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The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance
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Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer

First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany
Department of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, D-17487 Greifswald, Germany
Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena, Germany
Author to whom correspondence should be addressed.
Academic Editor: Andrei Turtoi
J. Clin. Med. 2016, 5(12), 111;
Received: 3 November 2016 / Revised: 22 November 2016 / Accepted: 28 November 2016 / Published: 30 November 2016
(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)
TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage. We have recently identified PAR2 as a factor required for TGF-β1-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-β-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-β signaling to a diverse range of other physiological processes, such as local inflammation, systemic coagulation or pathogen infection. Moreover, since PAR2 controls expression of the TGF-β type I receptor ALK5, PAR2 may also impact signaling by other TGF-β superfamily members that signal through ALK5, such as myostatin and GDF15/MIC-1. If so, PAR2 could represent a molecular linker between PDAC development and cancer-related cachexia. View Full-Text
Keywords: pancreatic carcinoma; signaling; TGF-β; ALK5; PAR2; myostatin; GDF15; cachexia pancreatic carcinoma; signaling; TGF-β; ALK5; PAR2; myostatin; GDF15; cachexia
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Witte, D.; Zeeh, F.; Gädeken, T.; Gieseler, F.; Rauch, B.H.; Settmacher, U.; Kaufmann, R.; Lehnert, H.; Ungefroren, H. Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer. J. Clin. Med. 2016, 5, 111.

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