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  • Review Article
  • Published:

The Hippo pathway and human cancer

Nature Reviews Cancer volume 13, pages 246–257 (2013)Cite this article

Subjects

Key Points

  • The Hippo pathway is an evolutionarily conserved regulator of tissue growth.

  • The Hippo pathway controls multiple cellular functions that are central to tumorigenesis, including proliferation and apoptosis.

  • Hippo pathway mutations in mice and flies give rise to tumours.

  • Hippo pathway activity seems to be frequently deregulated in different human cancers but most Hippo pathway genes are not commonly mutated.

  • Molecular events such as sensitivity to the mechanical properties of tumours and crosstalk with other cancer pathways might cause Hippo pathway deregulation in human cancers.

  • Hippo pathway therapeutics and new avenues to modulate pathway activity are beginning to emerge.

Abstract

The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer signalling network, and discuss cancer-relevant biological functions, potential mechanisms by which Hippo pathway activity is altered in cancer and emerging therapeutic strategies.

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Figure 1: Schematic representation of the Drosophila melanogaster Hippo pathway.
Figure 2: Schematic representation of the human Hippo pathway.
Figure 3: Biological functions of the Hippo pathway that are relevant to cancer.
Figure 4: Network-level regulation of the Hippo pathway.

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Acknowledgements

K.F.H. is a Sylvia and Charles Viertel Senior Medical Research Fellow. X.Z. is a Cure Cancer Australia and National Breast Cancer Foundation fellow. D.M.T is an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellow.

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Authors and Affiliations

  1. Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, 3002, Victoria, Australia

    Kieran F. Harvey, Xiaomeng Zhang & David M. Thomas

  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Kieran F. Harvey, Xiaomeng Zhang & David M. Thomas

  3. Department of Pathology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Kieran F. Harvey, Xiaomeng Zhang & David M. Thomas

Authors
  1. Kieran F. Harvey
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  2. Xiaomeng Zhang
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Correspondence to Kieran F. Harvey or David M. Thomas.

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Supplementary information

Supplementary information S1 (table)

Detailed somatic mutations in Hippo pathway genes in human cancer (PDF 361 kb)

Glossary

14-3-3 binding sites

Peptide sequences that bind to 14-3-3 proteins when phosphorylated. 14-3-3 proteins often function as adaptor proteins or subcellular localizers of their protein substrates.

Anoikis

Apoptosis resulting from inappropriate attachment of cells to a substrate.

Pluripotency

The capability of cells to give rise to multiple lineages.

Non-canonical WNT signalling

WNT signalling that is independent of β-catenin.

Adherens junctions

Intercellular junctions important for epithelial cell–cell adhesion.

Tight junctions

Intercellular junctions that form at the apical regions of epithelial cells.

Driver mutations

Mutations that are actively involved in tumour formation.

Passenger mutations

Mutations that are present in cancers but that do not promote tumour formation.

Pathognomonic

Distinctive for a particular disease.

Epithelioid haemangioendothelioma

A rare vascular tumour characterized by TAZ–CAMTA1 gene fusions.

Photocoagulation therapy

Light-based method used especially for treating retinal tears.

Photodynamic therapy

Activation of photosensitive compounds by light.

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Harvey, K., Zhang, X. & Thomas, D. The Hippo pathway and human cancer. Nat Rev Cancer 13, 246–257 (2013). https://doi.org/10.1038/nrc3458

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