The role of polypeptide growth factors in human carcinomas: new targets for a novel pharmacological approach.
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.
Favoni
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Department of Preclinical Oncology, Laboratory of Pharmacology, National Cancer Institute, Genoa, Italy. ref@hp380.ist.unige.it
de Cupis
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000503:physiopathology; D010455:Peptides / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D006133:Growth Substances; D010455:Peptides; D017978:Receptors, Growth Factor