title: Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.
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-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.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Byung-Gyu
authors.initials: BG
authors.lastname: Kim
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Wenhui
authors.initials: W
authors.lastname: Qiao
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.forename: Barbara
authors.initials: B
authors.lastname: Kasprzak
authors.forename: Barbara
authors.initials: B
authors.lastname: Kasperczak
authors.forename: Miriam
authors.initials: M
authors.lastname: Anver
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wolfraim
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mushinski
authors.forename: Michael
authors.initials: M
authors.lastname: Potter
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Fu
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000818:Animals; D002450:Cell Communication; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005770:Gastrointestinal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051901:Smad4 Protein; C490810:Smad4 protein, mouse