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  • Review Article
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The roles of TGFβ in the tumour microenvironment

Nature Reviews Cancer volume 13, pages 788–799 (2013)Cite this article

Subjects

Key Points

  • During the early stages of tumorigenesis, transforming growth factor-β (TGFβ) functions as a tumour suppressor. However, as tumours progress, tumour cells may lose their growth-inhibitory response to TGFβ and may instead respond by initiating epithelial-to-mesenchymal transition and by increasing cell migration.

  • Experimental data support the idea that both loss of and gain of TGFβ signalling is pro-tumorigenic, as mouse models show that the overexpression of TGFβ and the abrogation of signalling results in increased tumour cell metastasis. It is beginning to be appreciated that the effects of TGFβ signalling in the tumour epithelium extend beyond tumour cell-autonomous mechanisms into the tumour microenvironment.

  • Nearly every cell in the tumour microenvironment responds to TGFβ in a unique way, and these diverse biological responses have a variety of effects on tumour progression.

  • Given the pleotropic nature of TGFβ signalling, the numerous downstream signalling events of TGFβ offer new and intriguing targets for therapeutic intervention.

  • Successful therapeutic targeting of TGFβ itself remains a highly desirable goal and the considerable advances in understanding TGFβ signalling, not only in the tumour epithelium but also in the tumour microenvironment, bring the realization of this goal closer.

Abstract

The influence of the microenvironment on tumour progression is becoming clearer. In this Review we address the role of an essential signalling pathway, that of transforming growth factor-β, in the regulation of components of the tumour microenvironment and how this contributes to tumour progression.

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Figure 1: Epithelial TGFβ signalling during tumour progression.
Figure 2: TGFβ signalling in tumour cells determines microenvironmental modification.

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Acknowledgements

This work is supported by US National Institutes of Health (NIH) Grants CA085492 and CA102162. The authors would also like to thank all of the members of the Moses Laboratory for their thoughtful discussions. In addition, the authors would like to apologize to any investigators whose work could not be included owing to space limitations.

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Authors and Affiliations

  1. Vanderbilt University Medical Center, Vanderbilt-Ingram Comprehensive Cancer Center, Medicine and Pathology, Cancer Biology, 2220 Pierce Avenue, 691 Preston Research Building, Nashville, 37232, Tennessee, USA

    Michael Pickup, Sergey Novitskiy & Harold L. Moses

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  1. Michael Pickup
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  2. Sergey Novitskiy
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  3. Harold L. Moses
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Correspondence to Harold L. Moses.

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Glossary

Epithelial-to-mesenchymal transition

The process by which epithelial cells lose their epithelial characteristics, such as cellular polarity and cell–cell junctions, in favour of mesenchymal characteristics, which include high cellular motility.

Cohesive migratory phenotype

Contrary to single-cell invasion, this is a form of invasion by which cells maintain their cell–cell contacts and by which cells migrate as a unit.

MicroRNA

(miRNA). 20–30 nucleotide long non-coding RNA that modulates gene expression by binding to complementary sequences in the 3′ untranslated region of target genes, which induces repression of gene translation or mRNA degradation.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells that are defined by their myeloid origin, immature state and ability to potently suppress T cell responses.

Chemotaxis

The function of a cell responding to a chemokine gradient to promote directional migration towards sites of tissue injury or into tumour microenvironments.

Dominant-negative

A defective protein product that effectively inhibits the function of its wild-type counterpart by retaining essential interaction capabilities without having a desired effector function.

Desmoplasia

The accumulation of extracellular matrix proteins, usually through the enhanced activation of stromal fibroblasts.

Vogelgram

A model for colorectal cancer development in which specific genetic changes are acquired, which mark progression of the disease from benign to malignant.

Myofibroblast

A generalized term for an activated fibroblast. In tumour biology, these cells function to deposit and to remodel the extracellular matrix as well as to alter tumour progression through paracrine protein signalling.

T helper 1 cell

(TH1 cell). A primary effector cell of the adaptive immune system, which is classically defined as antitumorigenic.

1D11

An antibody which is specifically directed towards the three transforming growth factor-β ligands and used to sequester these ligands, thus inhibiting TGFβ signalling.

Losartan

An angiotensin II receptor antagonist that has been shown to have the off-target effects of downregulating expression of type I transforming growth factor-β receptor (Tgfbr1) and Tgfbr2.

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Pickup, M., Novitskiy, S. & Moses, H. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 13, 788–799 (2013). https://doi.org/10.1038/nrc3603

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