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  • Review Article
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TGFβ signalling: a complex web in cancer progression

Nature Reviews Cancer volume 10, pages 415–424 (2010)Cite this article

Subjects

Key Points

  • Transforming growth factor-β (TGFβ) signalling is mediated by TGFβ ligands, type 1 and type 2 receptors, and Smad proteins. TGFβ also regulates non-Smad pathways.

  • TGFβ stimulation inhibits cancer cell proliferation in some cellular contexts and promotes it in others. Numerous factors are involved in TGFβ-regulated cell proliferation and keep its signalling pathways balanced.

  • In addition to perturbation of TGFβ signalling, disruption or mutation of regulators of TGFβ signalling can lead to a loss of balanced TGFβ signalling, resulting in the generation and progression of tumours.

  • TGFβ signalling in cancer cells has dual roles in the regulation of cell death and proliferation.

  • TGFβ signalling has crucial roles in the maintenance of self-renewal and tumorigenic activity of glioma-initiating cells and leukaemia-initiating cells, whereas the function of TGFβ signalling in breast cancer-initiating cells is controversial.

  • TGFβ signalling is involved in several cell responses during cancer cell metastasis, and cell type-dependent and context-dependent factors contribute to the regulation of tumour metastasis.

  • The TGFβ pathway has been targeted for cancer therapy using multiple strategies. Some of them are currently in clinical trials.

Abstract

The distortion of growth factor signalling is the most important prerequisite in tumour progression. Transforming growth factor-β (TGFβ) signalling regulates tumour progression by a tumour cell-autonomous mechanism or through tumour–stroma interaction, and has either a tumour-suppressing or tumour-promoting function depending on cellular context. Such inherent complexity of TGFβ signalling results in arduous, but promising, assignments for developing therapeutic strategies against malignant tumours. As numerous cellular context-dependent factors tightly maintain the balance of TGFβ signalling and contribute to the regulation of TGFβ-induced cell responses, in this Review we discuss how they maintain the balance of TGFβ signalling and how their collapse leads to tumour progression.

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Figure 1: Intracellular signal transduction of TGFβ signalling.
Figure 2: The function of SKI and SKIL.
Figure 3: TGFβ and glioma-initiating cells.

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Acknowledgements

We apologize to those colleagues whose publications could not be cited because of space limitations. Work from the authors' laboratory is supported by KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas 'New strategies for cancer therapy based on advancement of basic research' and the Global COE Program (Integrative Life Science Based on the Study of Biosignalling Mechanisms) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 113-0033, Tokyo, Japan

    Hiroaki Ikushima & Kohei Miyazono

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  1. Hiroaki Ikushima
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Correspondence to Kohei Miyazono.

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Ikushima, H., Miyazono, K. TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer 10, 415–424 (2010). https://doi.org/10.1038/nrc2853

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