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.
Highlights
Prostate cancer is the second-leading cause of cancer-related deaths in both Europe and the United States [1]
In the series of LNCaP lineage cell lines, the expression of osteonectin correlated with increased bone metastatic potential, in which the hormone refractory and bone metastatic C4-2B expressed a higher level of osteonectin than did its parental androgen-dependent LNCaP and androgen-independent C4-2 cells
As prostate cancer bone metastasis is considered as a microenvironment-driven disease, the higher levels of osteonectin expressed by human bone stromal cells than that of prostate cancer cells was observed using hFOB osteoblast and HS27A bone marrow derived fibroblast cell lines (Fig 1A)
Summary
Prostate cancer is the second-leading cause of cancer-related deaths in both Europe and the United States [1]. Most patients initially respond to ADT; the intrinsic nature of the heterogeneity of tumor cells results in resistance to treatment and progression into highly morbid disease termed castration-resistant prostate cancer (CRPC) within 18–24 months [2]. End-stage CRPC is commonly associated with osseous metastasis, which causes significant mortality and morbidity with the development of severe skeletal complications in affected patients. Recent clinical approaches using agents that target distinct mechanisms of action, including tubulin-binding chemotherapy (cabazitaxel); immunotherapy (sipuleucel-T); CYP-17 inhibition (abiraterone); androgen receptor (AR) blockade (enzalutamide); and radioisotope therapy (radium-223) have shown promising results in delaying skeletal complications and improving overall survival [3], the management of patients with metastatic CRPC remains a challenge, with a mean survival time of less than 19 months [4]. Drugs are needed that target hormonerefractory prostate cancer cells regardless of differentiation state, with various levels of androgen receptor (AR) and prostate-specific antigen (PSA) expression
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