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色素上皮衍生因子通过诱导免疫抑制性巨噬细胞促进卵巢癌的腹膜扩散。

Pigment epithelium-derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages.

机构信息

Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Section of Translational Research, Hyogo Cancer Center, Hyogo, Japan.

出版信息

Commun Biol. 2022 Sep 2;5(1):904. doi: 10.1038/s42003-022-03837-4.

DOI:10.1038/s42003-022-03837-4
PMID:36056141
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9440245/
Abstract

Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium-derived factor (PEDF) as a promoting factor of OC dissemination, which functions through induction of CD206 Interleukin-10 (IL-10)-producing macrophages. High PEDF gene expression in tumors is associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum are significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors reduce PEDF expression and limit both OC cell survival and CD206 macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein-PEDF-IL-10 axis as a promising therapeutic target for OC.

摘要

卵巢癌（OC）的腹膜播散与预后不良相关，但 OC 细胞逃避腹腔免疫系统的机制仍不清楚。我们在这里确定色素上皮衍生因子（PEDF）是促进 OC 播散的一个因素，它通过诱导 CD206 白细胞介素 10（IL-10）产生的巨噬细胞发挥作用。肿瘤中高 PEDF 基因表达与 OC 患者的不良预后相关。OC 患者腹水中和血清中的 PEDF 浓度明显高于良性肿瘤患者，且与 OC 患者的早期复发相关，提示 PEDF 可能作为一种预后生物标志物。溴结构域和末端（BET）抑制剂可降低 PEDF 表达，并限制 OC 细胞在腹腔中的存活和 CD206 巨噬细胞的诱导。因此，我们的研究结果表明 PEDF 是 OC 播散的驱动因素，并确定 BET 蛋白-PEDF-IL-10 轴作为 OC 的一个有前途的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/cd3421f961ed/42003_2022_3837_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/a7d397b28118/42003_2022_3837_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/827ca8dba417/42003_2022_3837_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/4031cb9e82d1/42003_2022_3837_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/1b296cf1bda8/42003_2022_3837_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/f0ef0b177aab/42003_2022_3837_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/320bf99c47fa/42003_2022_3837_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/68a15348bfee/42003_2022_3837_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/cd3421f961ed/42003_2022_3837_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/a7d397b28118/42003_2022_3837_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/827ca8dba417/42003_2022_3837_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/4031cb9e82d1/42003_2022_3837_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/1b296cf1bda8/42003_2022_3837_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/f0ef0b177aab/42003_2022_3837_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/320bf99c47fa/42003_2022_3837_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/68a15348bfee/42003_2022_3837_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cb/9440245/cd3421f961ed/42003_2022_3837_Fig8_HTML.jpg

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