Fibroblast-Derived Dermal Matrix Drives Development of Aggressive Cutaneous Squamous Cell Carcinoma in Patients with Recessive Dystrophic Epidermolysis Bullosa

Yi-Zhen Ng,Wenfei Yan,John A Mcgrath,Mei Chen,Sheila Wright,Dedee F Murrell,Julio C Salas-Alanis,Jo-David Fine,Celine Pourreyron,Andrew P South,Irene M Leigh,Jasbani H.S Dayal,E Birgit Lane,Fiona J Hogg,Rodrigo Cepeda-Valdes

doi:10.1158/0008-5472.can-11-2996

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.

Highlights

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin blistering disease caused exclusively by mutations in the gene-encoding type VII collagen, COL7A1 [1]
To assess whether the difference in gene expression observed in RDEBSCCF, RDEBF, and UV-induced cSCCs excised from non-RDEB individuals (UVSCCF) were a result of positional information acquired as a result of a wounded environment and/or a tumor environment or whether the presence of full-length type collagen VII influences the expression of extracellular matrix components identified in our array, we examined the effect of COL7A1 knockdown in normal dermal fibroblasts populations (n 1⁄4 3)
Here we show through gene expression profiling of skin- and tumor-isolated fibroblasts that the RDEB cutaneous squamous cell carcinoma (cSCC) dermal microenvironment is strikingly distinct compared with normal skin and UV-induced cSCC

Summary

Introduction

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin blistering disease caused exclusively by mutations in the gene-encoding type VII collagen, COL7A1 [1]. In virtually all studies to date, RDEB cSCC exhibit similar characteristics to non-RDEB cSCC and a causative relationship with tumor progression has yet to be unequivocally identified [7,8,9,10,11,12,13,14,15]. With few exceptions these studies have focused on tumor keratinocytes and have ignored the surrounding stroma. Cancer-associated fibroblasts are the main cell type present in tumor stroma and have been shown to contribute toward cancer invasion [16], initiation, and progression via stromal–epithelial interactions [17,18,19] and can provide oncogenic signals such as fibroblast growth factors, 3522 Cancer Res; 72(14) July 15, 2012

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