TGF-β: duality of function between tumor prevention and carcinogenesis - PubMed (original) (raw)

Review

TGF-β: duality of function between tumor prevention and carcinogenesis

Daniel R Principe et al. J Natl Cancer Inst. 2014 Feb.

Abstract

Several mechanisms underlying tumor progression have remained elusive, particularly in relation to transforming growth factor beta (TGF-β). Although TGF-β initially inhibits epithelial growth, it appears to promote the progression of advanced tumors. Defects in normal TGF-β pathways partially explain this paradox, which can lead to a cascade of downstream events that drive multiple oncogenic pathways, manifesting as several key features of tumorigenesis (uncontrolled proliferation, loss of apoptosis, epithelial-to-mesenchymal transition, sustained angiogenesis, evasion of immune surveillance, and metastasis). Understanding the mechanisms of TGF-β dysregulation will likely reveal novel points of convergence between TGF-β and other pathways that can be specifically targeted for therapy.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Canonical transforming growth factor β (TGF-β) signaling. The TGF-β ligand binds its type 2 transmembrane receptor (TGFBR2), recruiting the type 1 receptor (TGFBR1), leading to the phosphorylation of SMAD2 and SMAD3. This phosphorylation event allows for complexing with SMAD4 and nuclear translocation, leading to growth arrest in benign epithelial cells. P = phosphorylation.

Figure 2.

Figure 2.

Mechanisms of transforming growth factor β receptor (TGFBR) repression. Repression of TGFBRs occurs at both the epigenetic and protein levels. It was recently discovered that the ubiquitination of TGFBR1 by tumor necrosis factor receptor associated factor 6 (TRAF6) leads to ADAM metallopeptidase domain 17 (ADAM17) mediated cleavage, liberating the TGFBR1 intracellular domain (ICD). The TGFBR1-ICD is then free to translocate to the nucleus and activate factors including Snail and matrix metalloproteinase 2 (MMP2). Additionally, epigenetic repression of the TGFBRs may be dependent on ERK activation of DNA methyltransferase (DNMT), which hypermethylates the TGFBR promoters, downregulating their expression.

Figure 3.

Figure 3.

Transforming growth factor β (TGF-β) control over ERK MAPK. It is hypothesized that in some cells, there is a reciprocal control mechanism involving ERK and the transforming growth factor β receptors (TGFBRs). ERK activation leads to DNA methyltransferase (DNMT) and activator protein (AP1) expression, which is believed to lead to epigenetic repression of the TGFBRs and upregulation of the TGF-β ligand. In some contexts, TGF-β suppresses ERK activation. A key step in this process appears to be recruitment of protein phosphatase 2A (PP2A) to the cell membrane by TGFBR1. In the proposed model, once a sufficient quantity of PP2A is recruited, it serves as a barrier to ERK activation, where DNMT and AP1 expression are not induced, and the canonical SMAD arm of the TGF-βcascade is favored.

Figure 4.

Figure 4.

Transforming growth factor β (TGF-β) in endothelial cell function. The effects of TGF-β on the vascular endothelia are complex and seemingly biphasic. Low TGF-β concentrations appear to activate the activin receptor-like kinase 1 (ALK1)/SMAD1/5 pathway, stimulating endothelial cell (EC) proliferation and migration associated with higher levels of ID1. Yet, at higher levels, TGF-β activates its canonical SMAD2/3 pathway in a transforming growth factor β receptor 1 (TGFBR1; also known as ALK5)–dependent manner to induce antiangiogenic factors plasminiogen activator inhibitor-1 (PAI-1) and fibronectin. P = phosphorylation.

Figure 5.

Figure 5.

Aberrant transforming growth factor β (TGF-β) signaling in cancer. TGF-β has several tumor suppressive functions in benign cells. However, these effects are commonly lost in advanced cancers, and TGF-β begins to actively contribute to disease progression. The figure describes a series of partial mechanisms underlying the uncontrolled response to TGF-β in cancer cells and the dysregulation of several associated oncogenic factors leading to enhanced cell proliferation and migration.

References

    1. Beerenwinkel N, Antal T, Dingli D, et al. Genetic progression and the waiting time to cancer. PLoS Comput Biol. 2007;3(11):e225. - PMC - PubMed
    1. Bozic I, Antal T, Ohtsuki H, et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A. 2010;107(43):18545–18550 - PMC - PubMed
    1. Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8(5):341–352 - PubMed
    1. Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol. 2001;11(11):S44–S51 - PubMed
    1. Massague J. TGFbeta in Cancer. Cell. 2008;134(2):215–230 - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources