Tumor Stroma Interactions Induce Chemoresistance in Pancreatic Ductal Carcinoma Cells Involving Increased Secretion and Paracrine Effects of Nitric Oxide and Interleukin-1β

  • Susanne Müerköster
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Kai Wegehenkel
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Alexander Arlt
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Maike Witt
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Bence Sipos
    2Department of Pathology, and
  • Marie-Luise Kruse
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Thorsten Sebens
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Günter Klöppel
    2Department of Pathology, and
  • Holger Kalthoff
    3Research Group of Molecular Oncology, Department of General Surgery, UKSH–Campus Kiel, Kiel, Germany
  • Ulrich R. Fölsch
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,
  • Heiner Schäfer
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine,

抄録

<jats:title>Abstract</jats:title> <jats:p>Pancreatic ductal carcinoma is characterized by a profound chemoresistance. As we have shown previously, these tumor cells can develop chemoresistance by interleukin (IL)-1β in an autocrine and nuclear factor-κB-dependent fashion. Because pancreatic ductal carcinoma contains many mesenchymal stromal cells, we further investigated how tumor–stroma interactions contribute to chemoresistance by using a transwell coculture model, including murine pancreatic fibroblasts and the chemosensitive human pancreatic carcinoma cell lines T3M4 and PT45-P1. If cultured with fibroblast-conditioned medium or kept in coculture with fibroblasts, both cell lines became much less sensitive toward treatment with etoposide than cells cultured under standard conditions. Furthermore, the secretion of IL-1β in T3M4 and PT45-P1 cells was increased by the fibroblasts, and IL-1β-receptor blockade abolished the resistance-inducing effect during cocultivation. This stimulated IL-1β secretion could be attributed to nitric oxide (NO) released by the fibroblasts as an IL-1β-inducing factor. Although both tumor cells secreted only little NO, which was in line with undetectable inducible nitric oxide synthase (iNOS) expression, fibroblasts exhibited significant iNOS expression and NO secretion that could be further induced by the tumor cells. Incubation of T3M4 and PT45-P1 cells with the NO donor S-Nitroso-N-acetyl-D,l-penicillamine up-regulated IL-1β secretion and conferred resistance toward etoposide-induced apoptosis. Conversely, the resistance-inducing effect of the fibroblasts was significantly abolished, when the specific iNOS inhibitor aminoguanidine was added during coculture. Immunohistochemistry on tissue sections from human pancreatic ductal carcinoma also revealed iNOS expression in stromal cells and IL-1β expression in tumor cells, thus supporting the in vitro findings. These data clearly demonstrate that fibroblasts contribute to the development of chemoresistance in pancreatic carcinoma cells via increased secretion of NO, which in turn leads to an elevated release of IL-1β by the tumor cells. These findings substantiate the implication of tumor–stromal interactions in the chemoresistance of pancreatic carcinoma.</jats:p>

収録刊行物

  • Cancer Research

    Cancer Research 64 (4), 1331-1337, 2004-02-15

    American Association for Cancer Research (AACR)

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