Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a -mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin o...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 21; no. 23; p. 9295
Main Authors:	Brandes, Nadine, Mitkovska, Slavica Hristomanova, Botermann, Dominik Simon, Maurer, Wiebke, Müllen, Anna, Scheile, Hanna, Zabel, Sebastian, Frommhold, Anke, Heß, Ina, Hahn, Heidi, Uhmann, Anja
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI 05-12-2020 MDPI AG
Subjects:	Age Factors Animals basal cell carcinoma Carcinoma, Basal Cell - genetics Carcinoma, Basal Cell - metabolism Carcinoma, Basal Cell - pathology Cell Transformation, Neoplastic - genetics Disease Susceptibility epidermal cells Epidermal Cells - metabolism Epidermal Cells - pathology epidermis Fluorescent Antibody Technique Gene Knock-In Techniques Genes, Reporter hair follicle Hair Follicle - metabolism Hair Follicle - pathology Humans Immunohistochemistry Immunophenotyping keratin 5 Mice Mice, Transgenic Mutation Patched receptor Patched-1 Receptor - genetics Patched-1 Receptor - metabolism Skin - metabolism Skin - pathology Skin Neoplasms - genetics Skin Neoplasms - metabolism Stem Cells - metabolism Stem Cells - pathology epidermal cells basal cell carcinoma hair follicle Patched receptor keratin 5 epidermis
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Summary:	Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a -mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of -targeted BCC progenitors as rare Keratin 5 epidermal cells and show that wildtype offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic depletion in rare Keratin 5 epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms21239295