Transformed Esophageal Epithelial Cells and the Tumor Microenvironment

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 食道腺癌（EAC）。食管癌在世界范围内构成了严重和紧迫的临床问题。 美国和全球范围内，如美国EAC的发病率增加所反映的，以及更严重的 在全球范围内，ESCC中明显的任何癌症。我们关注的是p120连环蛋白（p120 ctn）或 CTNND 1和TP 53肿瘤抑制基因。肿瘤细胞的进展通过侵袭到 细胞外基质（ECM）或气孔。这就涉及到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。这种相互交流和相互影响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、成纤维细胞、成纤维细胞和成纤维细胞。 细胞、周细胞、神经元和脂肪细胞。我们的统一观点是p120 ctn缺失或定位错误， 其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）促进肿瘤的发生，正如我们发表的关于条件性缺失的工作所揭示的那样。 p120 ctn在小鼠食管中，导致侵袭性ESCC（局部转移至淋巴结） 伴有结缔组织增生和髓源性抑制细胞（MDSC）的特异性募集，或 未成熟的骨髓细胞肿瘤进展需要获得TP 53突变，其共同驱动 进一步的肿瘤侵袭。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，部分涉及IL-6主细胞因子，其是促炎性和促炎性的。 致瘤的因此，我们的总体假设是，p120 ctn和TP 53蛋白在肿瘤中协同作用， 随着肿瘤的进展，TP 53突变触发了一个侵入性基因签名，驱动肿瘤细胞侵入ECM 并重塑ECM，微环境中的肿瘤侵袭涉及以下因素之间的相互作用： 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。 目的1：评估MDSC群体中的CD 38诱导及其通过iNOS在免疫抑制中的作用 activation.目的2：阐明IL-6作为肿瘤细胞间相互作用的介质的功能作用， ESCC微环境中的CAF。目的3：阐明p120 ctn与TP 53之间的相互作用 在食管肿瘤微环境中。我们成功实现这些具体目标是有利的 特别项目与核心小组提供的特别支持之间的协同作用， 设施，除了广泛和深入的机构支持。

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.