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

Abstract

Activation of the Raf/MEK/ERK pathway, often by gainof-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.

Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma

“…Thus, we created an in vitro scenario with the Ishikawa EEC cell line infected with lentiviruses carrying the V600 BRAF mutation. Some studies have reported that, in many different cell systems, Ras downstream signaling is required in the process of EMT [19][20][21][22]. The BRAF missense mutation V600E leads to a constitutive activation of the kinase activity of BRAF and, thus, to the activation of MEKs and ERKs [21,22].…”

“…It has been reported that Ras downstream signaling is required for EMT in many different cell systems [19][20][21][22]. Even if BRAF mutation is exceedingly rare in EEC, its V600 missense mutation induces a persistent activation of the MAPK/ERK pathway that allows tumor cells to undergo EMT [21,22].…”

Raf kinases in cancer–roles and therapeutic opportunities

“…Conversely, conditional ablation of endogenous B-Raf prevents the angiogenic switch in a mouse model of pancreatic islet carcinoma driven by loss of function of the tumor suppressors p53 and Rb. B-Raf-deficient tumor cells proliferate normally despite decreased ERK activation, but produce insufficient amounts of the proangiogenic factors VEGF and TGFb, resulting in reduced blood vessel density and tumor proliferation, and delayed tumor progression (Sobczak et al, 2008).…”

“…Raf can influence invasion at several levels. First, activated Raf is involved in the production of TGFb, which promotes invasion and metastasis (Lehmann et al, 2000;Sobczak et al, 2008;Riesco-Eizaguirre et al, 2009), as well as the epithelial-mesenchymal transition that precedes invasion in response to this factor (Janda et al, 2002). Second, both B-Raf and C-Raf have essential, if opposite, roles in cell contractility and migration: B-Raf increasing Rho-dependent contractility and opposing migration in an ERK-dependent manner (Pritchard et al, 2004), and C-Raf reducing contractility and increasing migration by inhibiting the Rho effector Rok-a (Ehrenreiter et al, 2005).…”

Inhibition of Heat Shock Protein 90 with AUY922 Represses Tumor Growth in a Transgenic Mouse Model of Islet Cell Neoplasms

“…The aforementioned serin/threonine-protein kinase BRAF is such a client of HSP90 and mutated in approximately 7% of all human malignancies [33]. Sobczak et al [34] could show that BRAF plays an essential role in the regulation of neoangiogenesis - a crucial step towards invasive carcinomas in RIP1-Tag2 mice. Our recent works went a step further.…”