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Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms

Oncogene volume 36, pages 5341–5355 (2017)Cite this article

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Abstract

The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. In addition to its effects on malignant cells, autocrine IGF2/IGF1R signaling in CAFs induced myofibroblast differentiation in terms of alpha-smooth muscle actin expression and contractility in floating collagen gels. This was further augmented in concert with transforming growth factor-β (TGFβ) signaling suggesting a cooperative mechanism. However, we demonstrated that IGF2 neither induced TGFβ/smooth muscle actin/mothers against decapentaplegic (SMAD) signaling nor synergized with TGFβ to hyperactivate this pathway in two dimensional and three dimensional cultures. IGF2-mediated physical matrix remodeling by CAFs, but not changes in extracellular matrix-modifying proteases or other secreted factors acting in a paracrine manner on/in cancer cells, facilitated subsequent tumor cell invasion in organotypic co-cultures. Consistently, colon cancer cells co-inoculated with CAFs expressing endogenous IGF2 in mouse xenograft models exhibited elevated invasiveness and dissemination capacity, as well as increased local tumor regrowth after primary tumor resection compared with conditions with IGF2-deficient CAFs. In line, expression of IGF2 correlated with elevated relapse rates and poor survival in CRC patients. In agreement with our results, high-level coexpression of IGF2 and TGFβ was predicting adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together, we demonstrate that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.

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Acknowledgements

We are grateful to Margit Schmeidl for expert technical assistance. We would like to thank Wolfgang Mikulits and Philipp Wittmann for providing TGFβ reagents and technical input.

Author information

Author notes

  1. M Scherzer

    Present address: 7Current address: Karolinska Institutet, Solnavägen 1, 171 77 Solna, Sweden.,

  2. M Stadler

    Present address: 8Current address: Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,

Authors and Affiliations

  1. Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria

    C Unger, N Kramer, D Unterleuthner, M Scherzer, A Burian, M Stadler, A Riedl, S Walter, M Hengstschläger & H Dolznig

  2. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

    A Rudisch, A Riedl, A Wernitznig & W Sommergruber

  3. Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria

    M Schlederer & L Kenner

  4. Oncotest GmbH, Am Flughafen 12, Freiburg, Germany

    D Lenhardt & J Schüler

  5. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    L Kenner

  6. Institute of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria

    L Kenner

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Unger, C., Kramer, N., Unterleuthner, D. et al. Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms. Oncogene 36, 5341–5355 (2017). https://doi.org/10.1038/onc.2017.116

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