Hedgehog signalling in prostate regeneration, neoplasia and metastasis

Sunil S Karhadkar; G Steven Bova; Nadia Abdallah; Surajit Dhara; Dale Gardner; Anirban Maitra; John T Isaacs; David M Berman; Philip A Beachy

doi:10.1038/nature02962

Hedgehog signalling in prostate regeneration, neoplasia and metastasis

Nature. 2004 Oct 7;431(7009):707-12. doi: 10.1038/nature02962. Epub 2004 Sep 12.

Authors

Sunil S Karhadkar¹, G Steven Bova, Nadia Abdallah, Surajit Dhara, Dale Gardner, Anirban Maitra, John T Isaacs, David M Berman, Philip A Beachy

Affiliation

¹ Department of Molecular Biology and Genetics and the Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

PMID: 15361885
DOI: 10.1038/nature02962

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 patterning, 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 component 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Cell Division / drug effects
Cell Line
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Hedgehog Proteins
Humans
Ligands
Male
Membrane Proteins / genetics
Mice
Mice, Inbred C57BL
Neoplasm Invasiveness
Neoplasm Metastasis*
Oncogene Proteins / genetics
Patched Receptors
Prostate / cytology
Prostate / metabolism*
Prostate / pathology
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Cell Surface
Receptors, G-Protein-Coupled / genetics
Regeneration*
Signal Transduction*
Smoothened Receptor
Stem Cells / cytology
Stem Cells / metabolism
Stem Cells / pathology
Trans-Activators / metabolism*
Transcription Factors / genetics
Veratrum Alkaloids / pharmacology
Zinc Finger Protein GLI1

Substances

Hedgehog Proteins
Ligands
Membrane Proteins
Oncogene Proteins
Patched Receptors
RNA, Messenger
Receptors, Cell Surface
Receptors, G-Protein-Coupled
SMO protein, human
Smo protein, mouse
Smoothened Receptor
Trans-Activators
Transcription Factors
Veratrum Alkaloids
Zinc Finger Protein GLI1
cyclopamine