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: 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
• Journal: PloS one (PLoS One) Vol. 11 Issue 4 Pg. e0153350 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27054343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Osteonectin
• RNA, Messenger
• Receptors, Androgen
• Thymidine Kinase

Topics

• Adenoviridae (genetics)
• Animals
• Blotting, Western
• Bone Neoplasms (genetics, secondary, therapy)
• Epithelium (metabolism, pathology)
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Humans
• Immunoenzyme Techniques
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Osteonectin (genetics)
• Promoter Regions, Genetic (genetics)
• Prostatic Neoplasms, Castration-Resistant (genetics, pathology, therapy)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Androgen (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Stromal Cells (metabolism, pathology)
• Thymidine Kinase (genetics)
• Tissue Array Analysis
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays