TGF‐β Signalling and Its Role in Cancer Progression and Metastasis

Abstract

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.

Keywords: cancer; metastasis; TGF‐β; cancer‐associated fibroblasts, CAFs; epithelial to mesenchymal transition, EMT; angiogenesis; apoptosis; Smad; TGF‐β receptors; tumour suppression; cancer therapy

Figure 1. TGF‐β signalling. TGF‐β ligands bind to their cognate cell surface type II receptor (TβRII) and to the type III receptor (TβRII), inducing the activation of TGF‐β type I receptor (TβRI) and forming a heterotetrameric complex. Then, two sets of signalling pathways can be stimulated/activated: (1) in the canonical Smad pathway (left), the activated receptor complex phosphorylates the receptor associated‐Smads (R‐Smads) and the resulting phosphorylated R‐Smads interact with Smad4, forming a heteromeric complex, which is translocated into the cell nucleus; and (2) in the non‐Smad pathway (right), the TGF‐β‐receptor complex may activate the MAPK (ERK1,2, JNK, p38) or PI3K (AKT) routes. The activation of both Smad and non‐Smad signalling pathways, in turn, initiates transcriptional or nontranscriptional activities to regulate cell behaviour and gene expression. Also, a crosstalk between Smad and non‐Smad routes has been described. The inhibitory effect of I‐Smads is indicated. DTF, downstream transcription factors.
Figure 2. TGF‐β in cancer. TGF‐β plays a dual role in human cancers, acting either as a tumour suppressor, in early stages, or as a promoter of tumour metastasis in the late stage of tumour progression. The tumour‐suppressive activities of TGF‐β, including inhibition of cell proliferation and induction of apoptosis, are observed in normal cells and early carcinomas. Conversely, in the late stage of cancer TGF‐β displays pro‐oncogenic activities, such as induction of epithelial–mesenchymal transition (EMT), which contributes to the increased migration and invasion of tumour cells. Also, the increment of TGF‐β within the tumour affects the stroma microenvironment by promoting (1) angiogenesis; (2) increase of tumour‐associated immune cells (T‐cells, neutrophils and macrophages, among others); (3) immunosuppression, allowing the tumour to escape host immunosurveillance; (4) activation of fibroblasts to cancer‐associated fibroblasts (CAFs), which further support tumour growth and promote tumour metastasis. ECM, extracellular matrix.
Figure 3. Therapeutic targeting of TGF‐β. TGF‐β can be targeted at different levels: (1) TGF‐β binding to its cellular receptors; (2) signalling receptors, such ALK1 by monoclonal antibodies (mAbs) or ALK5 by small chemical inhibitors; (3) endoglin by humanised mAbs; (4) TGF‐β expression can be downregulated by antisense oligo‐nucleotides (ODN); and (5) TGF‐β signalling can be inhibited by ectopic expression using gene therapy of a dominant negative TβRII mutant.
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Santibanez, Juan F, Krstic, Jelena, Quintanilla, Miguel, and Bernabeu, Carmelo(Aug 2016) TGF‐β Signalling and Its Role in Cancer Progression and Metastasis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025045]