Tumor Biology

, Volume 37, Issue 2, pp 2243–2255 | Cite as

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
Original Article

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.

Keywords

BMP GREM1 uPA Colorectal cancer Colitis Mouse 

Notes

Acknowledgments

The authors are grateful to the Bodossaki Foundation for the kind donation of the real-time PCR instrumentation.

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • George S. Karagiannis
    • 1
  • Hara Afaloniati
    • 2
  • Elisavet Karamanavi
    • 3
    • 4
  • Theofilos Poutahidis
    • 3
  • Katerina Angelopoulou
    • 2
  1. 1.Department of Anatomy and Structural Biology, Albert Einstein College of MedicineYeshiva UniversityBronxUSA
  2. 2.Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health SciencesAristotle University of ThessalonikiThessalonikiGreece
  3. 3.Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health SciencesAristotle University of ThessalonikiThessalonikiGreece
  4. 4.Department of Cardiovasular Sciences, Cardiovascular Research Centre, Glenfield General HospitalUniversity of LeicesterLeicesterUK

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