Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?

Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper...

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Autores principales:	Laura Eibenschutz, Silvia Caputo, Emanuela Camera, Anna Carbone, Vitaliano Silipo, Emilia Migliano, Caterina Aurizi, Carlo Cota, Pasquale Frascione, Barbara Bellei
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	basal cell carcinoma skin nevoid basal cell carcinoma syndrome Gorlin syndrome hedgehog pathway CAF Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b776a28ae7814168a4a7f14a0d71015a
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spelling	oai:doaj.org-article:b776a28ae7814168a4a7f14a0d71015a2021-11-25T17:04:51ZEvaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?10.3390/cancers132258582072-6694https://doaj.org/article/b776a28ae7814168a4a7f14a0d71015a2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5858https://doaj.org/toc/2072-6694Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the <i>PTCH1</i> gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/β-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3β axis and consequent increase of β-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.Laura EibenschutzSilvia CaputoEmanuela CameraAnna CarboneVitaliano SilipoEmilia MiglianoCaterina AuriziCarlo CotaPasquale FrascioneBarbara BelleiMDPI AGarticlebasal cell carcinomaskinnevoid basal cell carcinoma syndromeGorlin syndromehedgehog pathwayCAFNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5858, p 5858 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	basal cell carcinoma skin nevoid basal cell carcinoma syndrome Gorlin syndrome hedgehog pathway CAF Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	basal cell carcinoma skin nevoid basal cell carcinoma syndrome Gorlin syndrome hedgehog pathway CAF Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Laura Eibenschutz Silvia Caputo Emanuela Camera Anna Carbone Vitaliano Silipo Emilia Migliano Caterina Aurizi Carlo Cota Pasquale Frascione Barbara Bellei Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?
description	Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the <i>PTCH1</i> gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/β-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3β axis and consequent increase of β-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.
format	article
author	Laura Eibenschutz Silvia Caputo Emanuela Camera Anna Carbone Vitaliano Silipo Emilia Migliano Caterina Aurizi Carlo Cota Pasquale Frascione Barbara Bellei
author_facet	Laura Eibenschutz Silvia Caputo Emanuela Camera Anna Carbone Vitaliano Silipo Emilia Migliano Caterina Aurizi Carlo Cota Pasquale Frascione Barbara Bellei
author_sort	Laura Eibenschutz
title	Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?
title_short	Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?
title_full	Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?
title_fullStr	Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?
title_full_unstemmed	Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?
title_sort	evaluation of hedgehog pathway inhibition on nevoid basal cell carcinoma syndrome fibroblasts and basal cell carcinoma-associated fibroblasts: are vismodegib and sonidegib useful to target cancer-prone fibroblasts?
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b776a28ae7814168a4a7f14a0d71015a
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Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?

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