TGFβ and the Tumor Microenvironment in Colorectal Cancer

Growing evidence supports an important role of the tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC). Resident cells such as fibroblasts or immune cells infiltrating into the TME maintain continuous crosstalk with cancer cells and thereby regulate CRC progression. One of the most important molecules involved is the immunoregulatory cytokine transforming growth factor-beta (TGF beta). TGF beta is released by various cells in the TME, including macrophages and fibroblasts, and it modulates cancer cell growth, differentiation, and cell death. Mutations in components of the TGF pathway, including TGF beta receptor type 2 or SMAD4, are among the most frequently detected mutations in CRC and have been associated with the clinical course of disease. Within this review, we will discuss our current understanding about the role of TGF beta in the pathogenesis of CRC. This includes novel data on the molecular mechanisms of TGF beta signaling in TME, as well as possible strategies for CRC therapy targeting the TGF beta pathway, including potential combinations with immune checkpoint inhibitors.