Editors' ChoiceCancer

Aberrant T Cells Trigger GI Cancer

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Science's STKE  27 Jun 2006:
Vol. 2006, Issue 341, pp. tw213
DOI: 10.1126/stke.3412006tw213

Mutations in the gene encoding Smad4 are common in patients with familial juvenile polyposis, which is associated with gastrointestinal (GI) cancer. Kim et al. used mice with conditional knockouts of Smad4 in T cells or epithelial cells to investigate the mechanism by which loss of Smad4 signaling contributes to GI cancer. Smad4 is a common Smad (co-Smad) that participates in mediating signaling from the transforming growth factor-β (TGF-β) family of ligands. Kim et al. found that knockout of Smad4 only in T cells, not epithelial cells, contributed to an increased incidence of cancer in the mutant mice. The T cell-conditional Smad4 knockout mice exhibited GI pathology that resembled that in familial juvenile polyposis, with extensive B cell infiltration and high concentrations of circulating immunoglobulin A (IgA). The mice with conditional knockout of Smad4 in T cells also showed increased circulation of several cytokines, including the interleukins IL-4, IL-5, IL-6, and IL-13. IL-5 and IL-6 are both important for B cell proliferation and differentiation. In vitro, the Smad4-deficient T cells secreted higher concentrations of IL-4, IL-5, IL-6, and IL-13 and showed a disproportionately high number of TH2-type cells. Even mice heterozygous for Smad4 in T cells showed B cell hyperplasia, especially in the duodenum, and epithelial cell hyperplasia in the stomach. Thus, it appears that T cell Smad4 signaling is essential for the maintenance of the GI microenvironment and that loss of the TGF-β regulatory pathway alters the T cell phenotype and the cytokine environment, leading to epithelial cell cancer.

B.-G. Kim, C. Li, W. Qiao, M. Mamura, B. Kasperczak, M. Anver, L. Wolfraim, S. Hong, E. Mushinski, M. Potter, S.-J. Kim, X.-Y. Fu, C. Deng, J. J. Letterio, Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015-1019 (2006). [PubMed]

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