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Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts

Oncogene volume 33, pages 97–107 (2014)Cite this article

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Abstract

The interaction between epithelial cancer cells and cancer-associated fibroblasts (CAFs) has a major role in cancer progression and eventually in metastasis. In colorectal cancer (CRC), CAFs are present in high abundance, but their origin and functional interaction with epithelial tumor cells has not been elucidated. In this study we observed strong activation of the transforming growth factor-β (TGF-β)/Smad signaling pathway in CRC CAFs, accompanied by decreased signaling in epithelial tumor cells. We evaluated the TGF-β1 response and the expression of target genes including matrix metalloproteinases (MMPs) and plasminogen activator inhibitor (PAI)-1 of various epithelial CRC cell lines and primary CAFs in vitro. TGF-β1 stimulation caused high upregulation of MMPs, PAI-1 and TGF-β1 itself. Next we showed that incubation of CAFs with conditioned medium (CM) from epithelial cancer cells led to hyperactivation of the TGF-β signaling pathway, enhanced expression of target genes like PAI-1, and the expression of α-smooth muscle actin (α-SMA). We propose that the interaction of tumor cells with resident fibroblasts results in hyperactivated TGF-β1 signaling and subsequent transdifferentiation of the fibroblasts into α-SMA-positive CAFs. In turn this leads to cumulative production of TGF-β and proteinases within the tumor microenvironment, creating a cancer-promoting feedback loop.

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Acknowledgements

We thank Dr R Hanemaaijer (TNO Quality of Life BioSciences, Leiden, The Netherlands) for helpful suggestions and reagents. Eveline de Jonge-Muller (Department of Gastroenterology-Hepatology, LUMC), Adri Mulder-Stapel (TNO) and Gabi van Pelt (Department Surgery, LUMC) are acknowledged for excellent technical support. This work was supported by the EC Tumor-host genomic project, the Centre for Biomedical Genetics, the Swedish Cancer Fonden 090773 (EW, PtD) and the Bas Mulder Award 2011 (LJACH, MP, UL2011-5051).

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Author notes

  1. E Wiercinska

    Present address: 6Current address: German Red Cross Blood Centre and Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University, Frankfurt, Germany.,

Authors and Affiliations

  1. Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands,

    L J A C Hawinkels, H W Verspaget, J M van der Zon, P J Koelink & C F M Sier

  2. 2Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Centre, Leiden, The Netherlands,

    L J A C Hawinkels, M Paauwe, E Wiercinska, K van der Ploeg & P ten Dijke

  3. Department of Vascular Surgery, Leiden University Medical Centre, Leiden, The Netherlands,

    J H N Lindeman

  4. Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands

    W Mesker & C F M Sier

  5. Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden

    P ten Dijke

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Hawinkels, L., Paauwe, M., Verspaget, H. et al. Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts. Oncogene 33, 97–107 (2014). https://doi.org/10.1038/onc.2012.536

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