Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.
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.
Kim
Byung-Gyu
BG
Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Li
Cuiling
C
Qiao
Wenhui
W
Mamura
Mizuko
M
Kasprzak
Barbara
B
Kasperczak
Barbara
B
Anver
Miriam
M
Wolfraim
Lawrence
L
Hong
Suntaek
S
Mushinski
Elizabeth
E
Potter
Michael
M
Kim
Seong-Jin
SJ
Fu
Xin-Yuan
XY
Deng
Chuxia
C
Letterio
John J
JJ
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*
D016207:Cytokines; D051901:Smad4 Protein; C490810:Smad4 protein, mouse