Analyzing the impact of the tumor microenvironment on esophagealcarcinogenesis

Barretts食管癌（BE）代表了食管腺癌（EAC）进展的初始步骤，其发病率比任何其他癌症都要高。因此，迫切需要为不断增长的BE患者群体开发预防策略和疗法。然而，由于缺乏一个易于处理的临床前模型，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学的BE小鼠模型，并证明BE来自贲门干细胞，这是一种范式转变。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，癌症的终生风险与干细胞分裂的数量相关。因此，了解肿瘤微环境的功能和作用，对于设计更好的预防和治疗BE和EAC的策略具有重要意义。本课题旨在利用第一个BE/EAC炎症转基因小鼠模型，一个BE的三维器官型体外培养系统，以及在进展为EAC期间的不同时间点对人类患者进行活检，以分析癌症相关成纤维细胞（CAF）的重要性和功能，在BE和EAC发展过程中的微环境中，以及这些细胞对干细胞和癌症起始细胞的影响。我们提出，一个特定的炎症微环境中含有特定的CAFs，促进食管癌的发生，通过招募上皮干细胞，促进细胞增殖，凋亡，迁移，从而诱导突变和上皮（干）细胞的恶性转化。在致瘤小生境内检测特定因子或细胞类型将定义一种突破性的新模式，其允许定义处于发展EAC风险中的人群，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样的表型。

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.