BMP pathway suppression is an early event in inflammation-driven colon neoplasmatogenesis of uPA-deficient mice

George S. Karagiannis, Hara Afaloniati, Elisavet Karamanavi, Theofilos Poutahidis, Katerina Angelopoulou

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The suppression of the bone morphogenetic protein (BMP) signaling pathway has been recently shown to promote adenoma-to-carcinoma transition in sporadic colon cancer. However, its role in the evolution of early preneoplastic changes to neoplasia remains elusive. In the present study, we aimed to investigate the gene expression levels of multiple extracellular BMP family constituents, including BMP ligands/receptors and inhibitors, during the early stages of inflammation-associated colon carcinogenesis. For that, we used the recently developed urokinase-type plasminogen activator (uPA)-deficient mouse model of colonic polypoidogenesis, in which adenomatous polyps arise several months after the induction of dextran sodium sulfate (DSS) colitis. In DSS-treated wild-type mice, the preneoplastic lesions which did not eventually evolve to adenomas resided in a colitic microenvironment characterized by a balanced upregulation of both BMP ligands, i.e., Bmp4/7 and BMP inhibitors, such as chordin, noggin, and gremlin-1. In the uPA-deficient tumor-promoting inflammatory microenvironment, however, there was a clear evidence for BMP pathway suppression. By contrast to DSS-treated wild-type controls, the inflammation-associated Bmp4 upregulation was abolished, and the BMP signaling suppression was further enhanced by a particularly high increase of gremlin-1 expression. These findings propose that BMP pathway suppression in colon cancer could be associated with very early stages of the preneoplasia-to-neoplasia sequence of events.

Original languageEnglish (US)
Pages (from-to)2243-2255
Number of pages13
JournalTumor Biology
Volume37
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • BMP
  • Colitis
  • Colorectal cancer
  • GREM1
  • Mouse
  • uPA

ASJC Scopus subject areas

  • Cancer Research

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