A paracrine requirement for hedgehog signalling in cancer.
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.
Yauch
Robert L
RL
Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Gould
Stephen E
SE
Scales
Suzie J
SJ
Tang
Tracy
T
Tian
Hua
H
Ahn
Christina P
CP
Marshall
Derek
D
Fu
Ling
L
Januario
Thomas
T
Kallop
Dara
D
Nannini-Pepe
Michelle
M
Kotkow
Karen
K
Marsters
James C
JC
Rubin
Lee L
LL
de Sauvage
Frederic J
FJ