Commentaries 7 Kim JH, Chun YS, Kim JC. Clinical and immunological responses in ocular demodecosis. J Korean Med Sci 2011; 26:1231–7. 8 Chen W, Plewig G. Human demodicosis: revisit and a proposed classification. Br J Dermatol 2014; 170:1219–25.
Type VII collagen and squamous cell carcinoma DOI: 10.1111/bjd.12868 ORIGINAL ARTICLE, p 1256 Recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disease, is caused by mutations in COL7A1, the gene encoding type VII collagen (Col7), which is the main component of anchoring fibrils. Affected individuals have decreased or undetectable Col7 with skin and mucosal fragility, blistering and scarring. Over 787% of patients with severe generalized RDEB will die from metastatic squamous cell carcinoma (SCC) by the age of 45 years, suggesting a link between loss of Col7 and aggressive SCC.1 Treatment of RDEB by attempting to restore Col7 by protein, cell or gene therapy is currently the subject of intensive research, and existing and likely future clinical trials.2 In this issue of BJD, Pourreyron et al.3 engineer SCC keratinocytes derived from RDEB tumours and various controls to overexpress Col7 (up to 355-fold vs. normal endogenous levels), using recombinant COL7A1 cDNA in a retroviral vector. They show that high levels of Col7 expression generally induce increased migration and invasion in RDEB SCC keratinocytes, associated with an increase in activation of the phosphoinositide 3-kinase pathway, a pathway involved in regulation of migration/invasion. The authors conclude that caution should be exercised when considering therapeutic strategies where delivery of Col7 is likely to exceed greatly the levels seen under normal physiological conditions. Different models of loss/overexpression of Col7 produce varied results; however, in my opinion, the consensus view is veering towards loss of Col7 being proinvasion. Data from a Ras/IjBa-driven tumorigenesis model suggest that the noncollagenous (NC1) domain of Col7 is necessary for tumour formation by RDEB keratinocytes.4 However, many RDEB tumours do not express Col7.5 In ultraviolet-induced SCC cell lines expressing Col7, knock-down of Col7 using small inhibitory RNA promoted cell invasion and disorganized epithelial differentiation in vitro with an increase in transforming growth factor (TGF)-b signalling, a known contributor to cancer progression.6 In the hypomorphic mouse model of RDEB (10% Col7 expression), chemical carcinogenesis protocols produced more highly invasive tumours compared with benign papillomas in wild-type mice.7 The extracellular matrix composition in RDEB is permissive for tumour development, and invasion and tumour formation of RDEB SCC keratinocytes can be decreased by overexpressing Col7 in dermal fibroblasts.8 Finally, detailed proteome analysis of fibroblasts of patients with RDEB compared with control fibroblasts showed © 2014 British Association of Dermatologists
1215
a decrease in basement membrane matrix components and an increase in dermal matrix proteins, TGF-b and metalloproteinase expression, but not activity, in RDEB.9 Patients with dominant dystrophic epidermolysis bullosa who have one normal COL7A1 allele, hence approximately 50% normal Col7, rarely develop SCC. One would hope that restoring Col7 expression in RDEB to close to 50% of normal levels would decrease TGF-b signalling, improve wound healing, decrease scarring and chronic inflammation, and restore basement membrane function towards normal levels, thus reducing the risk of SCC. However, Col7 is a powerful matrix signalling molecule and, as cautioned by Pourreyron et al.,3 if overexpression is planned, preclinical dose–response studies will be needed in animal models. Conflicts of interest The author works on basement membrane, normal keratinocyte and squamous cell carcinoma biology. Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4AT, U.K. E-mail: [email protected]
E.A. O’TOOLE
References 1 Fine JD, Johnson LB, Weiner M et al. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006. J Am Acad Dermatol 2009; 60:203–11. 2 Fine JD. Inherited epidermolysis bullosa: recent basic and clinical advances. Curr Opin Pediatr 2010; 22:453–8. 3 Pourreyron C, Chen M, McGrath JA et al. High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increase PI3K and MAPK signalling, cell migration and invasion. Br J Dermatol 2014; 170:1256–65. 4 Ortiz-Urda S, Garcia J, Green CL et al. Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 2005; 307:1773–6. 5 Pourreyron C, Cox G, Mao X et al. Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression. J Invest Dermatol 2007; 127:2438–44. 6 Martins VL, Vyas JJ, Chen M et al. Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basementmembrane type VII collagen. J Cell Sci 2009; 122:1788–99. 7 Mittapalli V, Nystr€om A, Fritsch A, Bruckner-Tuderman L. Loss of collagen VII increases aggressive tumor behavior in Col7al hypomorphic mice. J Invest Dermatol 2013; 133 (Suppl. 1):S70. 8 Ng YZ, Pourreyron C, Salas-Alanis JC et al. Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa. Cancer Res 2012; 72:3522–34. 9 K€ uttner V, Mack C, Rigbolt KT et al. Global remodelling of cellular microenvironment due to loss of collagen VII. Mol Syst Biol 2013; 9:657. British Journal of Dermatology (2014) 170, pp1214–1218
