Abstract
Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs.
Highlights
Inherited epidermolysis bullosa (EB) comprises a clinically and genetically heterogeneous group of rare genetic diseases characterized by skin fragility and blister formation following minor trauma [1]
Almost all subjects affected with the severe recessive dystrophic Epidermolysis bullosa (EB) (RDEB) subtype suffer from early and extremely aggressive squamous cell carcinomas (SCCs) (RDEB-SCC), which represent the first cause of death in these patients
In the most severe and disabling EBtypes mutations in genes coding for specific components of the epidermal-dermal junction strongly compromise the healing process, and, in turn, skin erosions and blisters evolve in chronic wounds, inflammation and fibrosis [17]
Summary
Inherited epidermolysis bullosa (EB) comprises a clinically and genetically heterogeneous group of rare genetic diseases characterized by skin fragility and blister formation following minor trauma [1]. Four major EB types are distinguished based on the level of blister formation within the skin: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome (KS) (Figure 1). According to the current “onion skin” classification approach, each EB type comprises several subtypes characterized by different modes of inheritance, causative genes and mutations, phenotypic and molecular features [1]. .EpEipdiedrmeraml acel lclselllasylearys,efrrso,mfrothme sthtreatsutmratbuamsalbeatsoale to tthhee sttrraattuumm ccoorrnneeuumm((flflaat,t,oorraannggeebbooxxese)s,),ananddththe euunndderelryliynigngpappaipllialrlyaraynadndretriectuiclaurladredrmerims aisreare dedpeicptiecdte.dB. In recessive DEB, JEB and KS blistering occurs within or below the cutaneous basement membrane zone (BIMn Zr)eacensdsilveeadDs EtoBc, hJrEoBniacnwdouKnSdsblwisittehrifinbgrooscicsuarnsdwinitflhainmmoratbioenlohweatlhinegcwutiathnesocaursribnagsseemqeunetlae. SCCs occurring in recessive DEB, will be addressed
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