Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells
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Vegard Tjomsland1,2,*, Monica Aasrum1,*, Thoralf Christoffersen1 and Ivar P Gladhaug2,3
1Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
2Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
3Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway
*These authors contributed equally to this work
Ivar P Gladhaug, email: [email protected]
Keywords: pancreatic cancer, human pancreatic stellate cells, tumor-stroma interactions, HGF, cancer cell migration
Received: November 10, 2016 Accepted: April 26, 2017 Published: May 11, 2017
The pancreatic stellate cell (PSC) is the principal cell type of the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC). PSCs interact with cancer cells and influence the progression of the disease through a complex network of signaling molecules including hepatocyte growth factor (HGF). Functional heterogeneity of PSCs within a tumor might conceivably influence tumor progression. We investigated PSC populations isolated from different human PDACs and examined the effects of PSC-conditioned medium on BxPC-3 and AsPC-1 pancreatic cancer cells. The different PSC populations exhibited a wide range of variation (120−3,000 pg/ml) in their ability to secrete HGF. Media from high-HGF-producing PSCs stimulated phosphorylation of Met, Gab1, and ERK in the cancer cells and induced increases in DNA synthesis and migration which were blocked by the Met inhibitor SU11274, indicating a role of HGF as a mediator. HGF levels produced by PSCs and the effects of PSC media on the cancer cells were increased by IL-1α and inhibited by TGFβ. The functional heterogeneity of PSCs in terms of HGF-mediated tumor-stroma interactions suggests that inhibition of the HGF pathway as a novel treatment approach in PDAC might have different effects in different subsets of patients.
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