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催乳素促进纤维化和胰腺癌进展。

Prolactin Promotes Fibrosis and Pancreatic Cancer Progression.

机构信息

Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

出版信息

Cancer Res. 2019 Oct 15;79(20):5316-5327. doi: 10.1158/0008-5472.CAN-18-3064. Epub 2019 Aug 8.

DOI:10.1158/0008-5472.CAN-18-3064
PMID:31395607
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6801092/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1-induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer. SIGNIFICANCE: Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression.

摘要

胰腺导管腺癌（PDAC）与显著的纤维化有关。最近的研究结果强调了组织驻留巨噬细胞在胰腺癌微环境中的促纤维化活性。在这里，我们表明，肿瘤胰腺上皮以及一部分组织驻留巨噬细胞表达催乳素受体（PRLR）。高迁移率族蛋白 1 诱导的胰腺中催乳素的表达维持了上皮和基质中 FAK1 和 STAT3 的磷酸化。功能获得和功能丧失实验表明，催乳素在促进胶原蛋白沉积和纤维化中起着至关重要的作用。最后，催乳素/PRLR 的信号级联反应在 PDAC 中激活了 STAT3 而不是 STAT5。这些发现表明，靶向催乳素以及已知的 STAT3 主要激活剂 IL6，可能代表治疗胰腺癌的一种新的治疗策略。意义：催乳素是基质和肿瘤上皮之间相互作用的关键因素，可促进纤维化和 PDAC 的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c94/6801092/26ae81b7e795/nihms-1536977-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c94/6801092/aab9d5b84f12/nihms-1536977-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c94/6801092/56902046a6d6/nihms-1536977-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c94/6801092/26ae81b7e795/nihms-1536977-f0007.jpg

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