A paracrine requirement for Hedgehog signaling in cancer

5431 Ligand-dependent activation of the Hedgehog (Hh) signaling pathway has been associated with tumorigenesis in a number of human tissues. Surprisingly, in these malignancies, Hh ligands have been reported to function as autocrine growth factors. Utilizing both cell lines and primary human tumors, we show that the previously observed effects of Hh pathway antagonists used at high concentrations on tumor cells are non-specific and that Hh ligands produced by tumor epithelial cells fail to activate signaling in those cells. Instead, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment of such tumors. Specific inhibition of stromal Hh signaling results in growth inhibition in xenograft tumor models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signaling in the tumorigenesis of Hh-expressing cancers and has implications on the development of Hh pathway antagonists in cancer.