Turning promise into progress for antiangiogenic agents in epithelial ovarian cancer  Arne R.M. van der Bilt, Elisabeth G.E. de Vries, Steven de Jong, Hetty Timmer-Bosscha, Ate G.J. van der Zee, Anna K.L. Reyners  Critical Reviews in Oncology / Hematology  Volume 84, Issue 2, Pages 224-242 (November 2012) DOI: 10.1016/j.critrevonc.2012.03.006 Copyright © 2012 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 In sprouting angiogenesis, some of the vECs incorporated into established vessels are activated by proangiogenic factors (e.g. VEGFA) produced by both cancer cells and accessory cells (stromal and immune cells). These activated endothelial cells (tip cells) detach from the vascular structure and migrate towards the growth factor gradient. Remodeling of the extracellular matrix through the actions of matrix metalloproteases (MMPs) facilitates their migration. Following the highly motile tip cells are other endothelial cells, called trunk cells, which have the capacity to proliferate and form the new vessel sprout. Critical Reviews in Oncology / Hematology 2012 84, 224-242DOI: (10.1016/j.critrevonc.2012.03.006) Copyright © 2012 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 VEGF family members form dimers by covalent, disulfide linkage. These ligand dimers can bind the extracellular parts of VEGFRs, thereby promoting receptor homo- and heterodimerization. VEGF dimers can also interact with several coreceptors, like neuropilins (NRP-1 and NRP-2) and heparan sulfate proteoglycans, enhancing their signalling capacity. The receptor specificity for different VEGF family members is shown schematically. Transphosphorylation of the intracellular kinase domain will occur upon receptor dimerization, followed by recruitment of downstream signal transduction proteins. VEGF(R)-targeted drugs either interfere with ligand–receptor binding or receptor kinase activity (indicated in red and discussed subsequently). Other abbreviations: PlGF, placental growth factor; sVEGFR1, soluble VEGFR1. Critical Reviews in Oncology / Hematology 2012 84, 224-242DOI: (10.1016/j.critrevonc.2012.03.006) Copyright © 2012 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 HIFs can form transcriptionally active heterodimers consisting of an oxygen-regulated α-subunit (most commonly HIF-1α) and a constitutively expressed β-subunit (HIF-1β). In the presence of molecular oxygen, HIF-1α is targeted for proteasomal degradation by the association of Von Hippel–Lindau (VHL) ubiquitination complexes to hydroxylated prolyl residues. Under hypoxic conditions, however, stable HIF-1 (i.e. the complex formed by HIF-1α and HIF-1β) binds to hypoxia response elements (HREs) within the promoter regions of target genes, a precedent to their transcription. Many genes involved in angiogenesis harbour HREs, including VEGFA. Other abbreviations: E3, E3 ubiquitin ligase; Ub, ubiquitin group. Critical Reviews in Oncology / Hematology 2012 84, 224-242DOI: (10.1016/j.critrevonc.2012.03.006) Copyright © 2012 Elsevier Ireland Ltd Terms and Conditions

Fig. 4 HIF-1 has been linked to drug resistance upon treatment with VEGF(R)-targeted drugs. HIF-1 activity can be intrinsic or acquired in reaction to hypoxia resulting from antiangiogenic therapy. HIF-1 aids ovarian cancer cells in overcoming angiogenesis inhibition by upregulation of multiple proangiogenic factors. Furthermore, HIF-1 activity can enhance the invasive and metastatic potential of these cells by regulating several genes involved in epithelial-to-mesenchymal transition (EMT). Therapeutic strategies that are being explored in ovarian cancer aim at interfering with HIF-1α translation (e.g. mTOR inhibitors) or promoting its degradation (e.g. HSP90 inhibitors). Critical Reviews in Oncology / Hematology 2012 84, 224-242DOI: (10.1016/j.critrevonc.2012.03.006) Copyright © 2012 Elsevier Ireland Ltd Terms and Conditions