The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

Barbara Bellei,Anna Carbone,Federica Papaccio,Laura Eibenschutz,Mauro Picardo,Silvia Caputo,Vitaliano Silipo

doi:10.3390/ijms21030720

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/β-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous “pre-activated state” due to PTCH1 mutations to those of skin tumor stroma.

Highlights

Nevoid basal cell carcinoma syndrome (NBCCS OMIM #109400), known as Gorlin–Goltz syndrome or Gorlin syndrome (GS), is a rare genetic alteration with an estimated prevalence of around 1 in 100,000 on average [1,2] and of 1 in 256,000 in Italy [3]
The similarity of syndromic fibroblasts to carcinoma-associated fibroblasts (CAF) complemented our knowledge about the predisposition of these patients to develop a huge number of basal cell carcinomas (BCCs) in early life and in sun-unexposed body areas
In line with the idea that fibroblasts may be key players in cancer-prone hereditary diseases, abnormal dermal fibroblast activation and extracellular matrix remodeling has been described as a common hallmark of genodermatoses [109]

Summary

Introduction

Nevoid basal cell carcinoma syndrome (NBCCS OMIM #109400), known as Gorlin–Goltz syndrome or Gorlin syndrome (GS), is a rare genetic alteration with an estimated prevalence of around 1 in 100,000 on average [1,2] and of 1 in 256,000 in Italy [3]. It has been observed that NBCCS patients lack intrinsic resistance to Hh target therapy, such as Vismodegib and Sonidegib [25,26] It is unclear if the scarcity of drug resistance to Vismodegib in Gorlin syndrome is an intrinsic disease trait or if it refers to the fact that in these studies, locally advanced and metastatic sporadic basal cell carcinomas were compared to a more heterogeneous group of NBCCS-BCCs [22,27,28]. Brellier and collaborators reported normal nucleotide excision repair and survival capacity in UVB-treated NBCCS keratinocytes and fibroblasts [34]

Genetic Aspects

Hedgehog Signaling

Hh Signaling in Tumor Microenvironment

Hh Signaling in Cancer-Associated Fibroblasts

Findings

Conclusions