Title: Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy.
Authors: Deng, Xu-Bin; Xiao, Li; Wu, Yue; Jin, Fang; Mossman, Brooke; Testa, Joseph R; Xiao, Guang-Hui
Published In Int J Cancer, (2015 Jul 15)
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.
PubMed ID: 25501304
MeSH Terms: Adenoviridae/genetics*; Animals; Blotting, Western; Cell Line, Tumor; Cell Survival/drug effects; Cell Survival/genetics; Genetic Therapy/methods*; Genetic Vectors/genetics; Hepatocyte Growth Factor/genetics; Hepatocyte Growth Factor/metabolism; Hepatocyte Growth Factor/physiology*; Humans; Indoles/pharmacology; Lung Neoplasms/genetics; Lung Neoplasms/pathology; Lung Neoplasms/therapy*; Mesothelioma, Malignant; Mesothelioma/genetics; Mesothelioma/pathology; Mesothelioma/therapy*; Mice, Nude; Microscopy, Fluorescence; Neoplastic Stem Cells/drug effects; Neoplastic Stem Cells/metabolism*; Phosphorylation/drug effects; Proto-Oncogene Proteins c-met/metabolism; Spheroids, Cellular/metabolism; Sulfones/pharmacology; Xenograft Model Antitumor Assays; beta Catenin/metabolism