Transformed Epithelial Cells and Activated Fibroblasts in the Esopheageal Tumor M

食道癌在美国和世界范围内是一种常见的恶性肿瘤，但它带有一种令人沮丧的 5年生存率早期<30%，晚期<10%。 由于缺乏健壮的、可复制的模型，进展受到了阻碍。为此，我们开发了 器官培养和首次复制人类食道表型的动物的创新模型 鳞癌(ESCC)。这些模型强调了关键癌基因和肿瘤的作用。 抑制基因。我们推测，EGFR癌基因与细胞周期调控失调的相互作用 抑癌基因p53和p120-catenin(P120ctn)改变食道的致癌潜能 细胞，从而导致细胞迁移和侵袭增加。此外，我们假设这种变化 在肿瘤形成过程中发生在食道间充质间室，由此激活了肿瘤 成纤维细胞以旁分泌方式相互作用，诱导食道肿瘤细胞迁移和侵袭增加。 这些相互依赖的假设将被以下相互关联的具体目标所追求，以理解 食道肿瘤微环境：(1)探讨p120ctn在肿瘤微环境中的作用 EGFR在促进食道癌细胞在肿瘤微环境中的迁移和侵袭中的作用。 具体地说，我们将评估p120ctn和p120ctn的不同亚型和磷酸化突变体的作用。 用基因定义的器官型培养方法了解p120ctn在食道肿瘤发生中的作用 和体内模型；(2)研究EGFR过表达和p53突变如何协同诱导 相似模型中的食道肿瘤发生，强调不同的生物学特性 在食道癌中发现结构性p53突变；(3)确定关键的信号通路 活化的成纤维细胞参与旁分泌信号传递给肿瘤细胞，从而增加肿瘤细胞的迁移和 ‘在微环境中的渗透。这些集体方法提供了一个令人兴奋的、新的有针对性的平台 与项目2和项目3相配合的治疗方法，这些项目已准备好克服对 食道癌到目前的治疗方法。项目1将继续利用尚未完成的核心设施。 相关性(请参阅说明)： 本项目的重点是EGFR癌基因与p120ctn和p53抑癌基因的相互作用 促进食管鳞状上皮转化的基因及其与间质的相互作用 成纤维细胞，并揭示了新的模型和见解。这些发现在组合分析中具有相关性。 食道癌和其他鳞状细胞癌的治疗。

Esophageal cancer is a common malignancy in the United States and worldwide, and yet, carries a dismal prognosis with 5-year survival of less than 30% for early stages and less than 10%for advanced stages. Progress has been hampered by the lack of robust, reproducible models. To that end, we have developed innovative models in organotypic culture and in animals that phenocopy, for the first time, human esophageal squamous cell cancer (ESCC). These models emphasize the role of critical oncogenes and tumor suppressor genes. We hypothesize that the interplay of the EGFR oncogene with the dysregulation of the p53 and p120-catenin (p120ctn) tumor suppressor genes alters the tumorigenic potential of esophageal cells, thereby resulting in increased cell migration and invasion. Furthermore, we hypothesize that changes in the mesenchymal compartment of the esophagus occur during tumorigenesis whereby tumor activated fibroblasts interact in a paracrine manner to induce increased esophageal tumor cell migration and invasion. These interdependent hypotheses will be pursued by the following interrelated Specific Aims to understand the esophageal tumor microenvironment: (1) To investigate the role of p120ctn, a functional interactor with EGFR, in fostering esophageal cancer cell migration and invasion in the tumor microenvironment. Specifically, we will assess the effects different isoforms and phosphorylation mutants of p120ctn and understand the role of p120ctn in esophageal tumorigenesis using genetically defined organotypic culture and in vivo models; (2) To investigate how EGFR overexpression and p53 mutation cooperate to induce esophageal tumorigenesis in similar models with an emphasis upon the differential biological properties of structural p53 mutants found to occur in esophageal cancer; (3) To identify critical signaling pathways in activated fibroblasts involved in paracrine signaling to tumor cells that increase tumor cell migration and 'nvasion in the microenvironment. These collective approaches provide a platform for exciting, new targeted therapeutic approaches in concert with Projects 2 and 3 that are primed to overcome resistance of esophageal cancer to current therapy. Project 1will continue to utilize the outstanding core facilities. RELEVANCE (Seeinstructions): This Project focuses upon the interplay of the EGFR oncogene with the p120ctn and p53 tumor suppressor genes in fostering esophageal squamous epithelial transformation and the interaction with stromal fibroblasts, and has unraveled new models and insights. The findings have relevance in combinatorial therapy of esophageal cancer and other squamous cell cancers.