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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion
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Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion

机译：成纤维细胞分泌的肝细胞生长因子在食管鳞状细胞癌侵袭中起功能性作用

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摘要

Squamous cell cancers comprise the most common type of human epithelial cancers. One subtype, esophageal squamous cell carcinoma (ESCC), is an aggressive cancer with poor prognosis due to late diagnosis and metastasis. Factors derived from the extracellular matrix (ECM) create an environment conducive to tumor growth and invasion. Specialized cancer-associated f ibroblasts (CAFs) in the ECM influence tumorigenesis. We have shown previously that the nature and activation state of fibroblasts are critical in modulating the invasive ability of ESCC in an in vivo-like organotypic 3D cell culture, a form of human tissue engineering. Dramatic differences in invasion of transformed esophageal epithelial cells depended on the type of fibroblast in the matrix. We hypothesize that CAFs create an environment primed for growth and invasion through the secretion of factors. We find that fibroblast secretion of hepatocyte growth factor (HGF) fosters the ability of transformed esophageal epithelial cells to invade into the ECM, although other unidentified factors may cooperate with HGF. Genetic modifications of both HGF in fibroblasts and its receptor Met in epithelial cells, along with pharmacologic inhibition of HGF and Met, underscore the importance of this pathway in ESCC invasion and progression. Furthermore, Met activation is increased upon combinatorial over-expression of epidermal growth factor receptor (EGFR) and p53~(R175H), two common genetic mutations in ESCC. These results highlight the potential benefit of the therapeutic targeting of HGF/Met signaling in ESCC and potentially other squamous cancers where this pathway is deregulated.
机译：鳞状细胞癌是人类上皮癌的最常见类型。一种亚型，食管鳞状细胞癌（ESCC）是一种侵袭性癌症，由于诊断和转移较晚，预后较差。源自细胞外基质（ECM）的因素创造了有利于肿瘤生长和侵袭的环境。 ECM中专门与癌症相关的成纤维细胞（CAF）影响肿瘤发生。先前我们已经表明，成纤维细胞的性质和激活状态在调节体内样器官型3D细胞培养（一种人体组织工程形式）中的ESCC侵袭能力中至关重要。转化的食管上皮细胞浸润的戏剧性差异取决于基质中成纤维细胞的类型。我们假设，CAFs通过分泌因子创造了一个生长和入侵所需的环境。我们发现，肝细胞生长因子（HGF）的成纤维细胞分泌促进了转化的食管上皮细胞侵入ECM的能力，尽管其他未知因素可能与HGF协同作用。成纤维细胞中HGF及其上皮细胞中Met受体的遗传修饰，以及HGF和Met的药理抑制作用，突显了该途径在ESCC侵袭和发展中的重要性。此外，当表皮生长因子受体（EGFR）和p53〜（R175H）（ESCC中的两个常见遗传突变）组合过量表达时，Met的激活会增加。这些结果强调了在HCC / Met信号治疗中靶向该途径的ESCC和其他潜在的鳞状上皮癌的潜在治疗益处。

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    Katharine D. Grugan; rnCharles G. Miller; rnYao Yao; rnCarmen Z. Michaylira; rnShinya Ohashi; rnAndres J. Klein-Szanto; rnJ. Alan Diehl; rnMeenhard Herlyn; rnMay Han; rnHiroshi Nakagawa; rnAnil K. Rustgi;

  • 作者单位

    Gastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

    rnGastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

    rnGastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

    rnGastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

    rnGastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

    rnDepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111;

    rnAbramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA;

    rnWistar Institute,Philadelphia, PA 19104;

    rnAVEO Pharmaceuticals, Inc., Cambridge, MA 02139;

    rnGastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

    rnGastroenterology Division, Department of Medicine University of Pennsylvania, Philadelphia, PA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cancer-associated fibroblasts; esophageal cancer; tumor microenvironment; organotypic culture; c-met;

    机译：癌症相关的成纤维细胞;食道癌;肿瘤微环境有机型文化气象;

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