Understanding the Importance of Smart Drugs in Renal Cell Carcinoma Jean-Jacques Patard, Nathalie Rioux-Leclercq, Patricia Fergelot  European Urology  Volume 49, Issue 4, Pages 633-643 (April 2006) DOI: 10.1016/j.eururo.2006.01.016 Copyright © 2006 Elsevier B.V. Terms and Conditions

Fig. 1 VHL/HIF pathway and target genes. In normoxic conditions, the HIF-α subunit degradation depends on hydroxylation and binding to pVHL forms with elongin B, C, Cul2 and Rbx1, the E3 ubiquitin ligase complex. HIF-1α and HIF-2α are expressed constitutively either in case of hypoxia or pVHL alteration. HIF-α stabilisation leads to up-regulation of target genes such as VEGF and PDGF. HIF-2α activates TGF-α and, thus, is considered the oncogenic form of HIF-α. European Urology 2006 49, 633-643DOI: (10.1016/j.eururo.2006.01.016) Copyright © 2006 Elsevier B.V. Terms and Conditions

Fig. 2 Predicted structures of VEGF pre-mRNA and splice forms; exons are not drawn to scale. European Urology 2006 49, 633-643DOI: (10.1016/j.eururo.2006.01.016) Copyright © 2006 Elsevier B.V. Terms and Conditions

Fig. 3 Homodimerised VEGFRs and their respective ligands. Binding of ligand homodimers to the transmembrane receptor activates its dimerisation and signal transduction. VEGFR2 is essential for endothelial blood cells proliferation in tumors, whereas VEGFR3 mediates the lymphatic vessels development. The role of VEGFR1 in tumor angiogenesis is not well defined. European Urology 2006 49, 633-643DOI: (10.1016/j.eururo.2006.01.016) Copyright © 2006 Elsevier B.V. Terms and Conditions

Fig. 4 Summary of molecular mechanisms involved in angiogenesis and tumor growth. New anti-angiogenic molecules and their targets are indicated both in endothelial and tumor cells. European Urology 2006 49, 633-643DOI: (10.1016/j.eururo.2006.01.016) Copyright © 2006 Elsevier B.V. Terms and Conditions