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Utility of a bacterial infection model to study epithelial–mesenchymal transition, mesenchymal–epithelial transition or tumorigenesis

Oncogene volume 33, pages 2639–2654 (2014)Cite this article

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Abstract

DCLK1 and Lgr5 have recently been identified as markers of quiescent and cycling stem cells in the small intestinal crypts, respectively. Epithelial–mesenchymal transition (EMT) is a key development program that is often activated during cancer invasion and metastasis, and also imparts a self-renewal capability to disseminating cancer cells. Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we observed a relative decrease in DCLK1 expression in the colonic crypts, with significant shift towards stromal staining at peak (12 days post infection) hyperplasia, whereas staining for Lgr5 and Msi-1 increased several fold. When hyperplasia was regressing (days 20–34), an expansion of DCLK1+ve cells in the CR-infected crypts compared with that seen in uninfected control was recorded. Purified colonic crypt cells exhibiting epigenetic modulation of the transforming growth factor-β (TGFβ), Wnt and Notch pathways on 12 or 34 days post infection formed monolayers in vitro, and underwent trans-differentiation into fibroblast-like cells that stained positive for vimentin, fibronectin and DCLK1. These cells when trypsinized and regrown in soft agar, formed colonospheres/organoids that developed into crypt-like structures (colonoids) in Matrigel and stained positive for DCLK1. Mice exhibiting 12 or 34 days of TMCH were given azoxymethane once for 8 h (Gp1) or weekly for 3 weeks (Gp2), and subjected to crypt isolation. Crypt cells from Gp1 animals formed monolayers as well as colonospheres in soft agar and nodules/tumors in nude mice. Crypt cells isolated from Gp2 animals failed to form the monolayers, but developed into colonospheres in soft agar and nodules/tumors in nude mice. Thus, both hyperplasia and increased presence of DCLK1+ve cells promote cellular transformation in response to a second hit. The TMCH model, therefore, provides an excellent template to study how alterations in intestinal stem cells promote trans-differentiation, crypt regeneration or colon carcinogenesis following bacterial infection.

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Acknowledgements

This work was supported by the National Institutes of Health Grant R01 CA131413 (to SU), NIDDK’s U01DK085508–04S1 (to CWH) and start-up funds from the University of Kansas Medical Center, Kansas City, KS, USA.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Oklahoma City, OK, USA

    P Chandrakesan & C Houchen

  2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA

    B Roy, L U M R Jakkula, I Ahmed, P Ramamoorthy, S Anant & S Umar

  3. Department of Anatomic and Surgical Pathology, University of Kansas Medical Center, Kansas City, KS, USA

    O Tawfik

  4. Carestream Molecular Imaging, Woodbridge, CT, USA

    R Papineni

  5. The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA

    S Anant & S Umar

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Chandrakesan, P., Roy, B., Jakkula, L. et al. Utility of a bacterial infection model to study epithelial–mesenchymal transition, mesenchymal–epithelial transition or tumorigenesis. Oncogene 33, 2639–2654 (2014). https://doi.org/10.1038/onc.2013.210

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