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）。食管癌构成严重和紧迫的临床问题 美国和全球范围内的EAC发生率不断增长的情况，更糟的是 在全球ESCC中明显的任何癌症的预测。我们专注于P120卡宁（P120CTN）或 CTNND1和TP53肿瘤抑制基因。通过侵袭到肿瘤细胞进展 细胞外基质（ECM）或造口。然后，这涉及肿瘤细胞之间的相互关联的网络 肿瘤微环境中的细胞类型。这种串扰和交叉利用触发了必要的级联 在将肿瘤细胞传播到血液和淋巴管中以及局部和远处之前的事件 转移。其中包括但不限于免疫细胞/炎性细胞，成纤维细胞，内皮细胞 细胞，周细胞，神经元和脂肪细胞。我们统一的观点是P120CTN损失或错误定位，这是 这消除了其肿瘤抑制活动涉及的维护粘附连接处 （与E-钙粘蛋白复合）促进了我们发表的有关条件损失的工作所揭示的肿瘤起始 小鼠食道中的P120CTN，导致浸润性ESCC（局部转移至淋巴结） 伴随着脱木质和髓样衍生抑制细胞（MDSC）或 未成熟的髓样细胞。肿瘤的进展需要收购Conspire驱动的TP53突变 进一步的肿瘤入侵。肿瘤细胞与癌症相关的成纤维细胞（CAF）和这些MDSC相互作用 肿瘤微环境，涉及促炎和促疾病的IL-6主细胞因子 肿瘤。因此，我们的总体假设是P120CTN和TP53蛋白在肿瘤中合作 进展，TP53突变触发了一种侵入性基因特征，该特征驱动肿瘤细胞侵入ECM 并重塑ECM，并且微环境中的肿瘤侵袭涉及 肿瘤细胞，CAF和MDSC。以下相互关联的特定目的将提出这一假设。 目的1：评估MDSC种群中CD38的诱导及其在免疫抑制中的作用 激活。目标2：阐明IL-6作为肿瘤细胞之间交叉说话的介体的功能作用 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。我们成功实现这些特定目标的实现是促进的 大大获得了特殊项目与核心提供的卓越支持之间的协同作用 设施，除了广泛而深厚的机构支持外。