Angiogenesis and hepatocellular carcinoma David Semela, Jean-François Dufour  Journal of Hepatology  Volume 41, Issue 5, Pages 864-880 (November 2004) DOI: 10.1016/j.jhep.2004.09.006 Copyright © 2004 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Scanning electron microscopic (SEM) imaging of a polymer cast of normal liver sinusoids (right upper corner) and HCC tumor vasculature (centre and left lower corner) showing tumor vessels with irregular diameters and abnormal branching pattern (orthotopic HCC model in American Cancer Institute rats used in our laboratory, image kindly provided by V. Djonov, University of Bern, Switzerland. Original magnification ×161). Journal of Hepatology 2004 41, 864-880DOI: (10.1016/j.jhep.2004.09.006) Copyright © 2004 European Association for the Study of the Liver Terms and Conditions

Fig. 2 The angiogenic switch represented as imbalance between pro- and anti-angionic factors with subsequent activation of angiogenesis. Selected endogenous stimulatory and inhibitory factors of angiogenesis listed alphabetically. Adopted from Ref. [20]. Journal of Hepatology 2004 41, 864-880DOI: (10.1016/j.jhep.2004.09.006) Copyright © 2004 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Role of hypoxia as main trigger for tumor angiogenesis. Hypoxia in the centre of growing tumors leads to intracellular stabilization by hydroxylation of hypoxia-inducible factor (HIF)-1α, a constitutively expressed protein which is rapidly degraded by the proteasome under normoxic conditions. Stabilized HIF-1α acts as key transcription factor in hypoxic tissues and induces the expression of several hypoxia-response genes, such as vascular endothelial factor (VEGF). VEGF upregulation in turn promotes cell survival, proliferation and migration of endothelial cells, which will lead to the formation of new blood vessels especially in the tumor periphery. Improved vascularization and perfusion will lead to further tumor growth with persistent central hypoxia. Degradation of the basal membrane by matrix metalloproteinases (left) with release of sequestered VEGF, bFGF and PDGF or mutations in oncogenes and tumor suppressor genes (right) further upregulate proangiogenic factors in tumors. Journal of Hepatology 2004 41, 864-880DOI: (10.1016/j.jhep.2004.09.006) Copyright © 2004 European Association for the Study of the Liver Terms and Conditions

Fig. 4 Key steps in tumor angiogenesis and potential therapeutic targets. 1. Recruitment of endothelial progenitor cells from bone marrow. 2. Integrin antagonists inhibit incorporation of circulating endothelial progenitor cells in tumor vessels. 3. Vascular targeting agents embolize tumor vessels. 4. Trapping of proangiogenic growth factors. 5. Inhibition of growth factor receptors. 6. Interference with intracellular signaling pathways. 7. Inhibition of endothelial cell migration. 8. Administration of exogenous or increase of endogenous antiangiogenic factors. 9. Inhibition of locally proliferating endothelial cells or application of cytotoxic agents. 10. Inhibition of pericytes or pericyte-endothelial cell interaction. Journal of Hepatology 2004 41, 864-880DOI: (10.1016/j.jhep.2004.09.006) Copyright © 2004 European Association for the Study of the Liver Terms and Conditions