The Tumor Microenvironment in Esophageal Squamous Cell Carcinoma

食管鳞状细胞癌的肿瘤微环境

• 批准号: 7659132
• 负责人: Meenhard F Herlyn
• 金额: $ 6.57万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659132
• 关键词: Agonist; Apoptosis; Biologic Characteristic; Biological; Biological Models; Bortezomib; Cell Communication; Cell Surface Receptors; Cells; Clinical Protocols; Core Facility; Cues; Drug resistance; Endothelial Cells; Esophageal; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Feedback; Fibroblasts; Growth; Growth Factor; Human; Instruction; Invaded; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; N-Cadherin; Nature; Organ; Patients; Pharmaceutical Preparations; Phase; Production; Proteasome Inhibitor; Radiation; Resistance; Role; Stromal Cells; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Work; Xenograft procedure; angiogenesis; base; cancer cell; carcinogenesis; cell growth; cell type; conventional therapy; in vivo; neoplastic cell; novel; novel strategies; receptor; success; tumor

Our long-term objective is to develop new therapies for esophageal squamous cell carcinoma (ESCC) that are based on the unique biological characteristics of this malignancy. Our working hypothesis is that tumor cells establish a dominant relationship with stromal cells to control the formation of a primitive 'organ', in which all cellular constituents contribute to tumor cell growth, survival and invasion. We then hypothesize that tumor cell resistance to conventional therapies is due to intrinsic and microenvironmental factors. In preliminary studies we have developed three-dimensional culture models of the normal esophagus and of ESCC tumors that mimic conditions in vivo. These models allow us to dissect the roles for each cell type in a tissue-like context to determine how tumors progress and resist therapeutic drugs. This hypothesis will be pursued by the following interrelated Specific Aims: 1) To determine and define the functional synergy between stromal fibroblasts, endothelial cells, and ESCC cells with a focus upon the interplay between stromal fibroblasts and endothelial cells to nurture the microenvironment for esophageal tumor cells. To that end, tumors represent a finely tuned 'organ' in which the malignant cells dominate to drive activationof fibroblasts for matrix and growth factor production. Activated fibroblasts in turn attract endothelial cell and induce their differentiation for vessel formation and provide positive feedback for the tumor cells. We will analyze the secretion of soluble mediators (eg TGFbeta) and the dynamics of cell-cell interactions that together increase the invasive nature of tumors; 2) We will develop strategies to overcome the strong resistance of ESCC cells to current therapy. We believe that the unusual resistance to drugs is due to both microenvironmental and intrinsic cues. We will target the fibroblast-endothelial axis. In the second strategy, we have identified a proteasome inhibitor, Bortezomib, as very active. We will determine how we can enhance it's efficacy in SCC and plan to use it in combination with radiation and pro-apototic agents. Project 2 is closely integrated with Project 1 (Aims 2 and 3) and Project 3 (Aims 1 and 3), and makes extensive use of the outstanding, cohesive core facilities. RELEVANCE (See instructions): This Project focuses upon how activated fibroblasts impact upon endothelial cells to nurture neo- angiogenesis in the esophageal tumor microenvironment, which is very critial for tumor cell maintenance and growth. New stratagies are being developed to disrupt this axis and understand the role of novel biological modifiers in the tumor microenvironment and in vivo. Success has been achieved already in taking one approach to a Phase Ib clinical protocol _^_

我们的长期目标是开发食管鳞状细胞癌（ESCC）的新疗法， 都是基于这种恶性肿瘤的独特生物学特征。我们的假设是 细胞与基质细胞建立优势关系，以控制原始“器官”的形成， 所有的细胞成分都有助于肿瘤细胞的生长、存活和侵袭。然后我们假设 肿瘤细胞对常规疗法的抵抗是由于内在和微环境因素。在 初步研究，我们已经开发了三维培养模型的正常食管和 模拟体内条件的ESCC肿瘤。这些模型使我们能够剖析每种细胞类型的作用， 组织样背景来确定肿瘤如何进展和抵抗治疗药物。这一假设将是 通过以下相互关联的具体目标追求：1）确定和定义功能协同作用 间质成纤维细胞、内皮细胞和ESCC细胞之间的相互作用， 基质成纤维细胞和内皮细胞来培养食管肿瘤细胞的微环境。与 最后，肿瘤代表了一个微调的“器官”，其中恶性细胞占主导地位，以驱动激活 用于基质和生长因子生产的成纤维细胞。活化的成纤维细胞反过来吸引内皮细胞， 诱导其分化以形成血管并为肿瘤细胞提供正反馈。我们将 分析可溶性介质（如TGF β）的分泌和细胞间相互作用的动力学， 共同增加肿瘤的侵袭性; 2）我们将制定战略，克服强大的 ESCC细胞对当前疗法的抗性。我们认为，对药物的不寻常的耐药性是由于这两个原因 微环境和内在线索。我们将靶向成纤维细胞-内皮轴。在第二种策略中， 我们已经鉴定了一种蛋白酶体抑制剂Bortezaline，非常有效。我们将决定如何 增强其在SCC中的功效，并计划将其与放射和促凋亡剂联合使用。项目 项目2与项目1（目标2和3）和项目3（目标1和3）紧密结合， 优秀的、有凝聚力的核心设施。 相关性（参见说明）： 本项目的重点是活化的成纤维细胞如何影响内皮细胞， 食管肿瘤微环境中的血管生成，这对肿瘤细胞的维持非常关键， 增长正在开发新的战略来破坏这一轴，并了解新的生物学作用。 修饰剂在肿瘤微环境和体内。已经取得了成功， Ib期临床方案的方法_^_