title: Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer.
abstract: Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells.
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Dongli
authors.initials: D
authors.lastname: Yue
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Jieyao
authors.initials: J
authors.lastname: Li
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; School of Life Sciences, Zhengzhou University, Zhengzhou 450000, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ping
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; School of Life Sciences, Zhengzhou University, Zhengzhou 450000, PR China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Liu
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Shi
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China; Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China; School of Life Sciences, Zhengzhou University, Zhengzhou 450000, PR China; Institute of Clinical-Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, PR China. Electronic address: yizhang@zzu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1
keywords: Cancer stem cells (CSCs); Esophageal cancer; Sphere-forming cells; TGF-β1; Ultra low attachment surface culture