fig1

Figure 1. Cross-talking between TKI receptors, hypoxia and growth factor receptors and relationship with tumor growth and resistance to TKIs. Several trans-membrane TKI receptors interact with each other and mediate the activation of shared pathways, most implicated in tumor growth and angiogenesis. TGFβ/Smad pathway and the interaction of some cytokines, such as IL-6 with their receptors, together with the Notch signaling pathway and wnt/β-catenin pathway induce EMT transcription factors and EMT as a mechanism of resistance to the inhibition of angiogenesis. Finally, hypoxia promotes both angiogenesis and EMT. AKT: Protein kinase B; AXL: AXL Receptor; EMT: epithelial mesenchymal transition. EMT-TFs: epithelial mesenchymal transition transcription factors; Erk1/2: elk-related tyrosine kinase; FGF: fibroblast growth factor; FGFR: fibroblast growth factor receptor; Gas6: growth arrest specific protein-6; GSK-3: glycogen synthase kinase 3 beta; HGF: hepatocyte growth factor; HIF: hypoxia-inducible factor; IGF: insulin growth factor; TGF-: tumor growth factor; IGFR: insulin growth factor receptor; JAK: janus kinase; Mek1/2: MAP kinase-ERK kinase; MET: hepatocyte growth factor receptor; mTOR: mammalian target of rapamycin; NFκB: nuclear factor kappa B; PDGFR: platelet derived growth factor receptor; PDGF-β: platelet derived growth factor-β; PI3K: phosphatidyl inositol 3-kinase; Raf: RAF proto-oncogene serine/threonine-protein kinase; Ras: rat sarcoma protein; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; VHL: von hippel-lindau protein.