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Prolactin Promotes Fibrosis and Pancreatic Cancer Progression.
- Source :
-
Cancer research [Cancer Res] 2019 Oct 15; Vol. 79 (20), pp. 5316-5327. Date of Electronic Publication: 2019 Aug 08. - Publication Year :
- 2019
-
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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Animals
Carcinoma, Pancreatic Ductal physiopathology
Cell Line, Tumor
Collagen metabolism
Disease Progression
Epithelium metabolism
Female
Fibrosis
Focal Adhesion Kinase 1 metabolism
Genes, Reporter
HMGB1 Protein physiology
Humans
Macrophages metabolism
Male
Metoclopramide
Mice
Mice, Knockout
Neoplasm Proteins metabolism
Neoplasms, Hormone-Dependent physiopathology
Pancreatic Neoplasms physiopathology
Phosphorylation
Pregnancy
Prolactin deficiency
Prolactin physiology
Protein Processing, Post-Translational
RNA Interference
RNA, Small Interfering genetics
Receptors, Prolactin genetics
Receptors, Prolactin metabolism
Recombinant Proteins pharmacology
STAT3 Transcription Factor metabolism
Stromal Cells metabolism
Carcinoma, Pancreatic Ductal pathology
Neoplasms, Hormone-Dependent pathology
Pancreatic Neoplasms pathology
Prolactin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31395607
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-3064