HCC and angiogenesis: possible targets and future directions

Abstract

Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease.

Figure 1

Schematic representation of potential escape mechanisms from anti-VEGF therapy. HCCs might use four potential mechanisms to acquire new blood vessels for their growth and after VEGF blockade: co-option, angiogenesis (sprouting), vasculogenesis (bone-marrow-derived endothelial progenitor cell recruitment to increase the tumor vascular supply) and intussusception. SDF1α, bFGF, IL-6 and G-CSF are increased in the circulation of patients with HCC treated with anti-VEGF agents. These molecules may potentially contribute to HCC neovascularization during VEGF-pathway inhibition. Permission obtained from Nature Publishing Group © Carmeliet, P. & Jain, R. K. Nature 407, 249–257 (2000). Abbreviations: bFGF, basic fibroblast growth factor; G-CSF, granulocyte colony-stimulating factor; HCC, hepatocellular carcinoma; IL, interleukin; SDF1α, stromal-cell-derived factor 1α.