Transformed Esophageal Epithelial Cells and the Tumor Microenvironment

转化的食管上皮细胞和肿瘤微环境

• 批准号: 8936552
• 负责人: Anil K Rustgi
• 金额: $ 35.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8936552
• 关键词: Achievement; Adherens Junction; Adipocytes; Blood Vessels; Cell Cycle; Cell surface; Cells; Clinical; Complex; Core Facility; Cyclin D1; Cyclin E; DNA Sequence Alteration; Distant Metastasis; E-Cadherin; ERBB2 gene; Endothelial Cells; Epithelial Cells; Esophageal; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Event; Extracellular Matrix; Fertilization; Fibroblasts; Fostering; Genes; Immune; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Inflammatory; Insulin-Like Growth Factor Binding Protein 3; Interleukin-6; Invaded; Knockout Mice; Lymphatic vessel; Maintenance; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mediator of activation protein; Metastatic Neoplasm to Lymph Nodes; Mus; Mutation; Myelogenous; Myeloid Cells; Neurons; Outcome; Pathway interactions; Patients; Pericytes; Population; Pre-Clinical Model; Protein p53; Publications; Publishing; Role; Stomas; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TP53 gene; Translating; Tumor Cell Invasion; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Work; cADPR Hydrolase; carcinogenesis; cell type; combinatorial; cytokine; improved; innovation; mutant; neoplastic cell; novel; novel therapeutics; outcome forecast; pre-clinical therapy; therapeutic evaluation; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenic

PROJECT 1 ABSTRACT Esophageal cancer comprises two major subtypes, namely esophageal squamous cell carcinoma (ESCC), and esophageal adenocarcinoma (EAC). Esophageal cancer poses grave and pressing clinical problems in the United States and worldwide as reflected by the increasing incidence of EAC in the US, and of the worse prognoses of any cancers as evident in ESCC worldwide. We are focusing on the p120catenin (p120ctn) or CTNND1 and TP53 tumor suppressor genes. Tumor cell progression is illustrated by invasion into the extracellular matrix (ECM) or stoma. This then involves interrelated networks between tumor cells and diverse cell types in the tumor microenvironment. This cross-talk and cross-fertilization trigger a necessary cascade of events prior to dissemination of tumor cells into blood and lymphatic vessels, as well as local and distant metastasis. These include, but are not restricted to, immune cells/inflammatory cells, fibroblasts, endothelial cells, pericytes, neurons, and adipocytes. Our unified view is that p120ctn loss or mislocalization, either of which abrogates its tumor suppressor activities involved in the maintenance of the adherens junctions (complex with E-cadherin) fosters tumor initiation as revealed by our published work on the conditional loss of p120ctn in the mouse esophagus, resulting in invasive ESCC (with local metastasis to lymph nodes) accompanied by desmoplasia and the specific recruitment of myeloid derived suppressor cells (MDSCs) or immature myeloid cells. Tumor progression requires the acquisition of TP53 mutations, which conspire to drive further tumor invasion. The tumor cells interact with cancer-associated fibroblasts (CAFs) and these MDSCs in the tumor microenvironment, involving in part the IL-6 master cytokine that is pro-inflammatory and pro- tumorigenic. Thus, our overarching hypothesis is that p120ctn and TP53 proteins cooperate in tumor progression, TP53 mutation triggers an invasive gene signature that drives tumor cells to invade into the ECM and remodel the ECM, and that tumor invasion in the microenvironment involves the interactions between tumor cells, CAFs and MDSCs. This hypothesis will be pursued by the following interrelated Specific Aims. Aim 1: To evaluate CD38 induction in MDSC populations and its role in immunosuppression via iNOS activation. Aim 2: To elucidate the functional roles of IL-6 as a mediator of cross talk between tumor cells and CAFs in the ESCC microenvironment. Aim 3: To elucidate the functional interplay between p120ctn and TP53 in the esophageal tumor microenvironment. Our successful achievement of these Specific Aims is facilitated greatly by the synergy between the exceptional Projects and the exceptional support provided by the Core Facilities, apart from the broad and deep institutional support.

项目 1 摘要 食管癌包括两种主要亚型，即食管鳞状细胞癌（ESCC）和 食管腺癌（EAC）。食管癌给人类带来严重而紧迫的临床问题 美国和世界各地的 EA​​C 发病率不断上升，以及更严重的情况 全球 ESCC 中任何癌症的预后。我们关注的是 p120catenin (p120ctn) 或 CTNND1 和 TP53 肿瘤抑制基因。肿瘤细胞的进展通过侵入 细胞外基质（ECM）或造口。这涉及到肿瘤细胞和不同细胞之间的相互关联的网络。 肿瘤微环境中的细胞类型。这种串扰和交叉施肥触发了必要的级联 肿瘤细胞扩散到血管和淋巴管以及局部和远处之前的事件 转移。这些包括但不限于免疫细胞/炎症细胞、成纤维细胞、内皮细胞 细胞、周细胞、神经元和脂肪细胞。我们的统一观点是 p120ctn 丢失或错误定位，无论是 它消除了其参与维持粘附连接的肿瘤抑制活性 （与 E-钙粘蛋白复合）促进肿瘤发生，正如我们发表的关于条件性丧失的研究所揭示的那样 小鼠食道中的 p120ctn，导致侵袭性 ESCC（局部转移至淋巴结） 伴有结缔组织增生和骨髓源性抑制细胞 (MDSC) 的特异性募集或 未成熟的骨髓细胞。肿瘤进展需要获得 TP53 突变，这共同驱动 进一步的肿瘤侵袭。肿瘤细胞与癌症相关成纤维细胞 (CAF) 和这些 MDSC 相互作用 肿瘤微环境，部分涉及促炎和促炎症的 IL-6 主细胞因子 致瘤性。因此，我们的总体假设是 p120ctn 和 TP53 蛋白在肿瘤中合作 随着进展，TP53 突变触发侵入性基因特征，驱动肿瘤细胞侵入 ECM 并重塑 ECM，微环境中的肿瘤侵袭涉及 肿瘤细胞、CAF 和 MDSC。这一假设将通过以下相互关联的具体目标来实现。 目标 1：评估 MDSC 群体中 CD38 的诱导及其通过 iNOS 在免疫抑制中的作用 激活。目标 2：阐明 IL-6 作为肿瘤细胞与肿瘤细胞之间串扰介质的功能作用 ESCC 微环境中的 CAF。目标 3：阐明 p120ctn 和 TP53 之间的功能相互作用 在食管肿瘤微环境中。促进我们成功实现这些具体目标 很大程度上得益于特殊项目和核心提供的特殊支持之间的协同作用 设施，除了广泛而深入的制度支持。