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Hedgehog signalling in prostate regeneration, neoplasia and metastasis

Abstract

Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning1,2,3,4,5,6, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component1,2,7 that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential.

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Acknowledgements

We thank W. Bushman for sharing results before publication, S. Dalrymple, H. Fedor, M. Gerstenblith, T. Harcke, W. Kleeberger, R. Montes de Oca, E. Traband, Y. Xin and K. Young for help with experiments; M. Eisenberger, M. Carducci and W. Isaacs for support of autopsy studies; C. Sawyers, W. Nelson and D. Neil Watkins for discussions and A. Joyner, D. Coffey and J. Chen for reagents. We are very grateful to A. De Marzo and the Johns Hopkins Prostate Specimen Repository for generously providing tissue samples. This research was supported by NIH and the Prostate Cancer Foundation. P.A.B. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to David M. Berman or Philip A. Beachy.

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Competing interests

Under a licensing agreement between Curis, Inc. and the Johns Hopkins University, P.A.B. and the University hold equity in Curis and are entitled to a share of royalties from sales of the products described in this article. P.A.B. and D.M.B. also receive payment and/or equity for service as consultants to Curis, Inc. and Genentech Inc. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Figure 1: Hh pathway activity in growth of human prostate cancer cells.
Figure 2: Hh pathway activity in prostate progenitors.
Figure 3: Hh pathway activation in metastatic prostate cancer and determination of Hh pathway responsiveness by SMO.
Figure 4: Hh pathway activity determines metastatic potential.

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