title: DMBA/TPA treatment is necessary for BCC formation from patched deficient epidermal cells in Ptch(flox/flox)CD4Cre(+/-) mice.
abstract: The development of basal cell carcinoma (BCC), the most frequently diagnosed tumor among persons with European ancestry, is closely linked to mutations in the Hedgehog (Hh) receptor and tumor suppressor Patched1 (Ptch). Using Ptch(flox/flox)CD4Cre(+/-) mice, in which Ptch was ablated in CD4Cre-expressing cells, we demonstrate that the targeted cells can give rise to BCC after treatment with DMBA (7,12-dimethylbenz(a)anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate), but not after wounding of the skin. In addition, in this model, BCC are not caused by malfunctioning of Ptch-deficient T cells, as BCC did not develop when bone marrow (BM) of Ptch(flox/flox)CD4Cre(+/-) mice was transplanted into Ptch wild-type mice. Instead, lineage-tracing experiments and flow cytometric analyses suggest that the tumors are initiated from rare Ptch-deficient stem cell-like cells of the epidermis that express CD4. As DMBA/TPA is a prerequisite for BCC development in this model, the initiated cells need a second stimulus for expansion and tumor formation. However, in contrast to papilloma, this stimulus seems to be unrelated to alterations in the Ras signaling cascade. Together, these data suggest that biallelic loss of Ptch in CD4(+) cells does not suffice for BCC formation and that BCC formation requires a second so far unknown event, at least in the Ptch(flox/flox)CD4Cre(+/-) BCC mouse model.
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany. Electronic address: auhmann@gwdg.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Uhmann
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Heß
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Frommhold
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: König
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zabel
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Nitzki
authors.affiliation: Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.affiliation: Institute for Multiple Sclerosis Research, University of Göttingen, Göttingen, Germany.
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.affiliation: Department of Radiation Therapy and Radiation Oncology, University of Göttingen, Göttingen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Christiansen
authors.affiliation: Department of Neuropathology, University of Düsseldorf, Düsseldorf Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Reifenberger
authors.affiliation: Department of Neuropathology, University of Göttingen, Göttingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects* / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology* / Q000502:physiology; D063646:Carcinogenesis / Q000139:chemically induced* / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology; D002280:Basal Cell Carcinoma / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004817:Epidermis / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D002273:Carcinogens; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015127:9,10-Dimethyl-1,2-benzanthracene; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D013755:Tetradecanoylphorbol Acetate