Analyzing the impact of the tumor microenvironment on esophagealcarcinogenesis

巴雷特食管（BE）是发展为食管腺癌（EAC）的初始阶段，其发病率比其他任何癌症都要高。因此，迫切需要为日益增多的BE患者制定预防策略和治疗方法。然而，由于缺乏可处理的临床前模型，BE的监测策略和化学预防治疗的发展受到严重限制。为了满足这一需求，我们开发了一种类似于人类病理的BE小鼠模型，并证明BE起源于心脏干细胞，这是一种范式变化。越来越多的证据表明，干细胞受到宿主微环境的强烈影响，并且已经表明，一生中患癌症的风险与干细胞分裂的次数相关。因此，为了设计更好的BE和EAC的预防和治疗策略，了解肿瘤微环境的功能和贡献将是非常重要的。在本项目中，我们旨在利用首个BE/EAC炎症转基因小鼠模型、BE体外三维器官型培养系统和EAC发展过程中不同时间点的人类患者活检，分析BE和EAC发展过程中微环境中癌症相关成纤维细胞（cancer associated fibroblasts, CAFs）的重要性和功能，以及这些细胞对干细胞和癌起始细胞的影响。我们提出一个特定的炎症微环境包含特定的CAFs，通过招募上皮干细胞，促进细胞增殖、凋亡、迁移，从而诱导上皮（干细胞）的突变和恶性转化，从而促进食管癌的发生。在致瘤性生态位中检测特定因素或细胞类型将定义一种突破性的新模式，允许确定有患EAC风险的人群，这一发现可以外推到其他炎症诱导的癌症，并有助于开发新的预防和治疗策略。在我们之前的工作中，我们可以证明CAFs可以在胃癌中诱导这种表型。

Barretts Esophagus (BE) represents the initial step in the progression to esophageal adenocarcinoma (EAC) which incidence has increased greater than any other cancer. Therefore, there is a critical need to develop preventive strategies and therapies for a growing population of BE patients. However, the development of surveillance strategies and chemoprevention therapies for BE has been severely restricted by the absence of a tractable pre-clinical model. To address this need we have developed a mouse model of BE that resembles human pathology and demonstrates that BE arises from a cardia stem cell, a paradigm change. Accumulating evidence demonstrated that stem cells are strongly influenced by the host microenvironment and it has been shown that the lifetime risk of cancers is correlated with the number of stem cell divisions. Thus, in order to design better preventive and therapeutic strategies for BE and EAC, it will be of tremendous importance to understand the function and contribution of the tumor microenvironment.In this project we aim to utilize the first inflammatory transgenic mouse model of BE/EAC, a 3D organotypic in vitro culture system of BE, and biopsies of human patients at different time points during progression to EAC to analyze the importance and function of cancer associated fibroblasts (CAFs) in the microenvironment during the development of BE and EAC and the impact of these cells on stem cells and cancer initiating cells. We propose that a specific inflammatory microenvironment contains specific CAFs that promote esophageal carcinogenesis by recruiting epithelial tem cells, promoting cell proliferation, apoptosis, migration and consequently inducing mutagenesis and malignant transformation of epithelial (stem) cells. The detection of specific factors or cell types within a tumorigenic niche would define a ground breaking novel modality that allows do define a population at risk to develop EAC, this finding could be extrapolated to other inflammation induced cancers and help to develop new preventive and therapeutic strategies. In our prior work we could demonstrate that CAFs can induce such a phenotype in gastric cancer.