Pathobiology of transforming growth factor β in cancer, fibrosis and immunologic disease, and therapeutic considerations

Transforming growth factor β (TGF-β) is a highly pleiotropic cytokine that plays an important role in wound healing, angiogenesis, immunoregulation and cancer. The cells of the immune system produce the TGF-β1 isoform, which exerts powerful anti-inflammatory functions, and is a master regulator of the immune response. However, this is context dependent, because TGF-β can contribute to the differentiation of both regulatory (suppressive) T cells (Tr cells) and inflammatory Th17 cells. While TGF-β might be underproduced in some autoimmune diseases, it is overproduced in many pathological conditions. This includes pulmonary fibrosis, glomerulosclerosis, renal interstitial fibrosis, cirrhosis, Crohn's disease, cardiomyopathy, scleroderma and chronic graft-vs-host disease. In neoplastic disease, TGF-β suppresses the progression of early lesions, but later this effect is lost and cancer cells produce TGF-β, which then promotes metastasis. This cytokine also contributes to the formation of the tumor stroma, angiogenesis and immunosuppression. In view of this, several approaches are being studied to inhibit TGF-β activity, including neutralizing antibodies, soluble receptors, receptor kinase antagonist drugs, antisense reagents and a number of less specific drugs such as angiotensin II antagonists and tranilast. It might be assumed that TGF-β blockade would result in severe inflammatory disease, but this has not been the case, presumably because the neutralization is only partial. In contrast, the systemic administration of TGF-β for therapeutic purposes is limited by toxicity and safety concerns, but local administration appears feasible, especially to promote wound healing. Immunotherapy or vaccination stimulating TGF-β production and/or Tr differentiation might be applied to the treatment of autoimmune diseases. The benefits of new therapies targeting TGF-β are under intense investigation.