PEDF Gene Therapy Using Bone Marrow-derived Macrophages for Advanced Prostate Cancer

Macrophages have been described as one of the main inflammatory components involved in prostate cancer (PCa) initiation, progression, and metastases formation. PEDF (Pigment Epithelium-Derived Factor) is an anti-angiogenic factor with differentiation activities and was recently suggested as an immune-modulating factor. PEDF expression has been shown to be down-regulated in PCa compared to normal tissues. In previous studies, we have demonstrated that PEDF re-expression in PCa cells curbs tumor growth in vivo and prolongs the survival of tumor-bearing mice. Others have shown that PEDF expression increased the recruitment of tumor-cytotoxic macrophages into orthotopic MatLyLu rat prostate tumors suggesting a new way through which PEDF curbs PCa growth. While all of these results emphasize the anti-tumor properties of PEDF, the delivery of PEDF still remain challenging. The objective of the present study is to investigate PEDF gene therapy using bone marrow-derived macrophages (BMDMs) as a novel therapeutic modality for advanced PCa. Our central hypothesis is that PEDF expression will induce the migration and differentiation of BMDMs into a tumor-cytotoxic phenotype and, as a corollary, will block tumor growth and metastases formation, and prolong survival. We have formulated this hypothesis on the basis of our preliminary data that showed that PEDF stimulates the migration of monocytes/macrophages using in vitro chemotaxis assays and our immunohistochemistry studies that demonstrated a positive correlation between PEDF expression levels and macrophage density in human prostate specimens. The present proposal which will use subcutaneous and orthotopic preclinical models may potentially lead to development of improved therapeutic approaches to PCa.