Mechanisms of esophageal carcinogenesis

描述（申请人提供）：食管癌，尤其是鳞状细胞癌，由于患者多出现在晚期，预后不佳，因此传统的放化疗无效。分子发病机制和治疗的进展将为其他部位的鳞状细胞癌提供基础。这是NCI P01题为“食管癌发生机制”的竞争性更新，在阐明鳞状细胞癌发生的分子机制并转化为新的治疗策略方面取得了实质性进展。新的、创新的模型已经产生，涉及三维器官型培养，免疫缺陷小鼠体内生物发光成像和基因工程小鼠，首次允许重述食管鳞状细胞癌的主要遗传特征。对食管肿瘤微环境有了新的认识，揭示了转化的食管上皮细胞、间充质间质成纤维细胞和内皮细胞之间的相互作用对促进肿瘤发生至关重要。已经确定了对放化疗耐药的机制。项目负责人的经验和专业知识与核心设施提供的平台相结合，将导致研究的加强，如果项目彼此独立，这是不可能的。项目1 （Rustgi，项目负责人）将重点研究EGFR癌基因及其与p120-catenin和p53抑癌基因在食管癌发生中的生物学作用，以及活化的间质成纤维细胞在微环境中增强肿瘤细胞侵袭的作用。项目2 （Herlyn，项目负责人）定义了肿瘤微环境中成纤维细胞和内皮细胞之间的关系，并利用这一信息开发新的治疗方法。项目3 （Diehl，项目负责人）阐明了cyclin D1的调控方式，并定义了Fbx4突变在食管癌发生中的新作用，并将其转化为治疗方法的发展。四个非常成功的核心设施旨在为促进合作研究提供食管癌特定服务：形态学、分子生物学、生物统计学和行政管理。该项目得到了宾夕法尼亚大学癌症中心和医学院的明确支持（新资源的承诺），并将继续促进宾夕法尼亚大学和全国的跨学科研究，从而共同了解形成和调节食管癌发生的分子过程。

DESCRIPTION (provided by applicant): Esophageal cancer, especially squamous cell cancer, carries with it a dismal prognosis as the preponderance of patients present at late stages, thereby defying traditional chemoradiation therapy. Advances in molecular pathogenesis and therapy will provide a foundation for squamous cell cancers at other sites. This is a competing renewal of the NCI P01 entitled "Mechanisms of Esophageal Carcinogenesis" that has made substantial progress in elucidating the molecular mechanisms underlying squamous cell carcinogenesis with translation to new strategies in therapy. Novel, innovative models have been generated involving 3D organotypic cultures, in vivo bioluminescence imaging in immunodeficient mice and genetically engineered mice that permit recapitulation, for the first time, cardinal genetic features of esophageal squamous cell cancer. New insights have been gained into the esophageal tumor microenvironment, revealing that the interplay between transformed esophageal epithelial cells, mesenchymal stromal fibroblasts and endothelial cells is critical in fostering tumorigenesis. Mechanisms have been identified that underlie resistance to chemoradiation therapy. The experience and expertise of the Project Leaders, in concert with the platforms provided by the Core Facilities, will result in enhancement of the research that would not be possible if the projects were independent of each other. Project 1 (Rustgi, Project Leader) will focus upon the biological roles of the EGFR oncogene and cooperation with p120-catenin and p53 tumor suppressor genes in esophageal carcinogenesis, and the role of activated stromal fibroblasts in augmenting tumor cell invasion in the microenvironment. Project 2 (Herlyn, Project Leader) defines the relationship between fibroblasts and endothelial cells in the tumor microenvironment, and exploits this information to develop new therapeutics. Project 3 (Diehl, Project Leader) elucidates the manner in which cyclin D1 is regulated and defines the novel role of the Fbx4 mutations in esophageal carcinogenesis, with translation into the development of therapeutic approaches. Four highly successful Core facilities are designed to provide esophageal cancer-specific services for the stimulation of collaborative research: Morphology, Molecular Biology, Biostatistics and Administrative. The Program Project has the unequivocal support of the University of Pennsylvania Cancer Center and Medical School (with robus commitment of new resources) and will continue to foster interdisciplinary research at Penn and nationally which leads to a cooperative understating of the molecular processes that form and regulate esophageal carcinogenesis.