The Synergistic Cooperation between TGF-beta and Hypoxia in Cancer and Fibrosis

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-beta signaling promotes cancer initiation and fibrosis through epithelial-mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-beta is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-beta is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-beta and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-beta belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TNF receptor-associated factor 4 (TRAF4) and TNF receptor-associated factor 6 (TRAF6) to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-beta is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-beta and hypoxia in development, fibrosis and cancer.

Automated summary

Transforming growth factor beta (TGF-beta) regulates homeostasis and immune responses in adult animals and humans. Abnormal TGF-beta signaling promotes cancer and fibrosis, while suppressing immune responses in cancer patients. Understanding the synergistic cooperation between TGF-beta and hypoxia in development, fibrosis, and cancer can guide the development of novel anti-cancer therapeutic strategies.