About this Research Topic
TGF-βs are a family of essential multifunctional cytokines regulating (1) cell growth & development at both embryonic and adult stages, (2) inflammation and maintenance of host resistance mechanisms, and (3) remodelling and repair processes including angiogenesis and regeneration. However, with the vast impact of TGF-β on these diverse cellular processes having been extensively studied, paradoxical roles of its downstream signalling pathways in pathological conditions have simultaneously emerged.
The basic biological functions of TGF-βs in inflammatory diseases are anti-inflammatory, promoting healing but also contributing to fibrosis. While its anti-inflammatory and healing functions are both beneficial, the profibrotic effect of TGF-β is detrimental. The central role of TGF-β in human fibrosis, amongst multiple other profibrotic factors, is well established. However, its protective anti-inflammatory and wound-healing actions render it unsuitable as a therapeutic target for the prevention of fibrosis. Indeed, blockade of TGF-β to prevent fibrosis has been extensively investigated, with a compromise of sacrificing its potent anti-inflammatory and healing functions. For example, recent clinical trials in the treatment of diabetic nephropathy utilising neutralising antibodies against TGF-β have proven unsuccessful.
Similarly in cancer, TGF-β1 inhibits proliferation and induces apoptosis of cancer cells, but it also promotes metastasis by inducing the invasive phenotype of tumor cells through induction of epithelial-mesenchymal transition (EMT). The role of TGF-β as a potent tumor suppressor has been demonstrated by the fact that many inactivating mutations in TGF-β receptors and Smad genes have been implicated as an underlying cause for human cancer. While TGF-β acts as a tumor suppressor in normal cells and early carcinoma, its cytostatic effects are often lost during the progression of the disease. The pro-metastatic effects of TGF-β have been best characterized in breast cancer, whereby elevated TGF-β levels released from the extracellular matrix (ECM) reservoir exert a profound effect on the immune system. The increased concentration of released TGF-β in the tumor vicinity dramatically contributes to the tumor progression process, as local and systemic immunosuppression induced by TGF-β allows the tumor to escape host immunosurveillance.
In this Research Topic, we aim to discuss the controversial roles of TGF-β in human diseases, such as inflammatory diseases and cancer, in an effort to elucidate how these paradoxical functions may be taken into account when designing and optimising targeted therapeutic approaches for patients suffering with these conditions.
Keywords: FoxO, 𝛽-Catenin, TCF/LEF, TGF-𝛽, Fibrosis, Inflammation, Woung Healing
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