Impaired Wound Healing, Fibrosis, and Cancer: The Paradigm of Recessive Dystrophic Epidermolysis Bullosa

Abstract

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease caused by mutations in the gene encoding type VII collagen (C7), leading to epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wound and scar formation, and squamous cell carcinoma-the single biggest cause of death in this patient group. The molecular pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB, and squamous cell carcinomas arising in RDEB are thus far molecularly indistinct from other sub-types of aggressive squamous cell carcinoma (SCC). Collectively these data demonstrate RDEB is a model for understanding the molecular basis of both fibrosis and rapidly developing aggressive cancer. A number of studies have shown that RDEB pathogenesis is driven by a radical change in extracellular matrix (ECM) composition and increased transforming growth factor-beta (TGFβ) signaling that is a direct result of C7 loss-of-function in dermal fibroblasts. However, the exact mechanism of how C7 loss results in extensive fibrosis is unclear, particularly how TGFβ signaling is activated and then sustained through complex networks of cell-cell interaction not limited to the traditional fibrotic protagonist, the dermal fibroblast. Continued study of this rare disease will likely yield paradigms relevant to more common pathologies.

Keywords: fibrosis; recessive dystrophic epidermolysis bullosa; squamous cell carcinoma; therapies; wound healing.

Figure 1

Wound Healing Complications in RDEB. A schematic showing the process of wound healing in its four stages: hemostasis, inflammation, proliferation, and maturation. In RDEB, blister formation triggers the wound healing cascade, which contributes to the increased expression of TGFβ and TSP1, among others. Excessive amounts of these factors contribute to delays in keratinocyte and fibroblast migration, slowing down wound closure. There can also be a persistent infection in the wound area, denoted by the increased presence of activated immune cells. In the event of unresolved maturation, fibrosis occurs, which is demarked by altered ECM deposition. Crosslinked collagen in the wound bed is a prominent component of excessive ECM deposition, leading to the heavy scarring phenotype. Created with Biorender.com.

Figure 2

Age of Onset for SCCs in Different Populations. Head and Neck SCC (HNSCC) data [82], UV light-induced SCC (UVSCC) data [83,84], and RDEB SCC (RDEBSCC) data from our records of patient samples accumulated from 2005–2017. Data were plotted by GraphPad-Prism using a two-tailed, Mann–Whitney test assuming unequal variance. ****: p ≤0.0001. HNSCC: n = 278; UVSCC: n = 66; RDEBSCC: n = 36.