[Frontiers in Bioscience S4, 1487-1517, June 1, 2012]

Growth factor pathways in development and progression of hepatocellular carcinoma

Michael Andrew Nalesnik1, George Konstantine Michalopoulos2


1Department of Pathology, University of Pittsburgh Medical Center, Rm. E738 Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh PA 15213, 2Maud Menten Professor and Chair, Department of Pathology, University of Pittsburgh, S-410 Biomedical Science Tower, 203 Lothrop Street, Pittsburgh, PA 15261

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Specific growth factors and their pathways
3.1. The hepatocyte growth factor (HGF)/MET axis
3.1.1. Background
3.1.2. HGF and MET in hepatocellular carcinoma (HCC)
3.1.3. HGF/MET pathway in HCC
3.1.4. HGF/MET clinicopathologic correlations
3.1.5. HGF/MET therapeutic correlations
3.2. Epidermal growth factor receptors (EGFRs) and associated ligands
3.2.1. Background
3.2.2. EGFRs and their ligands in HCC
3.2.3. EGFR pathway in HCC
3.2.4. EGFR/ligand clinicopathologic correlations
3.2.5. EGFRs/ligands therapeutic correlations
3.3. The insulin-like growth factor (IGF) axis
3.3.1. Background
3.3.2. IGF and insulin-like growth factor receptor (IGFR) in HCC
3.3.3. IGFR pathway in HCC
3.3.4. IGF/IGFR clinicopathologic correlations
3.3.5. IGF/IGFR therapeutic correlations
3.4. The vascular endothelial growth factor (VEGF): vascular endothelial growth factor receptor (VEGFR) axis
3.4.1. Background
3.4.2. VEGF and VEGFR members in HCC
3.4.3. VEGF/VEGFR pathway in HCC
3.4.4. VEGF/VEGFR clinicopathologic correlations
3.4.5. VEGF/VEGFR therapeutic correlations
3.5. The fibroblast growth factor (FGF): fibroblast growth factor receptor (FGFR) axis
3.5.1. Background
3.5.2. FGF and FGFR in HCC
3.5.3. FGFR pathway in HCC
3.5.4. FGF/FGFR clinicopathologic correlations
3.5.5. FGF/FGFR therapeutic correlations
3.6. Platelet-derived growth factors (PDGFs)
3.6.1. Background
3.6.2. PDGF and platelet derived growth factor receptor (PDGFR) in HCC
3.6.3. PDGF/PDGFR pathway in HCC
3.6.4. PDGF/PDGFR clinicopathologic correlations
3.6.5. PDGF/PDGFR therapeutic correlations
3.7. The transforming growth factor-beta (TGF-beta): TGF-beta-receptor axis
3.7.1. Background
3.7.2. TGF-beta and TGF-beta-receptor in HCC
3.7.3. TGF-beta pathway in HCC
3.7.4. TGF-beta clinicopathologic correlations
3.7.5. TGF-beta therapeutic correlations
4. Perspective
5. References

1. ABSRACT

Hepatocellular carcinoma accounts for approximately 700,000 deaths per year. This tumor displays morphologic and phenotypic heterogeneity, and heterogeneity extends to the molecular level. Nevertheless, common pathways have been identified that are variably employed by these tumors. Such pathways often include aberrant signaling by growth factors, many of which are involved in liver development and regeneration. This review focuses on several such pathways and highlights patterns of structural expression of relevant molecules as well as effects of pathway stimulation or inhibition, both in vitro and in vivo. Specifically, the HGF/MET axis, epidermal growth factor receptors and associated ligands, insulin growth factor, vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor and TGF-beta pathways are reviewed in the context of experimental models of HCC. Clinical-pathologic correlations are drawn for each of these, and current status of molecular targeted therapies is assessed. Review of available information indicates that redundancies and interactions among these signaling pathways must be taken into account if they are to be exploited to block and reverse HCC growth and spread.