Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase

Clin Dev Immunol. 2012;2012:720768. doi: 10.1155/2012/720768. Epub 2012 Nov 20.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n = 115) were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and-by implication-to tumor progression is possible.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biopsy / methods
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Epithelial-Mesenchymal Transition
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Keratins / genetics
  • Keratins / metabolism
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Neutrophils / immunology*
  • Neutrophils / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Zinc Finger E-box-Binding Homeobox 1
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Cadherins
  • Homeodomain Proteins
  • Nuclear Proteins
  • Organic Cation Transport Proteins
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • beta Catenin
  • solute carrier family 22 (organic cation transporter), member 3
  • Keratins
  • Leukocyte Elastase