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Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity.

Yu L, Liu S, Zhang C, Zhang B, Simões BM, Eyre R, Liang Y, Yan H, Wu Z, Guo W, Clarke RB - Oncotarget (2013)

Bottom Line: However, the relationship between telomerase expression and cancer stem cells remains unknown.We sorted subpopulations with high or low telomerase activity (TEL) using hTERT transcriptional promoter-induced green fluorescent protein (GFP).Furthermore, the telomerase inhibitor MST312 prevented tumorigenic potential both in vitro and in vivo, preferentially targeting the TELpos cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopedics, Renmin Hospital of Wuhan University, Jiefang Road, Wuhan, Hubei, P.R. China.

ABSTRACT
Telomerase is crucial for the maintenance of stem/progenitor cells in adult tissues and is detected in most malignant cancers, including osteosarcoma. However, the relationship between telomerase expression and cancer stem cells remains unknown. We observed that sphere-derived osteosarcoma cells had higher telomerase activity, indicating that telomerase activity might be enriched in osteosarcoma stem cells. We sorted subpopulations with high or low telomerase activity (TEL) using hTERT transcriptional promoter-induced green fluorescent protein (GFP). The TELpos cells showed an increased sphere and tumor propagating capacity compared to TELneg cells, and enhanced stem cell-like properties such as invasiveness, metastatic activity and resistance to chemotherapeutic agents both in vitro and in vivo. Furthermore, the telomerase inhibitor MST312 prevented tumorigenic potential both in vitro and in vivo, preferentially targeting the TELpos cells. These data support telomerase inhibition as a potential targeted therapy for osteosarcoma stem-like cells.

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MST312 targets TELpos cells(A) Cell viability following MST312 treatment of MG63, MNNG/HOS, and 143B cells. Both TELpos and TELneg cells showed a decrease in cell viability but TELpos cells respond significantly more to the treatment (P<0.01). (B) In vitro sphere formation of TELpos cell was inhibited after exposure to MST312 (P<0.01). (C) MST312 inhibited in vivo tumor forming ability of TELpos MG63 cells (P<0.01). (D) TELpos cell population of xenografted tumors were decreased after MST312 treatment.
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Figure 6: MST312 targets TELpos cells(A) Cell viability following MST312 treatment of MG63, MNNG/HOS, and 143B cells. Both TELpos and TELneg cells showed a decrease in cell viability but TELpos cells respond significantly more to the treatment (P<0.01). (B) In vitro sphere formation of TELpos cell was inhibited after exposure to MST312 (P<0.01). (C) MST312 inhibited in vivo tumor forming ability of TELpos MG63 cells (P<0.01). (D) TELpos cell population of xenografted tumors were decreased after MST312 treatment.

Mentions: Next, we tested whether the telomerase inhibitor MST312 targets the osteosarcoma cells in vitro. We divided the cells into TELpos and TELneg subgroups and treated with MST312 for 96h. We found a decrease in the cell viability of both subgroups, but a significantly greater inhibitory effect was observed in TELpos cells (Fig. 6A). Furthermore, we found that MST312 inhibited in vitro sphere formation of TELpos cells, with an average inhibition rate of 58.3±5.1% (Fig. 6B). TELpos MG63 cells were then subcutaneously injected into nude mice, and the mice were treated with MST312. After 3 weeks the tumors in control mice were ~ 1cm3, while tumours in the MST312 treated mice were 5-fold smaller (Fig. 6C). We then analysed MG63-TELpos derived tumors treated with MST312 for the GFP positive cell population, and found it to be decreased from 27.3±3.0 to 7.9±2.2 (Fig. 6D).


Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity.

Yu L, Liu S, Zhang C, Zhang B, Simões BM, Eyre R, Liang Y, Yan H, Wu Z, Guo W, Clarke RB - Oncotarget (2013)

MST312 targets TELpos cells(A) Cell viability following MST312 treatment of MG63, MNNG/HOS, and 143B cells. Both TELpos and TELneg cells showed a decrease in cell viability but TELpos cells respond significantly more to the treatment (P<0.01). (B) In vitro sphere formation of TELpos cell was inhibited after exposure to MST312 (P<0.01). (C) MST312 inhibited in vivo tumor forming ability of TELpos MG63 cells (P<0.01). (D) TELpos cell population of xenografted tumors were decreased after MST312 treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926830&req=5

Figure 6: MST312 targets TELpos cells(A) Cell viability following MST312 treatment of MG63, MNNG/HOS, and 143B cells. Both TELpos and TELneg cells showed a decrease in cell viability but TELpos cells respond significantly more to the treatment (P<0.01). (B) In vitro sphere formation of TELpos cell was inhibited after exposure to MST312 (P<0.01). (C) MST312 inhibited in vivo tumor forming ability of TELpos MG63 cells (P<0.01). (D) TELpos cell population of xenografted tumors were decreased after MST312 treatment.
Mentions: Next, we tested whether the telomerase inhibitor MST312 targets the osteosarcoma cells in vitro. We divided the cells into TELpos and TELneg subgroups and treated with MST312 for 96h. We found a decrease in the cell viability of both subgroups, but a significantly greater inhibitory effect was observed in TELpos cells (Fig. 6A). Furthermore, we found that MST312 inhibited in vitro sphere formation of TELpos cells, with an average inhibition rate of 58.3±5.1% (Fig. 6B). TELpos MG63 cells were then subcutaneously injected into nude mice, and the mice were treated with MST312. After 3 weeks the tumors in control mice were ~ 1cm3, while tumours in the MST312 treated mice were 5-fold smaller (Fig. 6C). We then analysed MG63-TELpos derived tumors treated with MST312 for the GFP positive cell population, and found it to be decreased from 27.3±3.0 to 7.9±2.2 (Fig. 6D).

Bottom Line: However, the relationship between telomerase expression and cancer stem cells remains unknown.We sorted subpopulations with high or low telomerase activity (TEL) using hTERT transcriptional promoter-induced green fluorescent protein (GFP).Furthermore, the telomerase inhibitor MST312 prevented tumorigenic potential both in vitro and in vivo, preferentially targeting the TELpos cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopedics, Renmin Hospital of Wuhan University, Jiefang Road, Wuhan, Hubei, P.R. China.

ABSTRACT
Telomerase is crucial for the maintenance of stem/progenitor cells in adult tissues and is detected in most malignant cancers, including osteosarcoma. However, the relationship between telomerase expression and cancer stem cells remains unknown. We observed that sphere-derived osteosarcoma cells had higher telomerase activity, indicating that telomerase activity might be enriched in osteosarcoma stem cells. We sorted subpopulations with high or low telomerase activity (TEL) using hTERT transcriptional promoter-induced green fluorescent protein (GFP). The TELpos cells showed an increased sphere and tumor propagating capacity compared to TELneg cells, and enhanced stem cell-like properties such as invasiveness, metastatic activity and resistance to chemotherapeutic agents both in vitro and in vivo. Furthermore, the telomerase inhibitor MST312 prevented tumorigenic potential both in vitro and in vivo, preferentially targeting the TELpos cells. These data support telomerase inhibition as a potential targeted therapy for osteosarcoma stem-like cells.

Show MeSH
Related in: MedlinePlus