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Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: from Pathogenesis to Therapeutic Perspectives

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Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: from Pathogenesis to Therapeutic Perspectives International Journal of Molecular Sciences Review Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives Angelo Giuseppe Condorelli 1,* , Elena Dellambra 2 , Elena Logli 1, Giovanna Zambruno 1 and Daniele Castiglia 2 1 Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, viale di San Paolo 15, 00146 Rome, Italy; [email protected] (E.L.); [email protected] (G.Z.) 2 Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy; [email protected] (E.D.); [email protected] (D.C.) * Correspondence: [email protected]; Tel.: +39-06-6859-2655 Received: 12 October 2019; Accepted: 11 November 2019; Published: 14 November 2019 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. Keywords: cancer; wound-healing; basement membrane zone; extracellular matrix; fibrosis; inflammation; immunity; collagen VII; laminin-332; kindlin-1 1. Introduction 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) (Figure1). According to the current “onion skin” classification approach, each EB type then comprises several subtypes characterized by different modes of inheritance, causative genes and mutations, phenotypic and molecular features [1]. EB clinical spectrum ranges from early-lethal forms with extensive cutaneous and extracutaneous involvement to mild phenotypes with localized skin lesions only. Disease-causing variants in at least 20 different genes account for the genetic heterogeneity of EB [2] (Figure1). Int. J. Mol. Sci. 2019, 20, 5707; doi:10.3390/ijms20225707 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 5707 2 of 28 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 29 FigureFigure 1. 1.Schematic Schematic representation representation ofof thethe epidermisepidermis depi depictingcting levels levels of of cleavage cleavage sites sites and and mutated mutated proteinsproteins for for each each epidermolysis epidermolysis bullosabullosa (EB) (EB) type. type. Epidermal Epidermal cells cells layers, layers, from from the stratum the stratum basale basale to tothe the stratum corneum corneum (flat, (flat, orange orange boxes), boxes), and and the the underlying underlying papillary papillary and and reticular reticular dermis dermis are are depicted.depicted. Basal Basal keratinocytes keratinocytes areare attachedattached to the dermis by by multiprotein multiprotein complexes complexes linking linking keratin keratin intermediateintermediate filaments filaments to anchoringto anchoring fibrils fibrils through through hemidesmosomes hemidesmosomes and theand epithelial the epithelial laminin laminin isoform, laminin-332.isoform, laminin-332. Focal adhesions Focal alsoadhesions contribute also to cont stabilizingribute to the stabilizing cutaneous the basement cutaneous membrane basement zone (BMZ).membrane The skinzone level (BMZ). where The skin blisters level arise where in eachblisters epidermolysis arise in each epidermolysis bullosa (EB) typebullosa (red (EB) lines type and dots),(red andlines the and corresponding dots), and the corre mutatedsponding proteins mutated are proteins indicated. are indicated. Inset magnification Inset magnification shows the shows BMZ, withthe proteins BMZ, with mutated proteins in Kindlermutated syndrome, in Kindlerjunctional syndrome, EB junctional (JEB) and EB dystrophic (JEB) and EBdystrophic (DEB) shown EB (DEB) in red. Inshown EB forms in red. compatible In EB forms with compatible survival to with adulthood, survival theto adulthood, risk of cutaneous the risk squamousof cutaneous cell squamous carcinoma (SCC)cell occurrencecarcinoma (SCC) correlates occurrence with EB correlates severity with (green EB arrow severity turning (green into arrow red. tu Greenrning =intolow red./mild Green severity = EBlow/mild type and severity a low risk EB totype develop and a SCC, low redrisk =tosevere develop EB SCC, type andred = high severe risk EB to type develop and SCC).high risk to develop SCC). In recessive DEB, JEB and KS blistering occurs within or below the cutaneous basement membrane zone (BMZ)In recessive and leads DEB, to chronic JEB and wounds KS blistering with fibrosis occurs and within inflammation or below healing the cutaneous with scarring basement sequelae. membrane zone (BMZ) and leads to chronic wounds with fibrosis and inflammation healing with These patients have an increased risk to develop one or more cutaneous squamous cell carcinomas scarring sequelae. These patients have an increased risk to develop one or more cutaneous squamous (SCCs) [1]. Usually, the tumors are localized at sites of chronic, hard-to-heal wounds and scarring, cell carcinomas (SCCs) [1]. Usually, the tumors are localized at sites of chronic, hard-to-heal wounds they are frequently multiple, and, specific to recessive DEB, highly aggressive representing the first and scarring, they are frequently multiple, and, specific to recessive DEB, highly aggressive cause of death in this EB subtype. Though the age of onset, cancer localization and carcinogenetic representing the first cause of death in this EB subtype. Though the age of onset, cancer localization processes may be to some extent different across the various EB (sub)types, EB-related SCC (EB-SCC) and carcinogenetic processes may be to some extent different across the various EB (sub)types, EB- representsrelated SCC an important(EB-SCC) represents model towards an important a more completemodel towards understanding a more complete of mechanisms understanding responsible of formechanisms carcinogenesis responsible occurring withinfor carcinogenesis a fibrotic and inflamedoccurring microenvironment. within a fibrotic In thisand review, inflamed we will discussmicroenvironment. SCC clinical In and this molecular review, we features will discuss in each SCC cancer-proneclinical and molecular EB type, features focusing in each on thecancer- latest findingsprone unveilingEB type, novel focusing and potentiallyon the latest relevant findings pathomechanisms unveiling novel underlying and potentially tumor development relevant in EBpathomechanisms patients and highlighting underlying gaps tumor in the development current literature. in EB patients In addition, and highlighting the mostpromising gaps in the directcurrent and indirectliterature. therapeutic In addition, strategies the most to pr counteractomising direct EB-SCC, and indirect with special therapeutic reference strategies to the to devastating counteract EB- SCCs occurringSCC, with in special recessive reference DEB, will to the be devastating addressed. SCCs occurring in recessive DEB, will be addressed. 2. SCC in the General Population Cutaneous SCC (hereafter indicated as SCC) represents the second most common non- melanoma skin cancer (NMSC) after basal cell carcinoma (BCC). While the incidence ratio of BCC to SCC is traditionally considered to be 4:1, a recent study reported an age-weighted incidence ratio of 1.4:1 in the USA population [3]. However, statistics on the incidence of SCC are difficult to calculate Int. J. Mol. Sci. 2019, 20, 5707 3 of 28 2. SCC in the General Population Cutaneous SCC (hereafter indicated as SCC) represents the second most common non-melanoma skin cancer (NMSC) after basal cell carcinoma (BCC). While the incidence ratio of BCC to SCC is traditionally considered to be 4:1, a recent study reported an age-weighted incidence ratio of 1.4:1 in the USA population [3]. However, statistics on the incidence of SCC are difficult to calculate because of limited data, due to incomplete registration practices in many countries or, as in the USA, to the absence of a national SCC registry. According to a recent study, the age-standardized incidence rate of the first SCC in the UK population in the period 2013–2015 is equal to 77 cases per 100,000 person-years (PY) [4]. All reports agree that
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