1. Pancreatic cancer stimulates pancreatic stellate cell proliferation and TIMP-1 production through the MAP kinase pathway
- Author
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Woody Denham, Carolyn Pelham, Seiya Yoshida, Michael B. Ujiki, Xian-Zhong Ding, Thomas E. Adrian, Mark S. Talamonti, Tokuyasu Yokota, and Richard H. Bell
- Subjects
MAPK/ERK pathway ,Male ,endocrine system diseases ,Biophysics ,Pancreatic stellate cell ,Adenocarcinoma ,Biochemistry ,Rats, Sprague-Dawley ,Cell Line, Tumor ,medicine ,Animals ,Molecular Biology ,Pancreas ,Tissue Inhibitor of Metalloproteinase-1 ,biology ,Kinase ,Cell Biology ,Tissue inhibitor of metalloproteinase ,digestive system diseases ,Rats ,Fibronectin ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Cancer research ,biology.protein ,Hepatic stellate cell ,Pancreatic stellate cell proliferation ,Signal transduction ,Mitogen-Activated Protein Kinases ,Cell Division ,Signal Transduction - Abstract
Pancreatic adenocarcinoma is characterized by an intense desmoplastic reaction that surrounds the tumor. Pancreatic stellate cells (PSCs) are thought to be responsible for production of this extracellular matrix. When activated, PSCs have a myofibroblast phenotype and produce not only components of the extracellular matrix including collagen, fibronectin, and laminin, but also matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Since PSCs are found in the stroma surrounding human pancreatic adenocarcinoma, we postulate that pancreatic cancer could impact PSC proliferation and TIMP-1 production. Rat PSCs were isolated and cultured. Isolated PSCs were exposed to PANC-1 conditioned medium (CM) and proliferation, activation of the mitogen-activated protein (MAP) kinase pathway, and TIMP-1 gene induction were determined. Exposure to PANC-1 CM increased PSC DNA synthesis, cell number, and TIMP-1 mRNA (real-time PCR) as well as activating the extracellular-regulated kinase (ERK) 1/2. Inhibition of ERK 1/2 phosphorylation (U0126) prevented the increases in growth and TIMP-1 expression. PANC-1 CM stimulates PSC proliferation and TIMP-1 through the MAP kinase (ERK 1/2) pathway.
- Published
- 2004