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.
Highlights
Under pathological conditions, such as in the inherited disease, Recessive Dystrophic Epidermolysis Bullosa (RDEB), disruption to this equilibrium can lead to aberrant deposition of pathological extracellular matrix (ECM) and results in progressive scarring, tissue dysfunction, and altered outside-in signaling, which can result in cancer [7,8]
RDEB is characterized by digit contraction, healing with scarring, and progressive fibrosis, the net result of which is the development of highly metastatic squamous cell carcinomas (SCC) of the skin—up to 90% of patients with the severe-generalized form of RDEB will succumb to cancer during their lifetime [13]
While animal models recapitulated the phenotype in RDEB and identified increased transforming growth factor-beta (TGFβ) signaling [18,21], studies in primary human cells clearly demonstrated that absent expression of wild-type C7 in RDEB dermal fibroblasts or knockdown of C7 in normal dermal fibroblasts leads to increased TGFβ signaling and a disruption to ECM protein organization and composition that is tumorpromoting [15,17]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The composition and structure of ECM in normal skin is tightly controlled by the equilibrium between synthesis and degradation over time, and this can be transiently shifted towards ECM synthesis under specific conditions, such as growth and development as well as wound healing [6]. Under pathological conditions, such as in the inherited disease, Recessive Dystrophic Epidermolysis Bullosa (RDEB), disruption to this equilibrium can lead to aberrant deposition of pathological ECM and results in progressive scarring, tissue dysfunction, and altered outside-in signaling, which can result in cancer [7,8]
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