TGF-beta1, WNT, and SHH signaling in tumor progression and in fibrotic diseases.

Activation of resting fibroblasts to myofibroblasts characterizes several physiological and pathological conditions, from wound healing to aggressive metastatic cancers. In tissue damage, including wound healing, fibroblasts are activated in response to injury for a limited period of time to stimulate the healing process. Similar biological mechanisms are maintained in pathological conditions, e.g., scleroderma and cancer, where myofibroblasts persist in producing cytokines and growth factors to drive the development of fibrosis and the progression of disease. Studies characterizing the bi-directional signal transduction pathways between cancer cells and stromal cells have suggested novel druggable targets that may function in both the inhibition of fibrotic reactions in cancer stroma and in the inhibition of fibrotic diseases. In this review, we focus on transforming growth factor beta (TGF-beta), int/Wingless (WNT), and sonic hedgehog (SHH) signal transduction pathways and describe small molecule inhibitors that are used in phase I/II clinical trials to treat fibrosis or fibrotic cancers.