Transforming growth factors (TGF) are cytokines having many biologic activities, which include the regulation of epithelial proliferation, the promotion of extracellular matrix formation and the induction of angiogenesis 1.
Two distinct classes of TGFs have been identified, a and ß. TGFs-a compete with epidermal growth factor (EGF) for binding to the epidermal growth factor receptor (EGFR) and, therefore, elicit many biological actions similar to EGF. TGFs-a appear not to be produced by normal adult, fully differentiated cells, although they may be found during normal embryonic development. TGFs-ß does not bind to the EGF receptor but were found to require EGF or TGF-a for the induction of anchorage-independent growth in normal rat kidney cells 2.
TGFs were first isolated from the conditioned medium of Moloney murine sarcoma virus (MuSV)-infected mouse 3T3 cells by De Larco and Todaro and identified as a family of heat- and acid-stable transforming polypeptides and termed sarcoma growth factors (SGFs) in 1978 3.
The term TGF has been applied to peptides that have the ability to confer the transformed phenotype on untransformed fibroblastic indicator cells in vitro. Peptides representing two distinct classes of TGFs have been purified to homogeneity. Type a and type ß TGFs are distinguished both chemically by their unique amino acid sequences and biologically by their different activities on cells. Type a TGFs are single chain peptides of 50-53 amino acids cross-linked by three disulphide bonds. They have strong homology to EGF with which they compete for receptor binding. Type ß TGFs have a homodimeric structure comprised of two chains of 112 amino acids, each containing nine cysteine residues 4.
A fragment of rat TGF-a comprising the third disulfide loop (residues 34-43) was selected as a potential antigenic and receptor binding region. Immunization of rabbits with a peptide conjugate resulted in antibodies which were specific for both the peptide and rat TGF-a, but not for the homologous EGF. The synthetic decapeptide exhibited low affinity for EGF receptors on human cells 5. Assessment of biological activity of the TGF-a fragment indicated that none of the fragments significantly inhibited binding of EGF to the receptor, stimulated DNA synthesis of cells, inhibited EGF-induced DNA synthesis of cells, stimulated growth of cells in soft agar, or induced phosphorylation of the receptor or p35 protein. These results indicate that the receptor binding domain of TGF-a is not totally encompassed by any of the separate fragments tested and probably is formed by multiple separate regions of TGF-a 6.
Mode of Action
Growth factors and their receptors, including TGF-a and EGFR, are involved in cell proliferation, differentiation, and transformation. EGFR is a cell membrane protein, providing signal transduction and cell growth. Upon binding to its ligand, TGF-a undergoes autophosphorylation and activates downstream molecules, such as ras, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase. Previous studies have shown that this autocrine loop plays an important role in the growth of malignant mesotheliomas (as well as in tumors of the lung, breast, intestine, and other organs) 7. The signaling pathways for all members of the TGF-ß1 family are similar. Intracellular signaling is initiated upon the binding of the active cytokine to the TGF-ß receptor II (TßRII) homodimer and the assembly of a heterotetrameric complex consisting of receptors I and II. TßRII is a ubiquitously expressed constitutively active serine/threonine kinase. Once the heterotetrameric receptor complex is formed, TßRII phosphorylates TßRI and thereby greatly enhances TßRI serine/threonine kinase activity. The Smad family of proteins includes secondary mediators of TGF-ß signaling. Receptor-specific Smads that are phosphorylated by activated TßRI associate with Smad 4 and other factors to form a transcriptionally competent complex that enters the nucleus and modulates gene expression 8.
Type a TGFs are usually mitogenic for fibroblasts, whereas type ß TGFs have bifunctional effects on cell growth and can either stimulate or inhibit growth of the same cells, depending on conditions. The interactions of type a and ß TGFs can be either synergistic or antagonistic. Though the development of peptide antagonists to type a TGFs may have therapeutic potential for the treatment of malignancy, type ß TGFs may inhibit tumorigenesis 4. TGF-ß is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-ß are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. During the early phase of epithelial tumorigenesis, TGF-ß inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-ß due to inactivation of the TGF-ß signaling pathway or aberrant regulation of the cell cycle, the role of TGF-ß becomes one of tumor promotion. TGF-ß can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-ß to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-ß as a tumor suppressor and pro-oncogenic factor, members of the TGF-ß signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis 9.
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