title: Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.
abstract: Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.
authors.affiliation: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shian-Ying
authors.initials: SY
authors.lastname: Sung
authors.affiliation: Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan.|Biomedical Engineering Department, Ming Chuan University, Taoyuan City, Taiwan.
authors.forename: Junn-Liang
authors.initials: JL
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Urology, TMU-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan.
authors.forename: Kuan-Chou
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Division of Urology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Shauh-Der
authors.initials: SD
authors.lastname: Yeh
authors.affiliation: Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Division of General Surgery, Department of Surgery, TMU-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan.
authors.forename: Yen-Hao
authors.initials: YH
authors.lastname: Su
authors.affiliation: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Hsueh
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.affiliation: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Hsieh
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015676:Osteonectin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D013937:Thymidine Kinase / Q000235:genetics; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D015676:Osteonectin; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013937:Thymidine Kinase