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Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor.

Liu KC, Yo YT, Huang RL, Wang YC, Liao YP, Huang TS, Chao TK, Lin CK, Weng SJ, Ma KH, Chang CC, Yu MH, Lai HC - Oncotarget (2013)

Bottom Line: Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties.We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate.In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

ABSTRACT
Spheroid formation is one property of stem cells-such as embryo-derived or neural stem cells-that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial-mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.

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SR1 cells derived from various ovarian cancer cell lines show multiple differentiation potency(A, B) SR1, SR2, and their original counterpart cells from CP70 (A) and SKOV3 (B) cells were induced by adipogenesis-inducing medium for 14 days and stained with oil red O solution. Only SR1 and SR2 cells, but not the original cells, displayed lipid droplets in the cell body (white arrows). (C) Two independent clones of SR1 cells derived from OVCAR3 cells were seeded directly onto collagen-coating culture dishes in either adipogenesis-inducing medium or SR culture medium. Oil droplets were observed only in SR1 cells cultured in adipogenesis-inducing medium. (D) The osteogenesis capacity of SKOV3-derived SR1 cells and its original counterpart cells were examined. Only SR1 cells cultured in osteogenesis-inducing medium displayed osteocyte morphology with the osteogenic marker, ALP activity, 14 days after induction. Differentiated CP70SR1 were induced by osteogenesis (E) and chondrogenesis (F) and detected by specific staining. Undifferentiated CP70SR1 without induction retained a tumor-like morphology and showed no signals.
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Figure 3: SR1 cells derived from various ovarian cancer cell lines show multiple differentiation potency(A, B) SR1, SR2, and their original counterpart cells from CP70 (A) and SKOV3 (B) cells were induced by adipogenesis-inducing medium for 14 days and stained with oil red O solution. Only SR1 and SR2 cells, but not the original cells, displayed lipid droplets in the cell body (white arrows). (C) Two independent clones of SR1 cells derived from OVCAR3 cells were seeded directly onto collagen-coating culture dishes in either adipogenesis-inducing medium or SR culture medium. Oil droplets were observed only in SR1 cells cultured in adipogenesis-inducing medium. (D) The osteogenesis capacity of SKOV3-derived SR1 cells and its original counterpart cells were examined. Only SR1 cells cultured in osteogenesis-inducing medium displayed osteocyte morphology with the osteogenic marker, ALP activity, 14 days after induction. Differentiated CP70SR1 were induced by osteogenesis (E) and chondrogenesis (F) and detected by specific staining. Undifferentiated CP70SR1 without induction retained a tumor-like morphology and showed no signals.

Mentions: After observing this change in morphology (Figure 2E), we confirmed the adipogenic potency of CP70- and SKOV3-derived SR1 and SR2 (Figure 3A and 3B). The original tumor cells barely exhibited this differentiated capacity (Figure 3A and 3B). Only OVCAR-3SR1 differentiated into adipocyte-like cells under the induction condition (Figure 3C). Specific dye staining demonstrated the osteogenic induction of SKOV-3SR1 and CP70SR1 (Figure 3D and 3E) as well as chondrogenesis of CP70SR1 (Figure 3F).


Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor.

Liu KC, Yo YT, Huang RL, Wang YC, Liao YP, Huang TS, Chao TK, Lin CK, Weng SJ, Ma KH, Chang CC, Yu MH, Lai HC - Oncotarget (2013)

SR1 cells derived from various ovarian cancer cell lines show multiple differentiation potency(A, B) SR1, SR2, and their original counterpart cells from CP70 (A) and SKOV3 (B) cells were induced by adipogenesis-inducing medium for 14 days and stained with oil red O solution. Only SR1 and SR2 cells, but not the original cells, displayed lipid droplets in the cell body (white arrows). (C) Two independent clones of SR1 cells derived from OVCAR3 cells were seeded directly onto collagen-coating culture dishes in either adipogenesis-inducing medium or SR culture medium. Oil droplets were observed only in SR1 cells cultured in adipogenesis-inducing medium. (D) The osteogenesis capacity of SKOV3-derived SR1 cells and its original counterpart cells were examined. Only SR1 cells cultured in osteogenesis-inducing medium displayed osteocyte morphology with the osteogenic marker, ALP activity, 14 days after induction. Differentiated CP70SR1 were induced by osteogenesis (E) and chondrogenesis (F) and detected by specific staining. Undifferentiated CP70SR1 without induction retained a tumor-like morphology and showed no signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926833&req=5

Figure 3: SR1 cells derived from various ovarian cancer cell lines show multiple differentiation potency(A, B) SR1, SR2, and their original counterpart cells from CP70 (A) and SKOV3 (B) cells were induced by adipogenesis-inducing medium for 14 days and stained with oil red O solution. Only SR1 and SR2 cells, but not the original cells, displayed lipid droplets in the cell body (white arrows). (C) Two independent clones of SR1 cells derived from OVCAR3 cells were seeded directly onto collagen-coating culture dishes in either adipogenesis-inducing medium or SR culture medium. Oil droplets were observed only in SR1 cells cultured in adipogenesis-inducing medium. (D) The osteogenesis capacity of SKOV3-derived SR1 cells and its original counterpart cells were examined. Only SR1 cells cultured in osteogenesis-inducing medium displayed osteocyte morphology with the osteogenic marker, ALP activity, 14 days after induction. Differentiated CP70SR1 were induced by osteogenesis (E) and chondrogenesis (F) and detected by specific staining. Undifferentiated CP70SR1 without induction retained a tumor-like morphology and showed no signals.
Mentions: After observing this change in morphology (Figure 2E), we confirmed the adipogenic potency of CP70- and SKOV3-derived SR1 and SR2 (Figure 3A and 3B). The original tumor cells barely exhibited this differentiated capacity (Figure 3A and 3B). Only OVCAR-3SR1 differentiated into adipocyte-like cells under the induction condition (Figure 3C). Specific dye staining demonstrated the osteogenic induction of SKOV-3SR1 and CP70SR1 (Figure 3D and 3E) as well as chondrogenesis of CP70SR1 (Figure 3F).

Bottom Line: Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties.We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate.In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

ABSTRACT
Spheroid formation is one property of stem cells-such as embryo-derived or neural stem cells-that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial-mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.

Show MeSH
Related in: MedlinePlus