Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa.
Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa.
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DOI：
10.1158/0008-5472.can-11-2996
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发表时间：
2012-07
期刊：
影响因子：
11.2
通讯作者：
Y. Ng;C. Pourreyron;J. Salas-Alanis;J. Dayal;R. Cepeda-Valdes;Wenfei Yan;S. Wright;Mei Chen;J. Fine;F. Hogg;J. McGrath;D. Murrell;I. Leigh;E. Lane;A. South
中科院分区：
文献类型：
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作者：
Y. Ng;C. Pourreyron;J. Salas-Alanis;J. Dayal;R. Cepeda-Valdes;Wenfei Yan;S. Wright;Mei Chen;J. Fine;F. Hogg;J. McGrath;D. Murrell;I. Leigh;E. Lane;A. South
患有遗传性皮肤起泡疾病的隐性营养不良性大疱性表皮松解症 (RDEB) 患者会发展为侵袭性皮肤鳞状细胞癌 (cSCC)。 RDEB 中的转移导致的死亡率高于其他 cSCC 患者组。在这里，我们使用 mRNA 表达谱研究 RDEB 中的真皮成分，以比较从没有 cSCC 的个体中分离出的培养成纤维细胞以及直接从 RDEB 和非 RDEB 样本中的肿瘤基质中分离的培养成纤维细胞。虽然 RDEB 正常皮肤成纤维细胞的基因表达与癌症相关成纤维细胞相似，但 RDEB 癌症相关成纤维细胞表现出独特且不同的基因表达谱，其中很大一部分差异表达基因涉及基质和细胞粘附。 RDEB 癌症相关成纤维细胞增强了对肿瘤和非肿瘤角质形成细胞的粘附和侵袭。正常真皮成纤维细胞中 RDEB 中的缺陷基因 COL7A1 的减少导致 XII 型胶原、血小板反应蛋白-1 和 Wnt-5A 增加，而 RDEB 成纤维细胞中野生型 COL7A1 的重新表达降低了 XII 型胶原、血小板反应蛋白-1 和 Wnt-5A 的表达，减少了器官型培养中的肿瘤细胞侵袭，并限制了体内肿瘤的生长。总体而言，我们的研究结果表明，RDEB 患者的基质组成是肿瘤发展的宽松环境，VII 型胶原直接调节真皮和癌症相关成纤维细胞分泌的基质蛋白的组成。
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.