Carcinogenesis Advance Access originally published online on March 25, 2009
Carcinogenesis 2009 30(6):918-926; doi:10.1093/carcin/bgp068
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Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts
Institute of Human Genetics, University of Goettingen, Heinrich-Dueker Weg 12, 37073 Goettingen, Germany
1 Department of Reproduction and Development, Erasmus University, 3015 GE, Rotterdam, The Netherlands
2 Department of Clinical Chemistry, University of Goettingen, 37075 Goettingen, Germany
3 Department of Pharmacology, University of Mainz, 55101 Mainz, Germany
4 Institute of Pathology, University of Tuebingen, 72076 Tuebingen, Germany
5 Department of Dermatology, University of Duesseldorf, 40225 Duesseldorf, Germany
6 Department of Neuropathology, University of Goettingen, 37075 Goettingen, Germany
* To whom correspondence should be addressed. Tel: +49 551 3914010; Fax: +49 551 396580; Email: hhahn{at}gwdg.de
Mutations in Patched (PTCH) have been associated with tumors characteristic both for children [medulloblastoma (MB) and rhabdomyosarcoma (RMS)] and for elderly [basal cell carcinoma (BCC)]. The determinants of the variability in tumor onset and histology are unknown. We investigated the effects of the time-point and dosage of Ptch inactivation on tumor spectrum using conditional Ptch-knockout mice. Ptch heterozygosity induced prenatally resulted in the formation of RMS, which was accompanied by the silencing of the remaining wild-type Ptch allele. In contrast, RMS was observed neither after mono- nor biallelic postnatal deletion of Ptch. Postnatal biallelic deletion of Ptch led to BCC precancerous lesions of the gastrointestinal epithelium and mesenteric tumors. Hamartomatous gastrointestinal cystic tumors were induced by monoallelic, but not biallelic Ptch mutations, independently of the time-point of mutation induction. These data suggest that the expressivity of Ptch deficiency is largely determined by the time-point, the gene dose and mode of Ptch inactivation. Furthermore, they point to key differences in the tumorigenic mechanisms underlying adult and childhood tumors. The latter ones are unique among all tumors since their occurrence decreases rather than increases with age. A better understanding of mechanisms underlying this ontological restriction is of potential therapeutic value.
Abbreviations: AR, artificial reference; BCC, basal cell carcinoma; CTX, cardiotoxin; Hh, hedgehog; i.m., intramuscularly; i.p., intraperitoneally; MB, medulloblastoma; PCR, polymerase chain reaction; Ptch, patched; RMS, rhabdomyosarcoma; RT–PCR, reverse transcription–polymerase chain reaction; SP, side population; wt, wild-type
These authors contributed equally to this work. Received December 4, 2008; revised February 9, 2009; accepted March 19, 2009.
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