title: Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa.
abstract: Patients with the genetic skin blistering disease recessive dystrophic epidermolysis bullosa (RDEB) develop aggressive cutaneous squamous cell carcinoma (cSCC). Metastasis leading to mortality is greater in RDEB than in other patient groups with cSCC. Here we investigate the dermal component in RDEB using mRNA expression profiling to compare cultured fibroblasts isolated from individuals without cSCC and directly from tumor matrix in RDEB and non-RDEB samples. Although gene expression of RDEB normal skin fibroblasts resembled that of cancer-associated fibroblasts, RDEB cancer-associated fibroblasts exhibited a distinct and divergent gene expression profile, with a large proportion of the differentially expressed genes involved in matrix and cell adhesion. RDEB cancer-associated fibroblasts conferred increased adhesion and invasion to tumor and nontumor keratinocytes. Reduction of COL7A1, the defective gene in RDEB, in normal dermal fibroblasts led to increased type XII collagen, thrombospondin-1, and Wnt-5A, while reexpression of wild type COL7A1 in RDEB fibroblasts decreased type XII collagen, thrombospondin-1, and Wnt-5A expression, reduced tumor cell invasion in organotypic culture, and restricted tumor growth in vivo. Overall, our findings show that matrix composition in patients with RDEB is a permissive environment for tumor development, and type VII collagen directly regulates the composition of matrix proteins secreted by dermal and cancer-associated fibroblasts.
authors.affiliation: Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
authors.forename: Yi-Zhen
authors.initials: YZ
authors.lastname: Ng
authors.forename: Celine
authors.initials: C
authors.lastname: Pourreyron
authors.forename: Julio C
authors.initials: JC
authors.lastname: Salas-Alanis
authors.forename: Jasbani H S
authors.initials: JH
authors.lastname: Dayal
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cepeda-Valdes
authors.forename: Wenfei
authors.initials: W
authors.lastname: Yan
authors.forename: Sheila
authors.initials: S
authors.lastname: Wright
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Jo-David
authors.initials: JD
authors.lastname: Fine
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Hogg
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Dedee F
authors.initials: DF
authors.lastname: Murrell
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.forename: E Birgit
authors.initials: EB
authors.lastname: Lane
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D024143:Collagen Type VII / Q000096:biosynthesis / Q000235:genetics*; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D034741:RNA, Small Interfering; D012867:Skin / Q000166:cytology / Q000378:metabolism; D019700:Thrombospondin 1 / Q000096:biosynthesis; D051153:Wnt Proteins / Q000096:biosynthesis; D000071818:Wnt-5a Protein
chemical_list: D024143:Collagen Type VII; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein