Sci. Signal., 23 September 2008
Cancer A Two-Way Street
Elizabeth M. Adler
Science Signaling, AAAS, Washington, DC 20005, USA
Secreted hedgehog (Hh) ligands bind to receptors on target cells, thereby initiating a signaling pathway crucial to normal development. Noting that abnormal activation of the Hh signaling pathway is associated with various human cancers (see Curran and Ng), Yauch et al. evaluated the sensitivity of a panel of human tumor cell lines to HhAntag and cyclopamine, both of which bind to the transmembrane protein smoothened (Smo) and thereby antagonize Hh signaling. Cell growth inhibition required high concentrations of these antagonists; moreover, sensitivity to the Smo inhibitors failed to correlate with basal Hh signaling activity. Further analyses indicated that the inhibitory effects of high concentrations of HhAntag or cyclopamine on epithelial cancer cell lines were off target and did not depend on Smo inhibition. Microarray expression analysis of human tissue specimens, however, indicated that Hh ligand mRNA was indeed overexpressed in a subset of cancers, as did reverse transcription polymerase chain reaction (RT-PCR). In human tumor tissue implanted into immunodeficient mice, mouse stromal cells replaced human-derived stroma (as is known to occur in mouse xenograft systems); Hh activation in mouse stromal cells—but not human tumor cells—correlated with Hh ligand expression by the tumor cells. Moreover, expression of the Hh target gene Gli1 was greater in stromal tissue. Oral administration of HhAntag inhibited tumor growth in mice engrafted with tumor tissue that expressed mRNA encoding Hh ligands but not Smo, as did treatment with an Hh ligand-blocking antibody. Moreover, Hh ligand-expressing human tumor cells co-injected with mouse embryo fibroblasts (MEFs) expressing the gene that encodes Smo (Smo) elicited larger tumors than tumor cells co-injected with MEFs in which Smo was genetically deleted. Thus, the authors conclude that, in Hh-secreting tumors, tumorigenesis depends on paracrine signaling between the cancer cells and their stromal environment.
R. L. Yauch, S. E. Gould, S. J. Scales, T. Tang, H. Tian, C. P. Ahn, D. Marshall, L. Fu, T. Januario, D. Kallop, M. Nannini-Pepe, K. Kotkow, J. C. Marsters Jr., L. L. Rubin, F. J. de Sauvage, A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406-410 (2008). [PubMed]
T. Curran, J. M. Y. Ng, Hedgehog's other great trick. Nature 455, 293-294 (2008). [PubMed]
Citation: E. M. Adler, A Two-Way Street. Sci. Signal. 1, ec329 (2008).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882