TNF-Mediated Tumor Promotion: The Role of Vascular Leukocytes

TNF 介导的肿瘤促进：血管白细胞的作用

• 批准号: 7687265
• 负责人: Pampee P Young
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687265
• 关键词: Adhesions; Adjuvant Therapy; Aging; Antigens; Arthritis; Biomedical Research; Blood; Blood Vessels; Bone Marrow Transplantation; Breast Melanoma; CD14 gene; Cancerous; Cell Communication; Cell Lineage; Cells; Cessation of life; Chronic; Contralateral; Cues; Cutaneous Melanoma; Data; Disease; Dose; Endothelial Cells; FDA approved; Fibronectins; Generations; Genes; Goals; Grant; Growth; Health; Human; Immunophenotyping; Implant; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Integrins; Kinetics; Laboratories; Lead; Leukocytes; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Mission; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Names; Necrosis; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Phenotype; Play; Population; Property; Recruitment Activity; Relative (related person); Research; Role; Signal Transduction; Skin Cancer; Specificity; Stem cells; Testing; Therapeutic; Tumor Angiogenesis; Tumor Cell Line; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Promoters; Tumor Promotion; Tumor Stem Cells; Tumor-Derived; Up-Regulation; Veterans; Work; angiogenesis; base; cancer therapy; human TNFRSF1A protein; in vivo; inhibitor/antagonist; microbial; monocyte; mortality; mouse model; novel; peripheral blood; public health relevance; research study; tumor; tumor growth; tumor necrosis factor alpha receptor; tumor necrosis factor-alpha inhibitor; tumor progression; vasculogenesis

DESCRIPTION (provided by applicant): Background. Recently, we and others have characterized a significant population of tumor- associated leukocytes which co-express endothelial and myeloid markers, the so called "vascular leukocytes". Most studies indicate that they serve as potent mediators of tumor growth and angiogenesis. Generation of vascular leukocytes is likely modulated by cues from the tumor microenvironment. The mechanism of their generation is not known. Objective/Hypothesis: Our preliminary data suggest that TNF results in a dose-dependent upregulation of endothelial-specific markers in cultured monocytes. This effect was dependent on TNF receptors as cells isolated from mice lacking TNF receptors displayed dramatically delayed kinetics in myeloid/endothelial biphenotypic cell generation. Mice implanted with TNF overproducing tumors contained larger, more vascular tumors with increased numbers of vascular leukocytes than contralateral, control tumors. Based on these exciting data, we hypothesize that locally-derived TNF is an important regulator of tumor growth by regulating, in part, the generation of myeloid/endothelial biphenotypic cells. Specific Aims: 1) Determine the role of TNF in vascular leukocyte formation in mouse models of tumor growth by upregulating local tumor-derived expression and by immunoblocking approaches with bone marrow transplant models. 2) Delineate the mechanism(s) by which TNF promotes vascular plasticity of leukocytes. Relevance to VA mission: Cancer is a leading cause of morbidity and mortality among our aging Veterans. This grant is based on preliminary data that support a novel hypothesis that the "proangiogenic" and tumor-promoting properties of TNF are mediated, at least partly, by facilitating myeloid to endothelial differentiation that contributes directly to specific proangiogenic vascular leukocyte subpopulations within both breast and melanoma skin cancers. This work may lead to the use of TNF inhibitors as adjunct therapy to manipulate specific myeloid populations to abrogate tumor progression in our Veterans. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE. It is widely accepted that many aspects of cancerous growth is mediated by inflammation. Tumor necrosis factor-alpha (TNF) is an important mediator of inflammation. It was first isolated from the blood of mice suffering from severe microbial-induced inflammation and was shown to induce tumor necrosis or death (hence the name). Importantly, the doses of TNF used in such experiments were very large. Endogenous TNF, however, is produced at chronic, low levels in tumors. Several recent studies suggest that at these low, chronic doses, TNF promotes tumor growth. For example, mice that have a deletion in TNF gene or the machinery by which it acts, have delayed tumor growth and metastasis. However, there is a gap in our understanding on how TNF serves as a tumor promoter. Our laboratory has long studied the role of blood vessel stem cells in cancer. We and many others have shown that myeloid lineage cells can upregulate endothelial markers in vitro and in vivo. These myeloid/endothelial biphenotypic cells represent a subpopulation of myeloid cells that are promote tumor growth and blood vessels. Using tumors that express slightly higher levels of TNF, we have strong evidence that at least one important mechanism by which TNF works within tumors is by promoting the differentiation of myeloid/endothelial cells. These findings are entirely novel and have important implications in cancer therapy. TNF inhibitors are already available and FDA-approved to treat inflammatory disorders, such as arthritis. By understanding the details of TNF's role in tumor- myeloid cell interactions, we may be able to develop new cancer therapeutic strategies using TNF-inhibitors. Cancer continues to be a pervasive and prevalent health problem among our aging Veterans and critical to the biomedical research mission of the Veterans Affairs.

