TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with 20% of patients presenting with metastatic disease at diagnosis. TGF-beta signaling plays a crucial role in various cellular processes, including growth, differentiation, apoptosis, epithelial-mesenchymal transition (EMT), regulation of the extracellular matrix, angiogenesis, and immune responses. TGF-beta signals through SMAD proteins, which are intracellular molecules that transmit TGF-beta signals from the cell membrane to the nucleus. Alterations in the TGF-beta pathway and mutations in SMAD proteins are common in metastatic CRC (mCRC), making them critical factors in CRC tumorigenesis. This review first analyzes normal TGF-beta signaling and then investigates its role in CRC pathogenesis, highlighting the mechanisms through which TGF-beta influences metastasis development. TGF-beta promotes neoangiogenesis via VEGF overexpression, pericyte differentiation, and other mechanisms. Additionally, TGF-beta affects various elements of the tumor microenvironment, including T cells, fibroblasts, and macrophages, promoting immunosuppression and metastasis. Given its strategic role in multiple processes, we explored different strategies to target TGF-beta in mCRC patients, aiming to identify new therapeutic options.