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

Autor(en)

Izabela Sobczak, Gergana Galabova-Kovacs, Angelika Kren, Gerhard Christofori, Manuela Baccarini

Abstrakt

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.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik

Externe Organisation(en)

Medizinische Universität Wien, Universität Basel

Journal

Oncogene: including Oncogene Reviews

Band

27

Seiten

4779-4787

Anzahl der Seiten

9

ISSN

0950-9232

Publikationsdatum

2008

Peer-reviewed

Ja

ÖFOS 2012

106002 Biochemie, 106013 Genetik, 301904 Krebsforschung, 301114 Zellbiologie

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/braf-is-required-for-erk-activation-and-tumor-progression-in-a-mouse-model-of-pancreatic-sscell-carcinogenesis(c5c2a373-27d3-4a30-8ed0-a5675aadb8b7).html