Loss of SMAD4 in T cells in the microenvironment is sufficient for the formation of gastrointestinal carcinomas. Letterio and colleagues show that mice that lack SMAD4 in T cells develop carcinomas, whereas those that lack SMAD4 in epithelial cells do not.

SMAD4 is a mediator of transforming growth factor β signalling and is mutated in about half of patients with familial juvenile polyposis (FJP), a syndrome with a high frequency of gastrointestinal carcinomas. The gastric and intestinal mucosae of these patients are invariably infiltrated with inflammatory cells, which led the authors to suggest that a loss of SMAD4 signalling in the T-cell lineage is responsible for the carcinomas. To test this they created four mouse models, two of which had Smad4 mutated only in the T cells, and two of which had it mutated only in the epithelial cells. Only in the T-cell models did carcinomas occur, and these models were close phenocopies of human FJP.

These results pose many questions about the mechanism of tumorigenesis. In patients with FJP, loss of heterozygosity (LOH) of SMAD4 is observed in epithelial cells and has not been seen in lymphocytes. However, this does not preclude a role for LOH in T cells and other lineages. The authors also showed that in mice with T-cell disruption of SMAD4, those T cells produced more cytokines such as interleukin 4 (IL4), IL5, IL6 and IL13, which are known to promote proliferation.

To fully understand the significance of these data, further experiments are needed that combine the T-cell SMAD4 defect with defects in epithelial cells. However, they clearly illustrate the potential importance of the microenvironment in tumorigenesis.