Type VII collagen and squamous cell carcinoma DOI: 10.1111/bjd.12868 ORIGINAL ARTICLE, p 1256 Recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disease, is caused by mutations in COL7A1, the gene encoding type VII collagen (Col7), which is the main component of anchoring fibrils. Affected individuals have decreased or undetectable Col7 with skin and mucosal fragility, blistering and scarring. Over 787% of patients with severe generalized RDEB will die from metastatic squamous cell carcinoma (SCC) by the age of 45 years, suggesting a link between loss of Col7 and aggressive SCC.1 Treatment of RDEB by attempting to restore Col7 by protein, cell or gene therapy is currently the subject of intensive research, and existing and likely future clinical trials.2 In this issue of BJD, Pourreyron et al.3 engineer SCC keratinocytes derived from RDEB tumours and various controls to overexpress Col7 (up to 355-fold vs. normal endogenous levels), using recombinant COL7A1 cDNA in a retroviral vector. They show that high levels of Col7 expression generally induce increased migration and invasion in RDEB SCC keratinocytes, associated with an increase in activation of the phosphoinositide 3-kinase pathway, a pathway involved in regulation of migration/invasion. The authors conclude that caution should be exercised when considering therapeutic strategies where delivery of Col7 is likely to exceed greatly the levels seen under normal physiological conditions. Different models of loss/overexpression of Col7 produce varied results; however, in my opinion, the consensus view is veering towards loss of Col7 being proinvasion. Data from a Ras/IjBa-driven tumorigenesis model suggest that the noncollagenous (NC1) domain of Col7 is necessary for tumour formation by RDEB keratinocytes.4 However, many RDEB tumours do not express Col7.5 In ultraviolet-induced SCC cell lines expressing Col7, knock-down of Col7 using small inhibitory RNA promoted cell invasion and disorganized epithelial differentiation in vitro with an increase in transforming growth factor (TGF)-b signalling, a known contributor to cancer progression.6 In the hypomorphic mouse model of RDEB (10% Col7 expression), chemical carcinogenesis protocols produced more highly invasive tumours compared with benign papillomas in wild-type mice.7 The extracellular matrix composition in RDEB is permissive for tumour development, and invasion and tumour formation of RDEB SCC keratinocytes can be decreased by overexpressing Col7 in dermal fibroblasts.8 Finally, detailed proteome analysis of fibroblasts of patients with RDEB compared with control fibroblasts showed © 2014 British Association of Dermatologists
1215
a decrease in basement membrane matrix components and an increase in dermal matrix proteins, TGF-b and metalloproteinase expression, but not activity, in RDEB.9 Patients with dominant dystrophic epidermolysis bullosa who have one normal COL7A1 allele, hence approximately 50% normal Col7, rarely develop SCC. One would hope that restoring Col7 expression in RDEB to close to 50% of normal levels would decrease TGF-b signalling, improve wound healing, decrease scarring and chronic inflammation, and restore basement membrane function towards normal levels, thus reducing the risk of SCC. However, Col7 is a powerful matrix signalling molecule and, as cautioned by Pourreyron et al.,3 if overexpression is planned, preclinical dose–response studies will be needed in animal models. Conflicts of interest The author works on basement membrane, normal keratinocyte and squamous cell carcinoma biology. Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4AT, U.K. E-mail: [email protected]
E.A. O’TOOLE
References 1 Fine JD, Johnson LB, Weiner M et al. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006. J Am Acad Dermatol 2009; 60:203–11. 2 Fine JD. Inherited epidermolysis bullosa: recent basic and clinical advances. Curr Opin Pediatr 2010; 22:453–8. 3 Pourreyron C, Chen M, McGrath JA et al. High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increase PI3K and MAPK signalling, cell migration and invasion. Br J Dermatol 2014; 170:1256–65. 4 Ortiz-Urda S, Garcia J, Green CL et al. Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 2005; 307:1773–6. 5 Pourreyron C, Cox G, Mao X et al. Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression. J Invest Dermatol 2007; 127:2438–44. 6 Martins VL, Vyas JJ, Chen M et al. Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basementmembrane type VII collagen. J Cell Sci 2009; 122:1788–99. 7 Mittapalli V, Nystr€om A, Fritsch A, Bruckner-Tuderman L. Loss of collagen VII increases aggressive tumor behavior in Col7al hypomorphic mice. J Invest Dermatol 2013; 133 (Suppl. 1):S70. 8 Ng YZ, Pourreyron C, Salas-Alanis JC et al. Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa. Cancer Res 2012; 72:3522–34. 9 K€ uttner V, Mack C, Rigbolt KT et al. Global remodelling of cellular microenvironment due to loss of collagen VII. Mol Syst Biol 2013; 9:657. British Journal of Dermatology (2014) 170, pp1214–1218
