1. Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
2. Genetics of Disease and Development Branch, National Institutes of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
3. SAIC, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702, USA
4. Laboratory of Genetics, Center for Cancer Research, The National Institutes of Health, Bethesda, Maryland 20892, USA
5. Department of Microbiology and Immunology, Indiana School of Medicine, Indianapolis, Indiana 46202, USA

Correspondence to: John J. Letterio¹ Correspondence and requests for materials should be addressed to J.J.L. (Email: john.letterio@cwru.edu).

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- signalling^{1, 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 cancer^{5, 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 T_H2-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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