Figure 1.

Mutation in the von Hippel–Lindau gene (VHL) induces loss (red ×: HIF-2a is no longer inhibited) of the regulatory tumour suppressor p-VHL and catalyses the “von Hippel–Lindau-hypoxia-inducible factor” VHL-HIF pathway. Increased expression of transcription factor HIF-2α causes (blue arrows) higher levels of growth factors (GFs) VEGF, PDGF-β and TGF-α. Sorafenib and sunitinib block their receptors (in red TKI effects), and the intracellular Ras/Raf/MEK/ERK cascade (sorafenib) thereby inhibiting tumorigenesis and metastasis. Inhibition of GFs leads to a decrease in NO-production and reduced endothelial permeability, resulting in increased vasoconstriction, total peripheral resistance (TPR), and hypertension (red arrow).