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. 2006 Oct 15;66(20):10171-8.
doi: 10.1158/0008-5472.CAN-06-0657.

A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway

Junhao Mao  1 , Keith L Ligon, Elena Y Rakhlin, Sarah P Thayer, Roderick T Bronson, David Rowitch, Andrew P McMahon
Affiliations

A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway

Junhao Mao et al. Cancer Res. .

Abstract

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.

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Figures

Figure 1
Figure 1
A somatic mouse model of Hh-related tumorigenesis. A, schematic representation of the CAGGS-CreER transgene and SmoM2 Rosa26 targeted alleles in the CAGGS-CreER; R26-SmoM2 model. B, recombination-mediated activation of SmoM2 by sporadic leakage and tamoxifen induction.
Figure 2
Figure 2
Tumor fomation in CAGGS-CreER; R26-SmoM2 mice. A, distinct tumor spectra in CAGGS-CreER; R26-moM2 mice. Histograms show the fraction of Ptch1+/− (white), CAGGS-CreER; R26-SmoM2 sporadic leakage group (blue), and tamoxifen postnatal injection group (red) mice that developed the indicated tumors. B, survival curves of Ptch1+/−, sporadic leakage group of CAGGS-CreER; R26-SmoM2, and tamoxifen postnatal injection group showing the fraction of mice that survive up to 18 weeks. Genotypes are color coded.
Figure 3
Figure 3
Rhabdomyosarcoma (RBS), BCC, and medulloblastoma in CAGGS-CreER; R26-SmoM2 mice. A, characterization of rhabdomyosarcoma from a CAGGS-CreER; R26-SmoM2 mouse. The muscle tumor shows a mixture of round undifferentiated cells and elongated spindle-shape cells. Desmin is present in both undifferentiated and differentiated tumor cells. B, BCC in tail skin of mice in the postnatal tamoxifen injection group. C, sporadic and tamoxifen-induced SmoM2 expression in the cerebellum induces medulloblastoma. Typical histologic features of human classic medulloblastoma with small blue cells, numerous mitoses, and little histologic evidence of differentiation. Medulloblastomas in CAGGS-CreER; R26-SmoM2 mice expressed Zic1, an early marker of neuronal differentiation, and NeuN, a later marker of neuronal differentiation (C). Ki67 staining indicates a high mitotic index in tumors relative to the WT tissues (A, B, and C). Immunostaining using an anti-GFP antibody shows expression of SmoM2-YFP in tumor cells (A, B, and C).
Figure 4
Figure 4
Pancreatic mucinous cystic lesion in CAGGS-CreER; R26-SmoM2 mice. Alcian blue and PAS staining shows focal intestinal-type mucin expression (arrows) in the epithelium of the cysts, but not in normal pancreatic tissues. Note prominent mucin expression in smaller cysts.
Figure 5
Figure 5
SmoM2 activation in postnatal prostate epithelium is not sufficient to induce neoplastic transformation. H&E staining was done on dorsal prostate from a WT R26-SmoM2 mouse and a Pb-Cre4; R26-SmoM2 mouse at 12 months of age. GFP antibody staining shows SmoM2-YFP expression in prostate epithelium. Ki67 staining of proliferative cells (white arrows) does not reveal a higher mitotic index in the prostate of Pb-Cre4; R26-SmoM2 mice compared with a WT control.
Figure 6
Figure 6
Regulation of the Hh, PDGFRα, IGF, and MAPK pathways in Hh-related tumors. Immunohistochemistry using an anti-PDGFRα antibody identifies strong PDGFRα staining in rhabdomyosarcomas (A) and medulloblastomas (B), relative to control skeletal muscle and cerebellar tissues. C, semiquantitative RT-PCR analysis of Hh-regulated mRNA expression in cultured primary medulloblastoma cells from CAGGS-CreER; R26-SmoM2 mice in the presence or absence of the SmoM2 inhibitor, KAAD-cyclopamine. Treatments were done for 72 hours. Descending wedge, serial dilutions of cDNA templates.
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