Mechanisms of Esophageal Carcinogenesis

摘要 食道癌，尤其是鳞状细胞癌(ESCC)和腺癌(EAC) 预后：患者多数出现在晚期，因此违背了传统的放化疗。 心理治疗。分子发病机制和治疗进展将为鳞状细胞癌的治疗提供基础 其他部位(如头部和颈部以及肺部)的细胞癌和腺癌。这是一场竞争 NCI P01题为《食道癌发生机制》的续期，已取得实质性进展 阐明食道致病分子机制的重大而有影响的进展 癌症发生与治疗中的新策略的转换。新的、创新的模式已经产生 包括3D器官类型培养，免疫缺陷小鼠和遗传学的体内生物发光成像 第一次允许重述食道鳞状细胞主要遗传特征的基因工程小鼠 细胞癌和食管腺癌。对食道肿瘤有了新的认识 微环境，揭示转化的食道上皮细胞之间的相互作用，癌症 相关成纤维细胞(CAF)、未成熟髓系细胞(髓系来源抑制细胞(MDSCs)和 内皮细胞在促进肿瘤发生中起着关键作用。机制已被确定为基础 对放化疗的抵抗力。项目负责人的经验和专业知识，与 由核心设施提供的平台，将导致不可能的研究得到加强 如果这些项目彼此独立的话。项目1(Rustgi，项目负责人)将专注于生物 P120-catenin与P53抑癌基因协同作用在肿瘤形成中的作用 食道肿瘤细胞及其与CAF和MDSCs的相互作用 肿瘤微环境。项目2(Diehl，项目负责人)阐明了细胞周期蛋白D1的作用方式 调控和定义Fbx4突变在食道癌发生中的新作用，翻译成 治疗方法的发展。具体地说，SCFFBX4-AB晶体蛋白E3连接酶维持阈值水平 细胞周期蛋白D1/CDK4对食道细胞生长和动态平衡至关重要。治疗策略 靶向细胞周期蛋白D1/CDK4激酶或关键的下游效应物(如PRMT5)可能会提供显著的 食道癌的治疗效益。项目3(项目负责人K-K Wong) 发现了编码ERBB家族激酶和细胞周期调节因子的基因的基因组扩增 食道癌(ESCC和EAC)将作为生物标志物，指导靶向抑制剂的使用 在基因组定义的模型系统中测试治疗学将允许识别最佳药剂和 靶向药物的合理组合。三个非常成功的核心设施旨在提供 促进合作研究的食道癌专科服务：行政/生物统计学 (核心A)；分子病理学和成像或MPIC(核心B)；以及分子生物学(核心C)。该计划 该项目得到了宾夕法尼亚大学艾布拉姆森癌症中心和佩雷尔曼的明确支持 医学院、Dana Farber癌症研究所(DFCI)和Fox Chase癌症中心(各自致力于 以获得强大的新资源)，并将继续促进宾夕法尼亚大学、DFCI和全国的跨学科研究 导致对形成和调节食道的分子过程的合作理解 转化医学中具有创新机会的癌症发生。这一极具生产力和协同性的 P01涉及综合和创新项目，这些项目得到强大和独特的核心设施的支持。 制度支持是真正突出的。我们寻求为食道癌患者提供独特的益处 生物医学研究和临床社区以及我们的患者。

ABSTRACT Esophageal cancer, especially squamous cell cancer (ESCC) and adenocarcinoma (EAC), carries 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 therapy of squamous cell cancers and adenocarcinomas at other sites (e.g. head and neck, as well as lung). This is a competing renewal of the NCI P01entitled "Mechanisms of Esophageal Carcinogenesis" that has made substantial significant and impactful progress in elucidating the molecular mechanisms underlying esophageal 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 and esophageal adenocarcinoma. New insights have been gained into the esophageal tumor microenvironment, revealing that the interplay between transformed esophageal epithelial cells, cancer associated fibroblasts (CAFs), immature myeloid cells (myeloid derived suppressor cells (MDSCs), and endothelial cells are 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 cooperation between p120-catenin and p53 tumor suppressor genes in the formation of esophageal tumor cells as well as the interplay of these tumor cells with CAFs and MDSCs in the esophageal tumor microenvironment. Project 2 (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. Specifically, SCFFBX4-aB crystallin E3 ligase maintains threshold levels of the cyclin D1/CDK4 kinase critical for esophageal cell growth and homeostasis. Therapeutic strategies targeting the cyclin D1/CDK4 kinase, or key downstream effectors (such as PRMT5) may provide significant therapeutic benefit in the treatment of esophageal cancer. Project 3 (K-K Wong, Project Leader) has discovered genomic amplifications of genes encoding ERBB-family kinases and cell cycle mediators in esophageal cancers (both ESCC and EAC) will serve as biomarkers to guide use of targeted inhibitors and that testing of therapeutics in genomically defined model systems will allow the identification of optimal agents and rational combinations of targeted agents. Three highly successful Core facilities are designed to provide esophageal cancer-specific services for the stimulation of collaborative research: Administrative/Biostatistics (Core A); Molecular Pathology and Imaging or MPIC (Core B); and Molecular BIology (Core C). The Program Project has the unequivocal support of the University of Pennsylvania Abramson Cancer Center and Perelman School of Medicine, the Dana Farber Cancer Institute (DFCI) and Fox Chase Cancer Center (each committed to robust new resources) and will continue to foster interdisciplinary research at Penn, DFCI and nationally that leads to a cooperative understanding of the molecular processes that form and regulate esophageal carcinogenesis with innovative opportunities in translational medicine. This highly productive and synergistic P01 involves integrated and innovative Projects, which are supported by robust and unique Core Facilities. Institutional support is truly outstanding. We seek to provide unique benefits in esophageal cancer to the biomedical research and clinical communities as well as to our patients.