Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression

Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17146-51. doi: 10.1073/pnas.0901767106. Epub 2009 Aug 31.

Abstract

Chronic inflammation and cancer are intimately associated. This is particularly true for inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, which show a major increased risk for colorectal cancer. While the understanding of the molecular pathogenesis of IBD has recently improved, the mechanisms that link these chronic inflammatory states to colorectal cancer development are in large part unknown. One of these mechanisms is NF-kappaB pathway activation which in turn may contribute to tumor formation by providing anti-apoptotic survival signals to the epithelial cells. Based on the observation that netrin-1, the anti-apoptotic ligand for the dependence receptors DCC and UNC5H is up-regulated in colonic crypts in response to NF-kappaB, we show here that colorectal cancers from inflammatory bowel diseases patients have selected up-regulation of netrin-1. Moreover, we demonstrate that this inflammation-driven netrin-1 up-regulation is causal for colorectal cancer development as interference with netrin-1 autocrine loop in a mouse model for ulcerative colitis-associated colorectal cancer, while showing no effect on inflammation, inhibits colorectal cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3 / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Female
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Immunohistochemistry
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / pathology
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / metabolism
  • Netrin-1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation*

Substances

  • NF-kappa B
  • NTN1 protein, human
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Tumor Suppressor Proteins
  • Netrin-1
  • Caspase 3