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Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion

J Surg Res. 2005 Jan;123(1):96-101. doi: 10.1016/j.jss.2004.07.013.

Abstract

Background: Human CC chemokine Macrophage Inflammatory Protein-3alpha (MIP-3alpha) directs inflammatory cell migration through its binding to the transmembrane receptor CCR6. MIP-3alpha has recently been shown to promote tumor cell migration in pancreatic adenocarcinoma by up-regulation of matrix metalloproteinases (MMPs). We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase.

Materials, methods, and results: Immunohistochemistry and RT-PCR confirmed the presence of MIP-3alpha in PANC-1 cells, a human pancreatic adenocarcinoma cell line. MIP-3alpha stimulated the production of both latent and active forms of MMP-9 in PANC-1 by Western analysis. Tumor cell invasion was then evaluated using a modified Boyden chamber invasion assay. MIP-3alpha promoted a dose-dependent increase in pancreatic cancer cell invasion (P < 0.05) at 100 ng/ml. The activity at the putative MIP-3alpha receptor, CCR6, was demonstrated by receptor blockade. Anti-CCR6 antibody and anti-MMP-9 antibody inhibited MIP-3alpha-stimulated PANC-1 cell invasion of collagen to 37% and 35% of control, respectively (P < 0.05).

Conclusions: MIP-3alpha, through its CCR6 receptor, promotes tumor cell invasion by the up-regulation of MMP-9. Molecular based therapy aimed at the inhibition of MIP-3alpha activity through the CCR6 receptor may serve as a future target to prevent tumor cell invasion in pancreatic adenocarcinoma.

MeSH terms

  • Cell Line, Tumor
  • Chemokine CCL20
  • Chemokines, CC / analysis
  • Chemokines, CC / physiology*
  • Combined Modality Therapy
  • Humans
  • Immunohistochemistry
  • Macrophage Inflammatory Proteins / analysis
  • Macrophage Inflammatory Proteins / physiology*
  • Matrix Metalloproteinase 2 / physiology
  • Matrix Metalloproteinase 9 / physiology
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / therapy
  • Receptors, CCR6
  • Receptors, Chemokine / physiology

Substances

  • CCL20 protein, human
  • CCR6 protein, human
  • Chemokine CCL20
  • Chemokines, CC
  • Macrophage Inflammatory Proteins
  • Receptors, CCR6
  • Receptors, Chemokine
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9