This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mao, J. Articles by McMahon, A. P. Search for Related Content PubMed PubMed Citation Articles by Mao, J. Articles by McMahon, A. P.

A Novel Somatic Mouse Model to Survey Tumorigenic Potential Applied to the Hedgehog Pathway

¹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts; ² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School; ³ Department of Pathology, Brigham and Women's Hospital; ⁴ Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and ⁵ Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, Massachusetts

Requests for reprints: Andrew P. McMahon, Molecular and Cellular Biology, Harvard University, Biological Laboratories, Room 1059, 16 Divinity Avenue, Cambridge, MA 02138. Phone: 617-496-3757; E-mail: mcmahon{at}mcb.harvard.edu.

We report a novel mouse model for the generation of sporadic tumors and show the efficiency of this approach by surveying Hedgehog (Hh)–related tumors. Up-regulation of the Hh pathway is achieved by conditionally regulated expression of an activated allele of Smoothened (R26-SmoM2) using either sporadic leakage or global postnatal induction of a ubiquitously expressed inducible Cre transgene (CAGGS-CreER). Following postnatal tamoxifen induction, CAGGS-CreER; R26-SmoM2 mice developed tumors with short latency and high penetrance. All mice exhibited rhabdomyosarcoma and basal cell carcinoma; 40% also developed medulloblastoma. In addition, mice showed a novel pancreatic lesion resembling low-grade mucinous cystic neoplasms in humans. In contrast, widespread activation of SmoM2 in the postnatal prostate epithelium results in no detectable morphologic outcome in 12-month-old mice. Comparison of gene expression profiles among diverse tumors identified several signature genes, including components of platelet-derived growth factor and insulin-like growth factor pathways, which may provide a common mechanistic link to the Hh-related malignancies. This experimental model provides a robust tool for exploring the process of Hh-dependent tumorigenesis and the treatment of such tumors. More generally, this approach provides a genetic platform for identifying tumorigenic potential in putative oncogenes and tumor suppressors and for more effective modeling of sporadic cancers in mice. (Cancer Res 2006; 66(20): 10171-7)

This article has been cited by other articles:

				G. R. van den Brink Hedgehog Signaling in Development and Homeostasis of the Gastrointestinal Tract Physiol Rev, October 1, 2007; 87(4): 1343 - 1375. [Abstract] [Full Text] [PDF]