Positive correlation between PEDF expression levels and macrophage density in the human prostate

Nelius, Thomas; Samathanam, Christina; Martinez-Marin, Dalia; Gaines, Natalie; Stevens, J. C.; Hickson, J. C. D.; Riese, Werner de; Filleur, Stéphanie

doi:10.1002/pros.22595

Cited by 23 publications

(20 citation statements)

References 51 publications

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“…We have previously demonstrated that PEDF induces the migration of macrophages and their polarization towards the classically activated pathway [34]. In human prostate, we showed that PEDF expression correlates with macrophage density.…”

Section: Introductionmentioning

confidence: 68%

PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro

et al. 2017

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BackgroundAlthough 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.MethodsRAW 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.ResultsWe 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.ConclusionsThese data established that modulating the molecular interactions between macrophages and PCa cells using PEDF may be a promising strategy for PCa treatment.

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Section: Introductionmentioning

confidence: 68%

PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro

et al. 2017

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“…M1-type macrophages generally express iNOS, which is tumor-cytotoxic. Tumor progression stimulates a phenotypic switch to M2 macrophages that express arginase 1, and accelerate tumor growth, survival and metastasis (31). Similarly, it has been previously demonstrated that the density of iNOS-positive macrophages, which infiltrate the stroma, is decreased in highly aggressive gliomas compared with less aggressive cancer, which indicates that as malignant potential of the cancer increased, the cytotoxic activity of macrophages is reduced (32).…”

Section: Discussionmentioning

confidence: 93%

BAMBI promotes macrophage proliferation and differentiation in gliomas

2017

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The present study investigated the capacity of Bone morphogenic protein and activin membrane‑bound inhibitor homolog (BAMBI) to regulate the migration and differentiation of macrophages in gliomas. Using a migration assay, it was determined that BAMBI stimulated monocytes migration in a dose‑dependent effect. When induced by phorbol myristate acetate (PMA) the monocytes differentiated into macrophages, and BAMBI also increased the migration of PMA‑induced macrophages compared with control cells. The expression of CD68 and BAMBI protein and mRNA in glioma and normal specimens were detected using immunohistochemistry and reverse transcription‑quantitative polymerase chain reaction, respectively. The localization of BAMBI was primarily in macrophages, as demonstrated by staining for the macrophage marker CD68, and the mRNA expression of CD68 and BAMBI were higher in gliomas compared to normal tissues. In addition, the mRNA expression of CD68 and BAMBI were positively correlated (R2=0.64). After treatment with 50 nM PMA and 10 nM BAMBI for 48 h, RAW 264.7 macrophages were exhibited dendrite‑like morphology, indicating that the co‑treatment promoted the differentiation of monocytes to macrophages. The expression of specific markers of M1 [inducible nitric oxide synthase (iNOS) and interleukin (IL)-12] and M2 (IL-10 and arginase 1) type macrophages was determined following 10 nM BAMBI treatment. BAMBI promoted the expression of M1 markers, whereas the M2 markers were not affected, which indicated that BAMBI induced differentiation of M1 type macrophages. These results indicate that BAMBI may be involved in macrophage differentiation in gliomas.

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“…Besides inhibiting tumor angiogenesis, exogenous or naturally secreted PEDF also induces the differentiation of cancer cells to a less-malignant phenotype, 26,27 which provided the first suggestion that PEDF could reduce malignant phenotype and act directly on tumors. Moreover, PEDF reduction in prostate cancer has been linked to poor prognosis, 28,29 while increased PEDF may act directly on prostate tumors to promote apoptosis, inhibit proliferation, and strongly suppress metastasis. 16 Our data suggest that the altered expression of PEDF induced by metformin might be involved in its antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Chen

et al. 2016

Cancer Biology & Therapy

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Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose-and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.Abbreviations: PEDF, pigment epithelium-derived factor; AMPK, 5 0 -AMP-activated protein kinase; mTOR, mammalian target of rapamycin; IL8, interleukin8; MAPK, mitogen-activated protein kinase; Met, metformin; qPCR, quantitative polymerase chain reaction; PBS, fetal bovine serum; CCK8, Cell Counter Kit-8; PBS, phosphate-buffered saline solution; PtdIns, propidium iodide; SD, standard deviation

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Positive correlation between PEDF expression levels and macrophage density in the human prostate

Cited by 23 publications

References 51 publications

PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro

PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro

BAMBI promotes macrophage proliferation and differentiation in gliomas

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

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