Vol. 52, Issue 2, 179-206, June 2000

The Role of Polypeptide Growth Factors in Human Carcinomas: New Targets for a Novel Pharmacological Approach

Roberto E. Favoni¹ and Alessandra De Cupis

Department of Preclinical Oncology, Laboratory of Pharmacology, National Cancer Institute, Genoa, Italy

I. Background and Rationale
    A. Generalities on Growth Factors and Receptors
    B. Signal Transduction Pathway
    C. Cancer and Altered Growth Factor Signaling
II. Growth Factor Families
    A. Epidermal Growth Factor and Receptor
    B. EGF and Cancer
    C. Fibroblast Growth Factors and Receptors
    D. FGFs and Cancer
    E. Insulin-Like Growth Factors and Receptors
    F. IGF System and Cancer
    G. Transforming Growth Factors and Receptors
    H. TGFs and Cancer
    I. Vascular Endothelial Growth Factor and Receptors
    J. VEGF and Cancer
    K. Hepatocyte Growth Factor/Scatter Factor and Receptor
    L. HGF/SF and Cancer
    M. Platelet-Derived Growth Factor and Receptor
    N. PDGF and Cancer
III. Pharmacological Interference with Growth Factor Signaling Pathways
    A. Growth Factor Neutralization
    B. Growth Factor Receptor Neutralization
    C. Protein Tyrosine Kinase Inhibitors
    D. Phosphotyrosine Phosphatase Activators
    E. Inhibition of Growth Factor and Growth Factor Receptor Synthesis
    F. Farnesyltransferase Inhibitors
    G. Antisense Oligonucleotide Strategies
IV. Concluding Remarks
Acknowledgment
References

The processes of cellular proliferation and progressive acquisition of a specialized phenotype show a high degree of coordination. In particular, these complex signaling networks mediating cell growth, differentiation, migration, and apoptosis are regulated in part by polypeptide growth factors that can act, by autocrine and/or paracrine mechanisms of action, as positive or negative modulators. Because these growth factors are unable to cross the hydrophobic cell membrane, they exert their effects via binding to cell surface receptors, most of which possess intrinsic tyrosine kinase activity. Owing to the interaction of polypeptide growth factors with their specific transmembrane receptors, a cascade of intracellular biochemical signals, resulting in the activation and repression of various subsets of genes, is triggered. One of the major incentives for studying factors that regulate processes of proliferation and differentiation is the recognition of their involvement in tumorigenesis. Genetic aberrations in growth factors signaling pathways are, in fact, inextricably linked to cancer. Malignant cells arise as a result of a stepwise progression of genetic events characterized by the unregulated expression of growth factors or components of their signaling networks. The main aim of this review is to examine the current understanding of the crucial contribution that several growth factors may have on transformation, tumorigenesis, and progression in several human tumors among the most widespread in western countries. For this purpose, we will analyze the chemistry and the molecular organization of the most important growth factors and their specific receptors. In addition, we will focus on the mechanisms of signal transduction, the complex cascade of biochemical events ensued from the growth factor/receptor binding. The present knowledge of the role of growth factor biochemical signaling networks in cancer leads to improvements not only in diagnosis and prognosis for this disease, but also for new and more targeted therapeutic intervention. The second part of this review will focus on the novel pharmacological approaches for cancer therapy that have been developed already or are being developed with the aim to specifically interfere at various steps of the growth factors signaling pathways.