Research

Urology Research

Role of PEDF in Modulating the Molecular Interaction Between Prostate Cancer Cells and Macrophages

Neo-vascularization (angiogenesis) and inflammation in the tumor microenvironment have been described as favorable for tumor cell growth and survival. As a direct result, tumor cells are able to travel through the circulation to colonize distant organs or sites (metastases). A natural protein known as the Pigment Epithelium-Derived Factor (PEDF) is expressed in normal tissues and decreased in prostate cancer. In previous studies, we have shown that PEDF is a potent angio-inhibitory factor and we have demonstrated that engineering prostate cancer cells to increase PEDF blocks tumor growth, prolongs survival and enhances the anti-tumor efficacy of chemotherapy in vivo. Furthermore, by acting directly on macrophages inflammatory cells, we showed that PEDF stimulates the recruitment of these cells in vitro and in human prostate. As well, PEDF induces the polarization of macrophages towards tumor-cytotoxic M1 macrophages leading to the phagocytosis of tumor cells. PEDF, inflammation and prostate cancer development thus seem inter-related. As a logical extension of this previous work, we are now interested in characterizing the signaling pathway(s) involved in PEDF inflammatory function. We also propose to test short synthetic peptides, derived from the N-Terminal region of PEDF, with enhanced inflammatory activity. These studies which combine the use of both in vitro and in vivo experimental models, as well as in silico work should allow us to validate PEDF as a key regulator of the molecular interactions between prostate tumor cells and macrophages. This project may also lead to the development of improved therapeutic approaches for prostate cancer.

Understand Cabazitaxel Resistance in Prostate Cancer

Acquisition of resistance to chemotherapy remains a devastating and widespread phenomenon in clinical oncology including in metastatic prostate cancer. While some important single factors involved in chemo-resistance have been investigated, resulting clinical studies targeting these factors have been disappointing. A complete characterization of the signaling pathways involved in chemo-resistance is therefore urgently needed. For the present study, we have developed a cell experimental model for prostate cancer that mimics the development of resistance against cabazitaxel, an approved taxane drug which is currently used for the treatment of patients with metastatic prostate cancer. Using a RNA/miRNA sequencing approach, we have identified a transcriptomics signature associated with cabazitaxel resistance. Future studies will investigate this gene signature in patients with prostate cancer in correlation with cabazitaxel sensitivity. This study may lead to the development of a prognostic tool to predict patients’ response to cabazitaxel.