Mentions: After Oct4 knockdown, T3A-A3 cells cannot differentiate into different cancer cells, and the specific markers of three kinds of tumors cannot be detected both in vitro and in vivo even if under the corresponding tumor microenvironments as in the previous differentiation experiments (Figure 6).

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