title: Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor.
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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Kuei-Chun
authors.initials: KC
authors.lastname: Liu
authors.forename: Yi-Te
authors.initials: YT
authors.lastname: Yo
authors.forename: Rui-Lan
authors.initials: RL
authors.lastname: Huang
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Wang
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Liao
authors.forename: Tien-Shuo
authors.initials: TS
authors.lastname: Huang
authors.forename: Tai-Kuang
authors.initials: TK
authors.lastname: Chao
authors.forename: Chi-Kang
authors.initials: CK
authors.lastname: Lin
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Weng
authors.forename: Kuo-Hsing
authors.initials: KH
authors.lastname: Ma
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Chang
authors.forename: Mu-Hsien
authors.initials: MH
authors.lastname: Yu
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018874:Spheroids, Cellular; D055815:Young Adult
chemical_list: D000469:Alkaline Phosphatase