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Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

Oncogene volume 38, pages 5670–5685 (2019)Cite this article

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Abstract

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

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Acknowledgements

Research in the Cramer lab was supported by grants from Deutsche Krebshilfe (109160) and Deutsche Forschungsgemeinschaft (CR 133/2-1 until 2–4). NR was supported by a grant from the BMBF (MAPTor-NET (031A426A)). We are indebted to Ralf Weiskirchen (University Hospital Aachen) for help regarding the MLEC assay. We are grateful to Christine Sers (Charité, Berlin) and Florian R. Greten (Georg-Speyer-Haus, Frankfurt) for helpful discussions and to Ilia N. Buhtoiarov (Children’s Hospital of New Jersey, USA), Glenn S. Belinsky, Daniel W. Rosenberg (University of Connecticut Health Center, Farmington, USA), and Takuji Tanaka (Gifu Municipal Hospital, Japan) for providing control reagents. We are grateful to Deborah Gumucio (University of Michigan, USA) for providing Villin-Cre mice. The excellent technical assistance of Birgit Bogdanoff and Simone Spiekermann is highly appreciated. Parts of this work were granted the “Best Poster Award” at the 2015 CELL symposium “Cancer, Inflammation and Immunity” in Sitges, Spain.

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Author notes

  1. Maciej B. Malinowski

    Present address: Department for General Visceral, Vascular, and Pediatric Surgery, Saarland University Hospital, Homburg, Germany

  2. William Faller

    Present address: The Netherlands Cancer Institute, Amsterdam, The Netherlands

  3. These authors contributed equally: Sandra Jumpertz, Merve Erdem

Authors and Affiliations

  1. Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Nadine Rohwer & Ines Rudolph

  2. Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany

    Sandra Jumpertz, Merve Erdem, Antje Egners, Athanassios Fragoulis & Thorsten Cramer

  3. Medicine III, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany

    Klaudia T. Warzecha & Frank Tacke

  4. Research Center Immunosciences, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

    Anja A. Kühl

  5. Medicine II, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany

    Rafael Kramann

  6. Pathology, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany

    Sabine Neuss

  7. Experimental Endocrinology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Tobias Endermann & Lutz Schomburg

  8. Max-Delbrück-Centrum, Robert-Rössle-Straße 10, 13125, Berlin, Germany

    Christin Zasada & Stefan Kempa

  9. Nuclear Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Ivayla Apostolova & Winfried Brenner

  10. Biosciences and Nutrition, Karolinska Institutet, Alfred Nobels Allé 8, 17177, Stockholm, Sweden

    Marco Gerling

  11. Oncology and Metabolism, University of Sheffield Medical School, Sheffield, S10 2RX, UK

    Russell Hughes & Claire E. Lewis

  12. Surgery, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Maciej B. Malinowski & Martin Stockmann

  13. Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK

    William Faller & Owen J. Sansom

  14. Institute for Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

    Markus Morkel

  15. NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

    Thorsten Cramer

  16. ESCAM—European Surgery Center Aachen Maastricht, Aachen, Germany

    Thorsten Cramer

  17. ESCAM—European Surgery Center Aachen Maastricht, Maastricht, The Netherlands

    Thorsten Cramer

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  1. Nadine Rohwer
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Contributions

Conceptualization, NR, MM, and TC; methodology, NR, ME, SJ, AE, KTW, AAK, AF, SN, MG, IR, T.E., CZ, SK, RH, MBM, WF, and MM; formal analysis, investigation, and visualization, NR, ME, SJ, AE, AAK, RK, SN, IR, MG, CZ, SK, MBM, MM, and TC; writing, NR, FT, MM, and TC; supervision, resources, and funding acquisition, RK, SK, CEL, WB, MS, LS, OS, FT, MM, and TC; project administration, TC.

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Correspondence to Thorsten Cramer.

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Rohwer, N., Jumpertz, S., Erdem, M. et al. Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene 38, 5670–5685 (2019). https://doi.org/10.1038/s41388-019-0816-4

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  • DOI: https://doi.org/10.1038/s41388-019-0816-4

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