Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth

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.

PloS one. 2016 Apr 07*** epublish ***

Shian-Ying Sung, Junn-Liang Chang, Kuan-Chou Chen, Shauh-Der Yeh, Yun-Ru Liu, Yen-Hao Su, Chia-Yen Hsueh, Leland W K Chung, Chia-Ling Hsieh

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan., Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan., Division of Urology, Taipei Medical University Hospital, Taipei, Taiwan., Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan., Division of General Surgery, Department of Surgery, TMU-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan., The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America., The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

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