Targeting the TGFß pathway for cancer therapy.

The TGFß signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFß signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFß signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFß pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFß pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFß pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFß pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFß pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFß inhibition therapy in different tumor settings.