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<title lang=en>Basal Cell Carcinoma in Gorlin’s Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?</title>
<creator>Gache, Yannick</creator>
<creator>Brellier, Florence</creator>
<creator>Rouanet, Sophie</creator>
<creator>Al-Qaraghuli, Sahar</creator>
<creator>Goncalves-Maia, Maria</creator>
<creator>Burty-Valin, Elodie</creator>
<creator>Barnay, Stéphanie</creator>
<creator>Scarzello, Sabine</creator>
<creator>Ruat, Martial</creator>
<creator>Sevenet, Nicolas</creator>
<creator>Avril, Marie-Françoise</creator>
<creator>Magnaldo, Thierry</creator>
<contributor>Institut de Recherche sur le Cancer et le Vieillissement (IRCAN) ; Université Nice Sophia Antipolis (UNS) ; Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)</contributor>
<contributor>Génomes et cancer (GC (FRE2939)) ; Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Centre National de la Recherche Scientifique (CNRS)</contributor>
<contributor>Evolution Paris Seine ; Université Nice Sophia Antipolis (UNS) ; Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - Centre National de la Recherche Scientifique (CNRS) - Université des Antilles et de la Guyane (UAG) - Université Pierre et Marie Curie - Paris 6 (UPMC)</contributor>
<contributor>Institut des Neurosciences de Paris-Saclay (Neuro-PSI) ; Université Paris-Sud - Paris 11 (UP11) - Centre National de la Recherche Scientifique (CNRS)</contributor>
<contributor>Validation et identification de nouvelles cibles en oncologie (VINCO) ; Université Bordeaux Segalen - Bordeaux 2 - Institut Bergonié - CRLCC Bordeaux - Institut National de la Santé et de la Recherche Médicale (INSERM)</contributor>
<contributor>Service de Dermatologie, Hôpital Cochin, AP-HP, Paris ; Service de Dermatologie, Hôpital Cochin, AP-HP, Paris</contributor>
<description>International audience</description>
<source>ISSN: 1932-6203</source>
<source>PLoS ONE</source>
<publisher>Public Library of Science</publisher>
<identifier>hal-01257867</identifier>
<identifier>http://hal.upmc.fr/hal-01257867</identifier>
<identifier>http://hal.upmc.fr/hal-01257867/document</identifier>
<identifier>http://hal.upmc.fr/hal-01257867/file/journal.pone.0145369.pdf</identifier>
<source>http://hal.upmc.fr/hal-01257867</source>
<source>PLoS ONE, Public Library of Science, 2015, 10 (12), pp.e0145369. 〈10.1371/journal.pone.0145369〉</source>
<identifier>DOI : 10.1371/journal.pone.0145369</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0145369</relation>
<identifier>PUBMED : 26694869</identifier>
<relation>info:eu-repo/semantics/altIdentifier/pmid/26694869</relation>
<language>en</language>
<subject>[SDV.CAN] Life Sciences [q-bio]/Cancer</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description lang=en>Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings suggest that defects in dermo/epidermal interactions could contribute to BCC susceptibility in NBCCS patients.</description>
<rights>http://creativecommons.org/licenses/by/</rights>
<date>2015-12-22</date>
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