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

Byung Gyu Kim, Cuiling Li, Wenhui Qiao, Mizuko Mamura, Barbara Kasperczak, Miriam Anver, Lawrence Wolfraim, Suntaek Hong, Elizabeth Mushinski, Michael Potter, Seong Jin Kim, Xin Yuan Fu, Chuxia Deng, John J. Letterio

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231 Scopus citations

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 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 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 organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

Original languageEnglish (US)
Pages (from-to)1015-1019
Number of pages5
JournalNature
Volume441
Issue number7096
DOIs
StatePublished - Jun 22 2006

ASJC Scopus subject areas

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    Kim, B. G., Li, C., Qiao, W., Mamura, M., Kasperczak, B., Anver, M., Wolfraim, L., Hong, S., Mushinski, E., Potter, M., Kim, S. J., Fu, X. Y., Deng, C., & Letterio, J. J. (2006). Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature, 441(7096), 1015-1019. https://doi.org/10.1038/nature04846