Transformed Esophageal Epithelial Cells and the Tumor Microenvironment

项目1摘要 食道癌包括两个主要亚型，即食道鳞状细胞癌(ESCC)和 食管腺癌(EAC)。食道癌在中国是一个严重而紧迫的临床问题 美国和世界范围内的EAC发病率在美国和更糟的情况下不断增加 在全球ESCC中，任何癌症的预后都是显而易见的。我们关注的是p120catenin(P120ctn)或 CTNND1和TP53抑癌基因。肿瘤细胞的进展通过侵袭到 细胞外基质(ECM)或造口。这随后涉及到肿瘤细胞和不同物种之间的相互联系的网络 肿瘤微环境中的细胞类型。这种串扰和交叉受精引发了一系列必要的 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。这些细胞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。我们的统一观点是p120ctn丢失或本地化错误，无论是 它取消了与维持黏附连接有关的肿瘤抑制活性 (与E-钙粘素的复合体)促进肿瘤的启动，我们发表的关于条件性丢失的研究揭示了这一点 P120ctn基因在小鼠食道中的表达，导致侵袭性食管鳞癌(伴有局部淋巴结转移) 伴有纤维增生和髓系来源抑制细胞(MDSCs)的特异性募集 未成熟的髓系细胞。肿瘤的进展需要获得TP53突变，这一突变共同推动 进一步的肿瘤侵袭。肿瘤细胞与肿瘤相关成纤维细胞(CAF)和这些MDSCs相互作用 肿瘤微环境，部分涉及IL-6主细胞因子，它是促炎和促炎的 致癌的。因此，我们的主要假设是p120ctn和tp53蛋白在肿瘤中相互作用。 进展，TP53突变触发侵袭性基因信号，驱动肿瘤细胞侵袭ECM 并重塑细胞外基质，肿瘤在微环境中的侵袭涉及 肿瘤细胞、CAF和MDSCs。这一假设将被以下相互关联的具体目标所追求。 目的1：评价CD38在MDSC群体中的诱导及其通过iNOS在免疫抑制中的作用 激活。目的2：阐明IL-6作为肿瘤细胞与肿瘤细胞间串扰介质的功能作用。 ESCC微环境中的CAF。目的3：阐明p120ctn和tp53的功能相互作用 在食道肿瘤的微环境中。我们成功地实现这些具体目标是有帮助的。 这在很大程度上得益于特殊项目和核心提供的特殊支助之间的协同作用 设施，除了广泛而深入的制度支持。

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.