title: A paracrine requirement for hedgehog signalling in cancer.
abstract: Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, 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.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.forename: Tracy
authors.initials: T
authors.lastname: Tang
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.forename: Christina P
authors.initials: CP
authors.lastname: Ahn
authors.forename: Derek
authors.initials: D
authors.lastname: Marshall
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.forename: Dara
authors.initials: D
authors.lastname: Kallop
authors.forename: Michelle
authors.initials: M
authors.lastname: Nannini-Pepe
authors.forename: Karen
authors.initials: K
authors.lastname: Kotkow
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage