Normal body cells grow, proliferate and die in an orderly manner. By contrast, cancer cells grow out of control and can invade other tissues. The process of tumour progression and metastasis results from a complex molecular cascade that allows cancer cells to leave the site of the primary tumour mass and disseminate to distant anatomical sites where they proliferate and form secondary tumour foci. Disseminated disease is the most usual cause of death in cancer patients and is, therefore, a very serious clinical problem. Transforming growth factor beta (TGF‐β) has a dual role in tumour progression, acting as a tumour suppressor in early stages of carcinogenesis, and exerting a pro‐oncogenic role in the last steps of metastatic disease. TGF‐β induces the epithelial mesenchymal transition of transformed cells, which contributes to tumour invasion and metastasis, and is frequently overexpressed in cancer cells.
Key Concepts
TGF‐βs and their signalling components are widely expressed in all tissues and play a major role in human diseases.
The canonical signalling pathway triggered by TGF‐βs involves the activation of Smad proteins by the TGF‐β receptors and their translocation into the nucleus. In addition, TGF‐β receptors can activate Smad‐independent (non‐canonical) pathways, including MAPKs and Rho GTPases, among others.
Canonical and noncanonical TGF‐β signal transduction participates in and explains the broad spectrum of TGF‐β effects on tumour progression.
TGF‐β is postulated as a dual factor in cancer since it can act either as a tumour suppressor in early stages of tumourigenesis or as a tumour promoter in late stages of tumour progression.
One of the hallmarks at late stages of tumour progression is that cancer cells become refractory to the TGF‐β cell growth inhibitory response.
Many types of cancer cells leaving primary carcinomas appear to depend on EMT to facilitate execution of most of the steps of the invasion–metastasis process.
TGF‐β affects not only the tumour cells themselves but also the surrounding stroma by inhibiting cell adhesion, inducing immunosuppression and angiogenesis, and by promoting the degradation of the extracellular matrix, further modulating the metastatic process.
Induction of EMT by TGF‐β generates cancer cells with stem‐like properties.
By regulating TGF‐β expression and its canonical and noncanonical intracellular signalling, it may be possible to control the tumour microenvironment, including angiogenesis, immunosurveillance escape and activation of stromal fibroblasts resulting in cancer‐associated fibroblasts (CAFs), tumour‐stroma interactions and EMT.