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Pigment epithelium-derived factor, an anti-VEGF factor, delays ovarian cancer progression by alleviating polarization of tumor-associated macrophages

Cancer Gene Therapy volume 29, pages 1332–1341 (2022)Cite this article

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Abstract

Ovarian cancer (OC) is one of the most dangerous gynecological malignancies with no effective treatment so far. Pigment epithelium-derived factor (PEDF) has been reported to have ideal anti-tumor effects, but its relationship with the regulation of tumor-associated macrophage polarization is currently unclear. In this study, the mRNA expression of PEDF and macrophage markers were determined in OC tissues from clinic patients and five OC (A2780, SKOV3, CAOV3, OVCAR3, and OVCA433) cell lines through quantitative reverse transcription PCR. Afterwards, tumor growth, cell proliferation and apoptosis, and macrophage polarization in OC tumor-bearing mice with PEDF overexpression were recorded and investigated. Finally, the polarization of macrophages was explored in the presence of lentiviral PEDF overexpression, adipose triglyceride lipase (ATGL) and laminin receptor (LR) knockdown, and mitogen-activated protein kinase (MAPK) pathway inhibition. Our results suggest that PEDF mRNA level is significantly decreased in OC tissues and cells and has a significant negative correlation with OC progression and the level of tumor-related macrophage markers. Furthermore, OC tumors overexpressing PEDF show suppressed growth viability and increased apoptosis rate. The fluorescence activated cell sorting (FACS) analysis reveals that PEDF can promote macrophage polarization in OC tumors towards M1 subtype. Mechanistically, we found that ATGL and extracellular-regulated kinase 1/2 (ERK1/2) signaling are involved in the regulation of macrophage polarization in OC tumors by PEDF. Taken together, these data indicate that the role of PEDF in regulating the polarization of tumor-associated macrophages may make it a potential therapeutic strategy for the treatment of OC in the future.

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Fig. 1: Pigment epithelium-derived factor (PEDF) is down-regulated in ovarian cancer (OC) and correlates negatively with metastatic progression in OC patients.
Fig. 2: PEDF is associated with the polarization of macrophages in OC tissues and cells.
Fig. 3: PEDF slows OC progression in the tumor-bearing mice.
Fig. 4: PEDF decreases the polarization of tumor-associated M2 macrophages.
Fig. 5: PEDF modulates macrophage polarization through targeting adipose triglyceride lipase (ATGL) and extracellular-regulated kinase 1/2 (ERK1/2).

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The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai, 200072, China

    Rui Ma, Xiaolin Chu & Yiting Jiang

  2. Department of Oncology, Shanghai Tenth People’s Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai, 200072, China

    Qing Xu

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Contributions

Design and experimentation: RM, XC, YJ, and QX; supervision: QX; and manuscript writing: RM and QX.

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Correspondence to Qing Xu.

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The authors declare no competing interests.

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The present study was approved by the Ethics Review Committee of Shanghai Tenth People’s Hospital. Written informed consent was obtained from all participants before specimen collection.

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Ma, R., Chu, X., Jiang, Y. et al. Pigment epithelium-derived factor, an anti-VEGF factor, delays ovarian cancer progression by alleviating polarization of tumor-associated macrophages. Cancer Gene Ther 29, 1332–1341 (2022). https://doi.org/10.1038/s41417-022-00447-4

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