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Smad4 signalling in T cells is required for suppression of gastrointestinal cancer

Nature volume 441, pages 1015–1019 (2006)Cite this article

A Corrigendum to this article was published on 07 December 2006

Abstract

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-β signalling1,2,3,4. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer5,6. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis7. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4-/- T cells produce abundant TH2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ8, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

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Figure 1: Conditional deletion of exon 8 of the Smad4 gene in either epithelia or T lymphocytes.
Figure 2: T-cell-restricted deletion of the Smad4 gene in mice leads to gastrointestinal pathology and decreased survival.
Figure 3: T H 2 cytokines and plasma cells in mice with T-cell-restricted Smad4 gene deletion.
Figure 4: Spontaneous gastrointestinal tumours induced by T-cell-restricted deletion of Smad4.

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Acknowledgements

The authors thank A. B. Roberts for her thoughtful reading of this manuscript and considerate support of this research. Author Contributions B.-G.K. and J.J.L. are responsible for developing the hypothesis, planning and executing experiments, including analysis of models with T-cell-specific deletion of Smad4, and for preparation of the manuscript. C.L., W.Q., X.-Y.F. and C.D. are responsible for the development of models with epithelial-specific deletion of the Smad4 gene. S.-J.K. and S.H. developed and analysed the ITF-dnS4 transgenic model. M.M. established mouse colonies with T-cell-restricted deletion of Smad4. E.M. and M.P. provided immunohistochemical analysis of plasma cell infiltrates. M.A. provided analysis of histopathology and B.K. developed immunohistochemical procedures for Smad4. L.W. contributed in the preparation of the manuscript and in the evaluation of the data.

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Authors and Affiliations

  1. Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Byung-Gyu Kim, Mizuko Mamura, Lawrence Wolfraim, Suntaek Hong, Seong-Jin Kim & John J. Letterio

  2. Genetics of Disease and Development Branch, National Institutes of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Cuiling Li, Wenhui Qiao & Chuxia Deng

  3. Digestive & Kidney Diseases, National Institutes of Health,

    Cuiling Li, Wenhui Qiao & Chuxia Deng

  4. SAIC, National Cancer Institute-Frederick, Frederick, PO Box B, Maryland, 21702, USA

    Barbara Kasperczak & Miriam Anver

  5. Laboratory of Genetics, Center for Cancer Research, The National Institutes of Health, Bethesda, Maryland, 20892, USA

    Elizabeth Mushinski & Michael Potter

  6. Department of Microbiology and Immunology, Indiana School of Medicine, Indianapolis, Indiana, 46202, USA

    Xin-Yuan Fu

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Correspondence to John J. Letterio.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods and Supplementary Figure Legends. (DOC 34 kb)

Supplementary Figure 1

Smad4-dependent signaling is in stroma cells is key to maintaining intestinal homeostasis. (PDF 114 kb)

Supplementary Figures 2 and 3

Supplementary Figure 2 details diffuse plasma cell infiltration of intestines in mice with T cell-restricted deletion of the SMAD4 gene. Supplementary Figure 3 details epithelial-specific expression of a dominant-negative acting Smad4 transgene is not associated with spontaneous tumorigenesis. (PDF 105 kb)

Supplementary Figure 4

SMAD4+/co;Lck-cre mice develop plasma cell and epithelial cell hyperplasia. (PDF 116 kb)

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Kim, BG., Li, C., Qiao, W. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015–1019 (2006). https://doi.org/10.1038/nature04846

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