描述（由申请人提供）： 背景 最近，我们和其他人已经表征了一个显著的肿瘤相关白细胞群体，其共表达内皮和骨髓标志物，所谓的“血管白细胞”。大多数研究表明，它们是肿瘤生长和血管生成的有效介质。血管白细胞的产生可能受到来自肿瘤微环境的线索的调节。其生成机制尚不清楚。 目的/假设：我们的初步数据表明，TNF导致培养的单核细胞中内皮特异性标志物的剂量依赖性上调。这种效应依赖于TNF受体，因为从缺乏TNF受体的小鼠中分离的细胞在髓样/内皮双表型细胞生成中显示出显著延迟的动力学。与对侧对照肿瘤相比，植入TNF过度产生肿瘤的小鼠含有更大、更多的血管肿瘤，血管白细胞数量增加。基于这些令人兴奋的数据，我们假设局部来源的TNF是肿瘤生长的重要调节因子，部分通过调节髓样/内皮双表型细胞的产生。 具体目标：1）通过上调局部肿瘤衍生的表达和通过免疫阻断方法用骨髓移植模型确定TNF在肿瘤生长的小鼠模型中血管白细胞形成中的作用。2)描述TNF促进白细胞血管可塑性的机制。 与退伍军人事务部使命的相关性：癌症是我们老年退伍军人发病率和死亡率的主要原因。这项拨款是基于初步数据，支持一种新的假设，即“促血管生成”和肿瘤促进性质的TNF介导，至少部分，促进髓细胞内皮细胞分化，直接有助于特定的促血管生成血管白细胞亚群在乳腺癌和黑色素瘤皮肤癌。这项工作可能会导致使用TNF抑制剂作为辅助治疗，以操纵特定的骨髓细胞群，以消除我们的退伍军人的肿瘤进展。 公共卫生相关性： 项目叙述。 人们普遍认为，癌症生长的许多方面是由炎症介导的。肿瘤坏死因子-α（TNF）是炎症的重要介质。它最初是从患有严重微生物诱导炎症的小鼠血液中分离出来的，并显示出诱导肿瘤坏死或死亡（因此得名）。重要的是，这些实验中使用的TNF剂量非常大。然而，内源性TNF在肿瘤中以慢性低水平产生。最近的几项研究表明，在这些低，慢性剂量，TNF促进肿瘤生长。例如，TNF基因或其作用机制缺失的小鼠具有延迟的肿瘤生长和转移。然而，我们对TNF如何作为肿瘤促进剂的理解存在差距。我们的实验室长期以来一直在研究血管干细胞在癌症中的作用。我们和许多其他人已经表明，髓系细胞可以在体外和体内上调内皮标志物。这些髓样/内皮双表型细胞代表促进肿瘤生长和血管的髓样细胞亚群。使用表达稍高水平TNF的肿瘤，我们有强有力的证据表明，TNF在肿瘤内起作用的至少一个重要机制是通过促进髓样/内皮细胞的分化。这些发现是全新的，对癌症治疗具有重要意义。TNF抑制剂已经可用，并且FDA批准用于治疗炎性疾病，如关节炎。通过了解TNF在肿瘤-骨髓细胞相互作用中的作用细节，我们可能能够开发使用TNF抑制剂的新的癌症治疗策略。癌症仍然是一个普遍和普遍的健康问题，在我们的老年退伍军人和关键的生物医学研究使命的退伍军人事务。