TWEAK-Fn14 Signaling in the Tumor Microenvironment

肿瘤微环境中的 TWEAK-Fn14 信号转导

• 批准号: 8193138
• 负责人: JEFFREY A WINKLES
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-07 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193138
• 关键词: Angiogenic Factor; Apoptosis Promoter; Binding; Blood; Blood Vessels; Breast Cancer Model; Cell Line; Cell Surface Receptors; Cells; Complex; Development; Endothelial Cells; Fibroblast Growth Factor; Fibroblasts; Health; Human; Immune; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Malignant Neoplasms; Names; Neoplasm Metastasis; Normal Cell; Nuclear; Pathway interactions; Phase; Play; Primary Neoplasm; Production; Proteins; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Source; System; Testing; Tissues; Tumor Angiogenesis; Tumor Necrosis Factor-alpha; Tumor Tissue; Vascular Endothelial Cell; angiogenesis; cell type; cytokine; in vivo; insight; macrophage; monocyte; mortality; neoplastic; neoplastic cell; novel; paracrine; research study; response; therapeutic target; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Solid tumors are complex tissues containing both neoplastic tumor cells and non-neoplastic cell types (e.g., vascular endothelial cells (EC), fibroblasts and macrophages) and the interactions between these cells can regulate tumor progression. For example, tumor cells produce multiple proteins that act in a paracrine manner to influence neighboring EC. Some of the proteins induce angiogenesis, which is crucial for primary tumor growth and metastasis, while others trigger immune system cell infiltration, which has both pro- and anti-tumorigenic effects. In this proposal, we describe experiments to investigate whether the cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) may play a multifunctional role in the tumor microenvironment. TWEAK expression has been detected in human tumor cells and tumor-associated macrophages, and these cells are likely the predominant sources of this cytokine in tumor tissue. TWEAK, acting via binding to the fibroblast growth factor-inducible 14 (Fn14) cell surface receptor, is an angiogenic factor in vivo. Additionally, since TWEAK treatment of EC activates the nuclear factor-?B (NF-?B) signaling pathway and promotes pro-inflammatory molecule production, this cytokine may also be a pro-inflammatory factor in vivo. In consideration of these and other findings, we hypothesize that the TWEAK-Fn14 signaling system may play an important role in both tumor angiogenesis and inflammation. Specifically, we propose that TWEAK acts at two phases of tumor development. In phase 1, tumor cell-derived TWEAK functions primarily as a paracrine regulator of EC activation, triggering both tumor angiogenesis and immune cell infiltration. In phase 2, immune system cells within the tumor stroma, in particular blood monocyte-derived macrophages, become an important secondary source of this cytokine. This TWEAK protein can also act on EC, thereby further contributing to tumor angiogenesis and persistent monocyte infiltration. TWEAK released from both cellular sources may also act on the tumor cells themselves, and all of these interactions will ultimately contribute to tumor growth and metastasis. Four Specific Aims have been formulated to test our hypothesis. These Aims are: (1) To determine if TWEAK can induce pro-angiogenic and pro-inflammatory cellular responses in vitro, and to investigate if TWEAK activity is dependent on NF-?B pathway activation, (2) To determine whether TWEAK delivered into the tumor microenvironment can stimulate angiogenesis, inflammation, and tumor growth, and to investigate if these effects are dependent on NF-?B activation, (3) To determine whether TWEAK present in the tumor microenvironment promotes tumor growth, at least in part, by acting on non-neoplastic host cells and to determine if TWEAK produced by host immune cells contributes to tumor growth, and (4) To determine if TWEAK activity contributes to tumorigenesis in a spontaneous mammary cancer model and to investigate whether TWEAK antagonist administration can inhibit tumor growth in vivo. The proposed studies should provide important, novel information on the role of TWEAK and Fn14 in the tumor microenvironment and will provide insight into whether TWEAK is a potential therapeutic target for human cancer. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of mortality in the USA. Solid tumors are complex tissues containing both "transformed" tumor cells and "normal" cell types such as the vascular endothelial cells that line blood vessels and blood-derived immune system cells that infiltrate the tumor tissue. Previous studies have revealed that interactions between these different cell types can regulate tumor progression. In this application, we propose to investigate whether a particular cytokine, named TWEAK, is produced by multiple cell types in the tumor microenvironment and acts as an important stimulatory molecule contributing to blood vessel formation, tumor inflammation, and ultimately tumor growth.

