Targeting TGFβ signal transduction for cancer therapy

Transforming growth factor-beta (TGF beta) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGF beta family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGF beta, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGF beta are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGF beta to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGF beta have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGF beta in maintaining tissue homeostasis makes targeting TGF beta a challenge. Here, we review the pleiotropic functions of TGF beta in cancer initiation and progression, summarize the recent clinical advancements regarding TGF beta signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGF beta therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

Automated summary

TGF beta family members are cytokines with diverse effects on cell fate regulation during development and tissue homeostasis. Dysregulation of TGF beta signaling can lead to developmental disorders and diseases, including cancer. TGF beta plays a dichotomous role in cancer progression, acting as a tumor suppressor in early stages and a tumor promoter in late stages, with effects on proliferation, differentiation, apoptosis, metastasis, and the tumor microenvironment.