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

Nature. 2006 Jun 22;441(7096):1015-9. doi: 10.1038/nature04846.


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-beta signalling. 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 cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. 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 T(H)2-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 organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

MeSH terms

  • Adenomatous Polyposis Coli / etiology
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / pathology
  • Animals
  • Cell Communication
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Gastrointestinal Neoplasms / immunology*
  • Gastrointestinal Neoplasms / metabolism
  • Gastrointestinal Neoplasms / pathology
  • Gene Deletion
  • Gene Targeting
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Glandular and Epithelial / immunology
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Signal Transduction*
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*
  • T-Lymphocytes / metabolism*


  • Cytokines
  • Smad4 Protein
  • Smad4 protein, mouse