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.
©2019 American Association for Cancer Research.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Carcinoma, Pancreatic Ductal / pathology*
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Carcinoma, Pancreatic Ductal / physiopathology
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Cell Line, Tumor
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Collagen / metabolism
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Disease Progression
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Epithelium / metabolism
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Female
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Fibrosis
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Focal Adhesion Kinase 1 / metabolism
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Genes, Reporter
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HMGB1 Protein / physiology
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Humans
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Macrophages / metabolism
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Male
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Metoclopramide
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Mice
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Mice, Knockout
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Neoplasm Proteins / metabolism
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Neoplasms, Hormone-Dependent / pathology*
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Neoplasms, Hormone-Dependent / physiopathology
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Pancreatic Neoplasms / pathology*
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Pancreatic Neoplasms / physiopathology
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Phosphorylation
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Pregnancy
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Prolactin / deficiency
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Prolactin / pharmacology*
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Prolactin / physiology
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Protein Processing, Post-Translational
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RNA Interference
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RNA, Small Interfering / genetics
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Receptors, Prolactin / genetics
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Receptors, Prolactin / metabolism
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Recombinant Proteins / pharmacology
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STAT3 Transcription Factor / metabolism
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Stromal Cells / metabolism
Substances
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HMGB1 Protein
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HMGB1 protein, human
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Neoplasm Proteins
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RNA, Small Interfering
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Receptors, Prolactin
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Recombinant Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Prolactin
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Collagen
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Focal Adhesion Kinase 1
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PTK2 protein, human
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Metoclopramide