描述（由申请人提供）：实体瘤是含有肿瘤肿瘤细胞和非肿瘤细胞类型（例如，血管内皮细胞（EC），成纤维细胞和巨噬细胞）的复杂组织，这些细胞之间的相互作用可以调节肿瘤进展。 例如，肿瘤细胞产生多种蛋白质，可作用于旁分泌方式来影响相邻的EC。 某些蛋白质诱导血管生成，这对于原发性肿瘤生长和转移至关重要，而另一些蛋白质引发了免疫系统细胞浸润，该细胞均具有促肿瘤作用和抗肿瘤作用。 在该提案中，我们描述了研究细胞因子坏死因子样细胞凋亡（TWEAK）是否可能在肿瘤微环境中起多功能作用的实验。 在人类肿瘤细胞和肿瘤相关的巨噬细胞中已经检测到了调整表达，这些细胞可能是该细胞因子在肿瘤组织中的主要来源。 通过与成纤维细胞生长因子诱导因子14（FN14）细胞表面受体结合作用的调整是体内的血管生成因子。 此外，由于对EC的调整治疗会激活核因子 - ？b（NF-？b）信号通路并促进促炎性分子的产生，因此该细胞因子在体内也可能是促炎性因子。 考虑到这些发现和其他发现，我们假设Tweak-FN14信号传导系统可能在肿瘤血管生成和炎症中起重要作用。 具体而言，我们建议调整在肿瘤发育的两个阶段起作用。 在第1阶段，肿瘤细胞衍生的调整主要作为EC激活的旁分泌调节剂，触发肿瘤血管生成和免疫细胞浸润。 在第2阶段，肿瘤基质内的免疫系统细胞，特别是血单核细胞衍生的巨噬细胞，成为该细胞因子的重要次要来源。 这种调整蛋白也可以作用于EC，从而进一步有助于肿瘤血管生成和持续的单核细胞浸润。 从两个细胞来源释放的调整也可能作用于肿瘤细胞本身，所有这些相互作用最终将有助于肿瘤生长和转移。 已经制定了四个具体目标来检验我们的假设。 这些目的是：（1）确定在体外诱导tweak是否可以诱导促血管生成和促炎性细胞反应，并调查tweak活性是否取决于Nf- b途径的激活，（2）确定肿瘤微环境传递到肿瘤微环境中是否可以刺激脉络生成，炎症，以及是否对这些效果进行效果，是否依赖于这些效果，是否依赖于（是否效果），是否依赖（是否效应）是否存在（是否是？是否效果？是否效果？是否？是否？是否是否？是否？是否效果？是否效果？是否是否会造成（是否？是否？是否？是否效果？是否？是否效果吗？肿瘤微环境中存在的调整至少部分地通过作用于非塑性宿主细胞来促进肿瘤的生长，并确定宿主免疫细胞产生的tweak是否有助于肿瘤的生长，并确定TWEAK活性是否有助于自发性乳腺癌模型中的肿瘤性，并调查自发性癌症抗逆转型的vict型tamorant tumor nimy nimy nimy nimy nimy nimy rymor nimigy nimy rymor。 拟议的研究应提供有关Tweak和FN14在肿瘤微环境中的作用的重要新颖信息，并将深入了解调整是否是人类癌症的潜在治疗靶标。 公共卫生相关性：癌症是美国死亡率的第二主要原因。 实体瘤是复杂的组织，其中既包含“转化”肿瘤细胞和“正常”细胞类型，例如血管排成血管和血液来源的血管内皮细胞，并渗入肿瘤组织的血液衍生的免疫系统细胞。 先前的研究表明，这些不同细胞类型之间的相互作用可以调节肿瘤进展。 在此应用中，我们建议研究特定的细胞因子（称为Tweak）是否由肿瘤微环境中多种细胞类型产生，并充当重要的刺激分子，导致血管形成，肿瘤炎症和最终导致肿瘤生长。