2005 Fiscal Year Final Research Report Summary
Development of new therapy targetting pancreatic cancer-stellate cell interaction
| Project/Area Number |
16590572
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
MASAMUNE Atsushi TOHOKU UNIVERSITY, HOSPITAL, RESEARCH ASSOCIATE, 病院, 助手 (90312579)
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| Co-Investigator(Kenkyū-buntansha) |
SATOH Kennichi TOHOKU UNIVERSITY, HOSPITAL, RESEARCH ASSOCIATE, 病院・助手 (10282055)
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| Project Period (FY) |
2004 – 2005
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| Keywords | pancreatic cancer / pancreatic stellate cells / pancreatic fibrosis / galectin / glycoconjugates / polyphenol |
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| Research Abstract |
Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis and inflammation. Inhibition of activation and cell functions of PSCs is a potential target for the treatment of pancreatic cancer-associated fibrosis ("desmoplastic reaction"). The polyphenol compounds curcumin and ellagic acid have anti-inflammatory and anti-fibrotic properties. We here evaluated the effects of curcumin and ellagic acid on the activation and cell functions of PSCs. Curcumin and ellagic acid inhibited platelet-derived growth factor-induced proliferation, alpha-smooth muscle actin gene expression, interleukin-1beta- and tumor necrosis factor-alpha-induced MCP-1 production, type I collagen production, and expression of type I and type III collagen genes. In addition, Curcumin and ellagic acid inhibited transformation of freshly isolated cells to myofibroblast-like phenotype. In conclusion, curcumin and ellagic acid inhibited key cell functions and activation of PSCs
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, suggesting a potential application of these polyphenols for the treatment of pancreatic fibrosis.
Galectin-1 is a β-galactoside-binding lectin. Previous studies have shown that galectin-1 was expressed in fibroblasts of chronic pancreatitis and of desmoplastic reaction associated with pancreatic cancer. These fibroblasts are now recognized as activated PSCs. We here examined the role of galectin-1 in cell functions of PSCs. Galectin-1 was strongly expressed in culture-activated, but not freshly isolated, PSCs. Recombinant galectin-1 increased proliferation and production of monocyte chemoattractant protein-1 and cytokine-induced neutrophil chemoattractant-1. Galectin-1 activated ERK, JNK, activator protein-1, and NF-κB, but not p38 MAP kinase or Akt. Galectin-1 induced proliferation through ERK, and chemokine production mainly through the activation of NF-κB, and in part by JNK and ERK pathways. These effects of galectin-1 were abolished in the presence of thiodigalactosie, an inhibitor of β-galactoside binding. In conclusion, our results suggest a role of galectin-1 in chemokine production and proliferation through its β-galactoside binding activity in activated PSCs. Less
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