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?

Cancers

Caterina Aurizi¹  Carlo Cota²  Emilia Migliano³  Barbara Bellei⁴  Emanuela Camera⁴  Silvia Caputo⁴  Anna Carbone⁵  Vitaliano Silipo⁵  Laura Eibenschutz⁵  Pasquale Frascione⁵ 

[1] Department of Dermatological Clinic, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;Department of Dermophatology, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;

关键词: basal cell carcinoma;    skin;    nevoid basal cell carcinoma syndrome;    Gorlin syndrome;    hedgehog pathway;    CAF;   

DOI  :  10.3390/cancers13225858

来源: DOAJ

【 摘 要 】

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 PTCH1 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.

【 授权许可】

Unknown