Ovarian cancer stem-like cells with induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor
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Kuei-Chun Liu1, Yi-Te Yo2, Rui-Lan Huang3, Yu-Chi Wang2, Yu-Ping Liao1, Tien-Shuo Huang3, Tai-Kuang Chao3, Chi-Kang Lin2,4, Shao-Ju Weng4,5, Kuo-Hsing Ma5, Cheng-Chang Chang2,4, Mu-Hsien Yu2, Hung-Cheng Lai1,2,3,5,7,8
1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
2 Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
3 Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
4 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
5 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
6 Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
7 Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
8 School of Medicine, Taipei Medical University, Taipei, Taiwan.
Hung-Cheng Lai, email:
Keywords: alkaline phosphatase, cancer stem-like cells, epithelial-mesenchymal transition, epithelial ovarian cancer, levamisole, trans-lineage differentiation
Received: September 18, 2013 Accepted: November 14, 2013 Published: November 16, 2013
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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