1. ¹Department of Microbiology and Immunobiology, Max F Perutz Laboratories, University of Vienna, Vienna, Austria
2. ²Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Basel, Switzerland

Correspondence: Dr M Baccarini, Department of Microbiology and Immunobiology, Max F Perutz Laboratories, University of Vienna, Dr Bohr Gasse 9, Vienna 1030, Austria. E-mail: manuela.baccarini@univie.ac.at

³These authors contributed equally to this work.

Received 17 September 2007; Revised 11 February 2008; Accepted 10 March 2008; Published online 19 May 2008.

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.