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J Invest Dermatol. 2014 Oct;134(10):2620-2629. doi: 10.1038/jid.2014.157. Epub 2014 Mar 24.

DMBA/TPA treatment is necessary for BCC formation from patched deficient epidermal cells in Ptch(flox/flox)CD4Cre(+/-) mice.

Author information

1
Institute of Human Genetics, University of Göttingen, Göttingen, Germany. Electronic address: auhmann@gwdg.de.
2
Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
3
Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany.
4
Institute for Multiple Sclerosis Research, University of Göttingen, Göttingen, Germany.
5
Department of Radiation Therapy and Radiation Oncology, University of Göttingen, Göttingen, Germany.
6
Department of Neuropathology, University of Düsseldorf, Düsseldorf Germany.
7
Department of Neuropathology, University of Göttingen, Göttingen, Germany.

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.

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PMID:
24662765
DOI:
10.1038/jid.2014.157
[Indexed for MEDLINE]
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