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

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: basement membrane zone; cancer; collagen VII; extracellular matrix; fibrosis; immunity; inflammation; kindlin-1; laminin-332; wound-healing.

Figure 3

Collagen VII (COL7) deficiency in recessive dystrophic epidermolysis bullosa (RDEB) skin and extracutaneous tissues favors squamous cell carcinoma (SCC) development. The figure summarizes literature findings on relevant pro-tumorigenic processes triggered by COL7 loss in RDEB keratinocytes, fibroblasts and lymphoid organs [42,44,49,52,57,58,59,61,62,63,64,67,84]. Red up arrows indicate increase/up-regulation, green down arrows indicate decrease/down-regulation. Abbreviations: ECM, extracellular matrix; ELMO2, engulfment and cell motility 2; FAK, focal adhesion kinase; ITGA6, integrin subunit alpha 6; LM332, laminin-332; LOX, lysyl oxidase; LTBP1, latent-transforming growth factor beta-binding protein 1; MMP2, metalloproteinase 2; OATP1B3, organic anion transporting polypeptide 1B3; PAR3, partitioning defective 3; PI3K, phosphoinositide 3-kinase; PLC-β4, phospholipase C-β4; RDEB, recessive dystrophic epidermolysis bullosa cutaneous; SCC, squamous cell carcinoma; SLCO1B3, solute carrier organic anion transporter family member 1B3; RDEB-SCC, RDEB-related SCC; TNC, tenascin-C; TβR1, transforming growth factor β receptor 1; TGF-β1, transforming growth factor-β1; TGM2, transglutaminase 2, VEGF, vascular endothelial growth factor.

Figure 1

Schematic representation of the epidermis depicting levels of cleavage sites and mutated proteins for each epidermolysis bullosa (EB) type. Epidermal cells layers, from the stratum basale to the stratum corneum (flat, orange boxes), and the underlying papillary and reticular dermis are depicted. Basal keratinocytes are attached to the dermis by multiprotein complexes linking keratin intermediate filaments to anchoring fibrils through hemidesmosomes and the epithelial laminin isoform, laminin-332. Focal adhesions also contribute to stabilizing the cutaneous basement membrane zone (BMZ). The skin level where blisters arise in each epidermolysis bullosa (EB) type (red lines and dots), and the corresponding mutated proteins are indicated. Inset magnification shows the BMZ, with proteins mutated in Kindler syndrome, junctional EB (JEB) and dystrophic EB (DEB) shown in red. In EB forms compatible with survival to adulthood, the risk of cutaneous squamous cell carcinoma (SCC) occurrence correlates with EB severity (green arrow turning into red. Green = low/mild severity EB type and a low risk to develop SCC, red = severe EB type and high risk to develop SCC).

Figure 2

Schematic representation of squamous cell carcinoma (SCC) microenvironment in recessive dystrophic epidermolysis bullosa (RDEB) patients. Left panel. Normal skin. Basal keratinocytes firmly adhere to the basement membrane zone (BMZ) through hemidesmosome protein components (blue ovals) and are also the main producers of laminin-332, an essential component of epithelial BMZs, and of type VII collagen (COL7) that assembles into anchoring fibrils (AFs). AFs extend from the lower part of the BMZ into the upper dermis (papillary dermis), ensuring dermal-epidermal cohesion. Middle panel. In RDEB patients, COL7 deficiency impairs anchoring fibrils formation and leads to skin fragility and blistering (red asterisk) after minor traumas. At sites of chronic blistering, the dermis is enriched in inflammatory cells (neutrophils, macrophages and T-cells) and myofibroblasts: Both cell types produce high amounts of transforming growth factor (TGF)-β1, a master regulator of fibrosis, in an unremitting and self-renewing cycle. In addition, myofibroblasts abundantly produce extracellular matrix components, contributing to dermal stiffening. Chronic wounds (black asterisks) also show high levels of bacterial colonization that contribute to exacerbating inflammation. In the dermis of RDEB patients, the derailed production of cytokines, growth factors and ECM members create the permissive environment for keratinocyte transformation. Right panel. RDEB-SCC microenvironment. Stromal inflammation and fibrosis represent the scaffold for tumor development and progression. Cells with features of cancer-associated fibroblasts (CAFs-like cells) populate tumor stroma and contribute to tumor growth. Keratinocytes undergo epithelial-mesenchymal transition (EMT) and convert to carcinoma cells. SCC microenvironment is characterized by huge inflammation and fibrosis.