A paracrine requirement for hedgehog signalling in cancer

Hedgehog signalling in cancer The hedgehog (Hh) signalling pathway acts in the developing embryo as part of the network controlling cell proliferation and cell fate. It has also been implicated in a number of solid tumours, where it was thought to mediate tumour cell proliferation directly. But a new study suggests a rather different role for hedgehog in cancers. Hedgehog ligands secreted by cancer cells failed to activate signalling in tumour epithelial cells but instead acted on the stroma, the mass of extracellular matrix, fibroblasts, endothelial cells and microvasculature in which the malignant cells are embedded. Tumour growth was promoted, but apparently via an effect on the tumour cells' microenvironment. These findings have important implications for the use of hedgehog antagonists as anticancer drugs. Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues 1 , 2 , 3 , 4 , 5 , 6 , 7 . Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours 1 , 2 , 3 , 4 , 5 , 6 , 7 , Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened ( Smo ) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.