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  • Review Article
  • Published:

Beyond TGFβ: roles of other TGFβ superfamily members in cancer

Nature Reviews Cancer volume 13, pages 328–341 (2013)Cite this article

Subjects

Key Points

  • The bone morphogenetic proteins (BMPs), activins, NODAL, and growth and differentiation factors (GDFs) (collectively referred to as BANGs) have essential roles in early embryonic development and in regulating tissue homeostasis in adults, frequently acting in gradients shaped by the activity of ligand antagonists. Their roles in human cancer frequently constitute a redeployment of their activities in embryonic development or a perturbation of their roles in tissue homeostasis.

  • Abberant BMP signalling disrupts stem cell self-renewal and differentiation, and can contribute to tumour formation. This may occur, for example, at the level of genetic or epigenetic changes resulting in the overexpression of BMP antagonists, or the loss of BMP receptors, ligands or SMAD4.

  • NODAL is not expressed in most normal adult tissues, but is expressed, along with the co-receptor CRIPTO, in many different tumours. It promotes phenotypic plasticity, which is important for tumour progression, and can positively regulate cancer stem cell self-renewal.

  • High BMP signalling provides a natural barrier to tumour progression and metastasis. In the primary tumour, BMP signalling inhibits epithelial-to-mesenchymal transition (EMT), which can prevent tumour invasion. At metastatic sites, high BMP signalling prevents tumour cell colonization by enforcing a dormant state. This can be reversed by tumour-expressed BMP antagonists.

  • BANGs sculpt the tumour microenvironment by promoting angiogenesis and suppressing immune responses.

  • Increased expression of BANGs in tumours and as a result of chemotherapy can contribute to severe complications of cancer such as cachexia, anaemia and bone loss.

  • Strategies are under development to target BANG signalling for therapeutic ends. These include inhibiting NODAL–CRIPTO signalling in the tumour cells, reducing tumour angiogenesis by inhibiting activin receptor-like kinase 1 (ALK1), and inhibiting activin receptors and myostatin to treat cachexia, anaemia and bone loss. Therapies that aim to increase BMP activity are also being developed.

Abstract

Much of the focus on the transforming growth factor-β (TGFβ) superfamily in cancer has revolved around the TGFβ ligands themselves. However, it is now becoming apparent that deregulated signalling by many of the other superfamily members also has crucial roles in both the development of tumours and metastasis. Furthermore, these signalling pathways are emerging as plausible therapeutic targets. Their roles in tumorigenesis frequently reflect their function in embryonic development or in adult tissue homeostasis, and their influence extends beyond the tumours themselves, to the tumour microenvironment and more widely to complications of cancer such as cachexia and bone loss.

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Figure 1: Signalling downstream of TGFβ superfamily ligands.
Figure 2: Roles for BMPs in normal tissue homeostasis and tumorigenesis.
Figure 3: Role of NODAL signalling in HESCs and in cancer.
Figure 4: Therapeutic approaches to targeting the BANGs in cancer.

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Acknowledgements

The authors thank members of the Hill and Wakefield laboratories, K. Hunter, E. Sahai, M. Sporn, S. Yuspa and Y. Zhang for useful comments on the manuscript. C.S.H. acknowledges Cancer Research UK and the European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082) for funding. L.M.W. acknowledges the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research for funding.

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Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Room 4032A, 37 Convent Drive, MSC 4255, Bethesda, 20892–4255, Maryland, USA

    Lalage M. Wakefield

  2. Developmental Signalling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK

    Caroline S. Hill

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  1. Lalage M. Wakefield
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Correspondence to Lalage M. Wakefield or Caroline S. Hill.

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Glossary

Mesoderm

The middle germ layer of the developing embryo. Gives rise to the musculoskeletal, vascular and urinogenital systems, and to connective tissue (including that of the dermis).

Endoderm

The innermost of the three germ layers of the developing embryo. It differentiates to form the linings of two tubes in the body: the digestive tube, which extends the entire length of the body and the respiratory tube. Buds from the digestive tube form the liver, gall bladder and pancreas.

Cell-sorting behaviour

The process by which a heterogeneous population of cells with different attractive and repellent properties migrate and sort themselves into homogeneous populations.

Epithelial-to-mesenchymal transition

(EMT). Conversion from an epithelial to a mesenchymal phenotype, which is a normal process in embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Mesendoderm

The term given to an embryonic tissue layer that can differentiate into mesoderm and endoderm.

Ectoderm

The outermost of the three germ layers of the developing embryo. It differentiates to form the nervous system, tooth enamel, the epidermis, hair, nails and the lining of mouth, anus, nostrils and sweat glands.

Hamartomatous polyps

Intestinal polyps in patients with juvenile polyposis syndrome. They are characterized by increased crypt formation and cell proliferation but otherwise normal epithelial cell maturation, and are associated with an abnormally expanded mesenchymal component with a pronounced inflammatory infiltrate. Unlike intestinal adenomas, they do not show epithelial dysplasia.

Mesenchymal-to epithelial transition

(MET). The conversion of non-polarized and motile mesenchymal cells into polarized epithelial cells.

Ligand traps

Chimeric proteins that typically contain the ligand-binding domain of a receptor coupled to the Fc domain of an immunoglobulin. This generates an antibody-like ligand antagonist with the ligand specificity and high affinity of the parent receptor, coupled with the in vivo stability and distribution characteristics of the parent immunoglobulin.

Osteoblast

A cell responsible for bone formation.

Osteoclast

A cell that breaks down mineralized bone and that is responsible for bone resorption.

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Wakefield, L., Hill, C. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer 13, 328–341 (2013). https://doi.org/10.1038/nrc3500

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