title: Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy.
abstract: Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the α-chain of hepatocyte growth factor. The therapeutic potential of NK4 has been demonstrated in a variety of tumor types. However, the mechanisms by which NK4 inhibits tumor growth have not been well delineated. In this study, it is shown that the NK4 adenovirus (Ad-NK4) potently inhibits cell viability, invasiveness and tumorigenicity of human MM cells. Significantly, this study demonstrates for the first time that Ad-NK4 inhibits cancer stem-like cell (CSC) properties as assessed by spheroid formation assay, side population analysis and flow cytometric sorting of CD24 cells. In addition to inhibiting phosphorylation of Met and AKT, Ad-NK4 markedly suppressed the active form of β-catenin, a key mediator of both Wnt and AKT pathways. It is further demonstrated that expression of NK4 suppresses β-catenin nuclear localization and transcriptional activity. Intriguingly, the expression levels of Oct4 and Myc, two critical stem cell factors and downstream targets of β-catenin, were also diminished by Ad-NK4. Furthermore, the strong antitumor effect of NK4 was found to be linked to its ability to inhibit CSCs as revealed by immunohistochemical examination of tumor specimens from a mouse xenograft model of human MM. These findings suggest that NK4 acts as a CSC inhibitor by impeding Met/AKT/β-catenin signaling and holds promise for achieving durable therapeutic responses in MM by constraining the CSC component of these aggressive tumors.
authors.affiliation: Cancer Institute, Southern Medical University, Guangzhou, China.
authors.forename: Xu-Bin
authors.initials: XB
authors.lastname: Deng
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Cancer Institute, Southern Medical University, Guangzhou, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Brooke
authors.initials: B
authors.lastname: Mossman
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.affiliation: Cancer Institute, Southern Medical University, Guangzhou, China.|Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Xiao
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C066855:HGF protein, human; D007211:Indoles; D013450:Sulfones; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: HGF/Met; NK4; cancer stem-like cells; malignant mesothelioma; therapy