TWEAK-Fn14 Signaling in the Tumor Microenvironment

肿瘤微环境中的 TWEAK-Fn14 信号转导

• 批准号: 7835631
• 负责人: JEFFREY A WINKLES
• 金额: $ 31.13万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835631
• 关键词: Angiogenic Factor; Apoptosis Promoter; Binding; Blood; Blood Vessels; Breast Cancer Model; Cell Line; Cell Surface Receptors; Cells; Complement Factor B; Complex; Development; Endothelial Cells; Fibroblast Growth Factor; Fibroblasts; 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 Necrosis Factors; Tumor Tissue; Vascular Endothelial Cell; angiogenesis; cell type; cytokine; in vivo; insight; macrophage; monocyte; mortality; neoplastic; neoplastic cell; novel; paracrine; public health relevance; 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）：实体瘤是包含肿瘤细胞和非肿瘤细胞类型（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的进展。例如，肿瘤细胞产生多种以旁分泌方式影响邻近EC的蛋白质。其中一些蛋白诱导血管生成，这对原发性肿瘤的生长和转移至关重要，而另一些蛋白则引发免疫系统细胞浸润，具有促肿瘤和抗肿瘤的作用。在本提案中，我们描述了实验来研究细胞因子肿瘤坏死因子样弱诱导细胞凋亡（TWEAK）是否可能在肿瘤微环境中发挥多功能作用。在人类肿瘤细胞和肿瘤相关巨噬细胞中检测到TWEAK表达，这些细胞可能是肿瘤组织中该细胞因子的主要来源。TWEAK通过与成纤维细胞生长因子诱导14 （Fn14）细胞表面受体结合而起作用，在体内是一种血管生成因子。此外，由于EC的TWEAK处理激活了核因子-？B (NF - ?B)信号通路并促进促炎分子的产生，该细胞因子在体内也可能是促炎因子。考虑到这些和其他发现，我们假设TWEAK-Fn14信号系统可能在肿瘤血管生成和炎症中发挥重要作用。具体来说，我们提出TWEAK在肿瘤发展的两个阶段起作用。在第一阶段，肿瘤细胞来源的TWEAK主要作为EC激活的旁分泌调节因子，触发肿瘤血管生成和免疫细胞浸润。在第2期，肿瘤基质内的免疫系统细胞，特别是血液单核细胞来源的巨噬细胞，成为该细胞因子的重要二次来源。这种TWEAK蛋白也可以作用于EC，从而进一步促进肿瘤血管生成和持续的单核细胞浸润。这两种细胞源释放的TWEAK也可能作用于肿瘤细胞本身，所有这些相互作用最终将促进肿瘤的生长和转移。为了验证我们的假设，我们制定了四个具体目标。这些目的是：(1)确定TWEAK是否能诱导体外促血管生成和促炎症细胞反应，并研究TWEAK活性是否依赖于NF-？(2)确定进入肿瘤微环境的TWEAK是否能刺激血管生成、炎症和肿瘤生长，并研究这些作用是否依赖于NF-？(3)确定存在于肿瘤微环境中的TWEAK是否至少部分通过作用于非肿瘤宿主细胞来促进肿瘤生长，并确定宿主免疫细胞产生的TWEAK是否有助于肿瘤生长；(4)在自发性乳腺癌模型中确定TWEAK活性是否有助于肿瘤发生，并研究施加TWEAK拮抗剂是否可以抑制肿瘤生长。拟议的研究应提供关于TWEAK和Fn14在肿瘤微环境中的作用的重要新信息，并将深入了解TWEAK是否为人类癌症的潜在治疗靶点。公共卫生相关性：癌症是美国第二大死亡原因。实体瘤是一种复杂的组织，包含“转化”的肿瘤细胞和“正常”细胞类型，如血管内皮细胞和浸润肿瘤组织的血源性免疫系统细胞。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的进展。在本应用中，我们拟研究一种名为TWEAK的特定细胞因子是否由肿瘤微环境中的多种细胞类型产生，并作为促进血管形成、肿瘤炎症和最终肿瘤生长的重要刺激分子。