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B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis

Oncogene volume 27, pages 4779–4787 (2008)Cite this article

Abstract

Activation of the Raf/MEK/ERK pathway, often by gain-of-function mutations of RAS or RAF, is observed in many human cancers. The extracellular signal-regulated kinase (ERK) pathway is required for the proliferation of cancer cell lines harboring activating BRAF or, to a lesser extent, activating RAS mutations. It is still unclear, however, whether the pathway is required in vivo for tumor development, particularly in tumors in which B-Raf is not mutationally activated. During embryonic development, B-Raf is essential for angiogenesis in the placenta. To address the question of whether B-Raf contributed to tumor angiogenesis in vivo we conditionally ablated B-Raf in a model of pancreatic islet carcinoma driven by the functional inactivation of tumor suppressors (RIP1Tag2), which critically depends on angiogenesis for growth. We find that B-Raf is dispensable for the proliferation of tumor cells in culture, but necessary for ERK activation and for the expression of angiogenic factors by tumor cells in vivo and in vitro. In vivo, these defects result in the formation of hollow tumors with decreased vessel density and strongly reduced proliferation. The progression from adenoma to carcinoma is also significantly impaired. Thus, endogenous B-Raf contributes to the development of RIP1Tag2 tumors by supporting the stromal response and tumor progression.

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Acknowledgements

We thank Matthias Hamerl and the animal house team for excellent technical help. This work was supported by European Community Grant LSH-CT-2003-506803 (to MB) and the NCCR Molecular Oncology of the Swiss National Science Foundation (to GC).

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Author notes

  1. I Sobczak and G Galabova-Kovacs: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunobiology, Max F Perutz Laboratories, University of Vienna, Vienna, Austria

    I Sobczak, G Galabova-Kovacs, I Sadzak & M Baccarini

  2. Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Basel, Switzerland

    A Kren & G Christofori

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  1. I Sobczak
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  2. G Galabova-Kovacs
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Correspondence to M Baccarini.

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Sobczak, I., Galabova-Kovacs, G., Sadzak, I. et al. B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis. Oncogene 27, 4779–4787 (2008). https://doi.org/10.1038/onc.2008.128

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