Abstract 3359: PEDF modulatory action on macrophages: A new way to curb prostate cancer development

Abstract

Abstract Macrophages have been described as one of the main inflammatory components involved in prostate cancer (PCa) initiation, progression, and metastasis. 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 significantly 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 link between PEDF and inflammation in PCa. While PEDF's role in inflammation has been suggested, the precise modes of action of PEDF on macrophages still remain unknown and necessitate further investigation. Our preliminary data have showed that PEDF stimulates the migration of monocytes/macrophages using in vitro chemotaxis boyden chamber assay and towards tumor 3D spheroids. We showed that PEDF expression levels positively correlate with macrophage density in human prostate. In both cell lines and prostate specimens, we have demonstrated that PEDF directly induces the polarization of macrophages and bone marrow derived macrophages (BMDMs) towards a M1/tumor-cytotoxic pathway. As a result of their differentiation, we have found that PEDF stimulates the phagocytosis of tumor cells, which suggest another mechanism by which PCa growth is halted. We are currently investigating the molecular mechanisms by which PEDF induces migration, differentiation and phagocytic activity in macrophages. PEDF mechanisms are being investigated by expression levels of PEDF receptors (ATP5B, PNPLA2, LRP6) in macrophage cell lines and BMDMs. So far we have been identified ATP5B and PNPLA2 as the two main receptors expressed in both cell types. While all three receptors in cell lines increased, only ATP5B and PNPLA2 receptors increased in BMDMs in response to PEDF. To map the functional region involved in PEDF's inflammatory action, we are investigating the PEDF-derivative synthetic 18-mer peptide (residues 39-57). P18 has been shown to block endothelial cell chemotaxis and induces apoptosis in vitro, and to be more effective than its parental 34-mer peptide (residues 24-57) in blocking growth and angiogenesis in PCa. We were able to demonstrate that macrophages treated with P18 in comparison to PEDF, show a higher efficacy for macrophages differentiation. Using confocal microscopy we demonstrated a larger rate of phagocytosis of PCa cells by macrophages than compared to PEDF. The results of our study are of importance as they suggest that macrophages may play a key role in PEDF anti-tumor effects. A better understanding of PEDF may lead to further development of PEDF-based anticancer therapy or improvement of alternatives to chemotherapy for PCa. Citation Format: Dalia Martinez-Marin, Thomas Nelius, Olga Volpert, Stephanie Filleur. PEDF modulatory action on macrophages: A new way to curb prostate cancer development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3359. doi:10.1158/1538-7445.AM2015-3359