Mechanisms of Esophageal Carcinogenesis

摘要 食管癌，特别是鳞状细胞癌（ESCC）和腺癌（EAC），携带着令人沮丧的癌症。 预后作为晚期患者的优势，从而无视传统的放化疗 疗法分子发病机制和治疗的研究进展将为鳞状细胞癌的治疗提供基础 其他部位的细胞癌和腺癌（例如头颈部以及肺）。这是一个竞争 更新NCI P01，题为"食管癌发生机制"， 在阐明食管癌的分子机制方面取得了重大进展， 致癌作用与治疗新策略的转化。新的、创新的模式已经产生， 涉及3D器官型培养，免疫缺陷小鼠体内生物发光成像和遗传学 第一次允许重现食管鳞状上皮细胞癌的主要遗传特征的工程小鼠 细胞癌和食管腺癌。对食管肿瘤有了新的认识 微环境，揭示了转化的食管上皮细胞，癌症 相关成纤维细胞（CAF）、未成熟髓样细胞（髓源性抑制细胞（MDSC），和 内皮细胞在促进肿瘤发生中是关键的。已查明的机制， 对放化疗的抵抗力。项目负责人的经验和专业知识，与 核心设施提供的平台，将导致研究的增强，这是不可能的。 如果这些项目是相互独立的。项目1（Rustgi，项目负责人）将侧重于生物 p120-catenin和p53抑癌基因协同作用在肿瘤形成中的作用 食管肿瘤细胞以及这些肿瘤细胞与食管中CAF和MDSC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在细胞周期中的作用方式。 调节并定义了Fbx4突变在食管癌发生中的新作用， 治疗方法的发展。具体而言，SCFFBX 4-aB晶状体蛋白E3连接酶维持阈值水平 细胞周期蛋白D1/CDK4激酶对食管细胞生长和稳态至关重要。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PRMT 5）可以提供显著的 在食管癌治疗中的治疗益处。项目3（K-K Wong，项目负责人） 发现了编码ERBB家族激酶和细胞周期介质的基因的基因组扩增， 食管癌（ESCC和EAC）将作为生物标志物指导靶向抑制剂的使用， 在基因组学定义的模型系统中测试治疗剂将允许鉴定最佳药剂， 靶向药物的合理组合。三个非常成功的核心设施旨在提供 食管癌特异性服务促进合作研究：行政/生物统计学 (Core分子病理学和成像或MPIC（核心B）;和分子生物学（核心C）。程序 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，达纳法伯癌症研究所（DFCI）和福克斯大通癌症中心（每个承诺 强大的新资源），并将继续促进跨学科研究在宾夕法尼亚州，DFCI和全国， 导致对形成和调节食管癌的分子过程的合作理解， 转化医学的创新机会。这种高效和协同的 P01涉及综合和创新项目，这些项目由强大而独特的核心设施提供支持。 机构支持确实出色。我们寻求为食管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.