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

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Tumor Biology

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.

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Acknowledgments

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

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Author notes

  1. Elisavet Karamanavi

    Present address: Department of Cardiovasular Sciences, Cardiovascular Research Centre, Glenfield General Hospital, University of Leicester, Leicester, UK

Authors and Affiliations

  1. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

    George S. Karagiannis

  2. Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Hara Afaloniati & Katerina Angelopoulou

  3. Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Elisavet Karamanavi & Theofilos Poutahidis

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  1. George S. Karagiannis
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  2. Hara Afaloniati
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  3. Elisavet Karamanavi
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Correspondence to Katerina Angelopoulou.

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Karagiannis, G.S., Afaloniati, H., Karamanavi, E. et al. BMP pathway suppression is an early event in inflammation-driven colon neoplasmatogenesis of uPA-deficient mice. Tumor Biol. 37, 2243–2255 (2016). https://doi.org/10.1007/s13277-015-3988-8

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  • DOI: https://doi.org/10.1007/s13277-015-3988-8

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