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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro
Dalia Martinez-Marin1, Courtney Jarvis1,2, Thomas Nelius1
1Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America.
Background:
Although inflammation and prostate cancer (PCa) have been linked, the molecular interactions between macrophages and PCa cells are poorly explored. Pigment Epithelium-Derived Factor (PEDF) is an anti-angiogenic and anti-tumor factor. We previously showed that PEDF induces macrophages recruitment in vitro, correlates with macrophages density in human prostate, and stimulates macrophages polarization towards the classically activated pathway. Here, we demonstrate that PEDF modulates the interaction between macrophages and PCa cells through a bidirectional signalling leading to tumor cell apoptosis and phagocytosis.
Methods:
RAW 264.7 and THP-1 cells, and BMDMs were grown in vitro as mono- or co-cultures with PC3 or CL1 tumor cells. The effects of PEDF and its derived P18 peptide were measured on macrophages differentiation, migration, and superoxide production, and tumor cell apoptosis and phagocytosis. PEDF receptors (ATP5B, PNPLA2, and LRP6) and CD47 mRNA and protein expression were quantified in macrophages and tumor cells by quantitative RT-PCR, western blot, immunofluorescence and flow cytometry.
Results:
We found that PEDF induced the migration of macrophages towards tumor 3D spheroids and 2D cultures. In co-culture, PEDF increased PCa cells phagocytosis through an indirect apoptosis-dependent mechanism. Moreover, PEDF stimulated the production of superoxide by macrophages. Conditioned media from macrophages exposed to PEDF induced tumor cells apoptosis in contrast to control conditioned media suggesting that ROS may be involved in tumor cells apoptosis. ATP5B and PNPLA2 PEDF receptors on macrophages and CD47 on tumor cells were respectively up- and down-regulated by PEDF. As PEDF, blocking CD47 induced phagocytosis. Inhibiting ATP5B reduced phagocytosis. Inversely, PNPLA2 inhibition blocks differentiation but maintains phagocytosis. CD47-induced phagocytosis was partially reverted by ATP5B inhibition suggesting a complementary action. Similar effects were observed with P18 PEDF-derived peptide.
Conclusions:
These data established that modulating the molecular interactions between macrophages and PCa cells using PEDF may be a promising strategy for PCa treatment.
Insights
Pigment Epithelium-Derived Factor (PEDF) enhances macrophage interaction with prostate cancer (PCa) cells, promoting tumor cell apoptosis and phagocytosis. This suggests PEDF is a promising therapeutic strategy for PCa treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Inflammation and prostate cancer (PCa) link is established, but macrophage-PCa cell interactions are under-explored.
- Pigment Epithelium-Derived Factor (PEDF) exhibits anti-angiogenic and anti-tumor properties.
- Previous studies show PEDF recruits and polarizes macrophages towards an M1-like phenotype.
Purpose of the Study:
- To investigate the bidirectional signaling between macrophages and PCa cells modulated by PEDF.
- To elucidate the molecular mechanisms underlying PEDF's effects on macrophage-PCa cell interactions.
- To assess the therapeutic potential of targeting these interactions in PCa.
Main Methods:
- In vitro co-culture models using RAW 264.7, THP-1, and bone marrow-derived macrophages (BMDMs) with PC3 or CL1 PCa cells.
- Assessment of macrophage migration, superoxide production, and phagocytosis, alongside tumor cell apoptosis.
- Quantitative analysis of PEDF receptors (ATP5B, PNPLA2, LRP6) and CD47 expression via RT-PCR, Western blot, immunofluorescence, and flow cytometry.
Main Results:
- PEDF promoted macrophage migration towards PCa cells and enhanced phagocytosis via an apoptosis-dependent pathway.
- PEDF-stimulated macrophages produced superoxide, and conditioned media induced tumor cell apoptosis, suggesting a role for reactive oxygen species (ROS).
- PEDF modulated receptor expression: up-regulated ATP5B and PNPLA2 on macrophages, and down-regulated CD47 on PCa cells. Blocking CD47 or inhibiting ATP5B influenced phagocytosis, with complementary actions observed.
Conclusions:
- PEDF effectively modulates macrophage-PCa cell interactions, leading to tumor cell apoptosis and phagocytosis.
- The study highlights a promising therapeutic strategy for PCa by targeting PEDF-mediated molecular interactions.
- Further research into PEDF-based therapies could offer new avenues for prostate cancer treatment.
