Disruptive neighbours can cause turmoil in any community and, in cancer, abnormal changes in one cell type can lead to tumorigenesis in other nearby cells. Reporting in Science, Harold Moses and colleagues now describe a new mechanism for this, showing that loss of transforming growth factor-β (TGF-β) signalling in stromal fibroblasts leads to oncogenic changes in adjacent epithelial cells.

It is well known that disrupting the normal interactions between epithelial cells and fibroblasts in the underlying stroma can lead to tumorigenesis, but the signalling pathways that are involved in this are poorly understood. To investigate a potential role of Tgf-β signalling in stroma–epithelium interactions, Moses and co-workers made transgenic mice in which the gene encoding the Tgf-β type II receptor (TGF-βRII) — a crucial component of Tgf-β signalling — is specifically inactivated in fibroblasts (Tgfbr2fspKO mice). Increased proliferation of both fibroblasts and epithelial cells was seen in prostate tissue from these mice, with prostate epithelial cells also showing neoplastic characteristics. In the forestomach, even more marked effects on epithelial cells were seen, with invasive squamous-cell carcinomas developing in 100% of Tgfbr2fspKO mice.

But how does loss of Tgf-β signalling in fibroblasts trigger tumorigenesis in adjacent epithelia? Hepatocyte growth factor (Hgf) is one target of Tgf-β signalling, so Moses and colleagues analysed Hgf signalling in Tgfbr2fspKO animals. Cultured fibroblasts from Tgfbr2fspKO mice were found to secrete three times as much of the active form of Hgf as cells from control mice. Furthermore, increased levels of the phosphorylated, active form of the Hgf receptor — c-Met — were seen in prostate and forestomach epithelial cells from Tgfbr2fspKO mice.

The authors also showed increased expression of the tumour promoter c-Myc and decreased levels of the cyclin-dependent kinase inhibitors Waf1 and Kip1 in prostate and forestomach tissue from Tgfbr2fspKO mice. This indicates that when Tgf-β signalling is disrupted in fibroblasts, increased Hgf signalling in neighbouring cells might lead to changes in the expression of proteins such as c-Myc, Waf1 and Kip1 that lead to uncontrolled proliferation. In support of this, the overexpression of c-Myc was shown to co-localize with that of active c-Met in epithelial cells.

So, it seems that in addition to its well-known influence on tumorigenic processes in cells in which it acts directly, Tgf-β also functions as an indirect suppressor of epithelial tumorigenesis through its effects on neighbouring fibroblasts. The question of why the effects of loss of Tgf-β signalling were seen in the prostate and forestomach, but not in other organs, remains to be investigated.