MAD homologue 4 (SMAD4), also known as DPC4 is a tumor suppressor gene that encodes a central mediator of transforming growth factor-ß signalling.
This tumor suppressor gene is deleted in pancreatic cancer.
Germline mutations in SMAD4 are also found in over 50% of patients with familial juvenile polyposis.
Familial juvenile polyposis is 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.
The 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.
|SMAD4-/-T cells produce mediators of plasma cell expansion|
Dr Byung-Gyu Kim and colleagues from the USA investigated the effect of SMAD4-dependent signalling in T cells in mice.
The researchers showed that selective loss of SMAD4-dependent signalling in T cells leads to spontaneous epithelial cancers in the gastrointestinal (GI) tract.
In addition, the research team found that epithelial-specific deletion of the SMAD4 gene does not lead to gastrointestinal tract cancers.
Tumors 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-5, -6 and -13.
These interleukins are known mediators of plasma cell and stromal expansion.
Dr Kim's team concluded, “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.”
“This research indicates that SMAD4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbors.”