Determining Tumor Metabolism and Biochemical Mechanism of beta-glucan Action in

确定肿瘤代谢和 β-葡聚糖作用的生化机制

• 批准号: 8744923
• 负责人: Teresa Whei-Mei Fan
• 金额: $ 26.15万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-19 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8744923
• 关键词: Affect; Antigen Presentation; Arginine; Biochemical; Biochemical Pathway; Biochemistry; Cancer Biology; Cell Communication; Cell Line; Cells; Cessation of life; Clinical; Complex; Data; Development; Early Diagnosis; Event; Genes; Glucans; Glucose; Glutamine; Glutathione; Goals; Human; Human Characteristics; Immune; Immune response; Immune system; Immunomodulators; Immunophenotyping; Immunosuppression; Implant; In Situ; In Vitro; In Vivo NMR Spectroscopy; Instruction; Investigation; Knowledge; Label; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measurement; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; North America; Nutrient; Outcome; Particulate; Pathway interactions; Patients; Pattern; Phenotype; Play; Polysaccharides; Primary Neoplasm; Process; Protein Analysis; Role; SCID Mice; Slice; Source; System; T-Lymphocyte; Tissues; Tracer; Tumor Angiogenesis; Yeasts; angiogenesis; beta-Glucans; cancer cell; chemotherapy; immunoregulation; improved; in vivo; lung Carcinoma; macrophage; metabolomics; neoplastic cell; novel strategies; outcome forecast; response; stable isotope; subcutaneous; transcriptomics; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor xenograft; uptake

Deaths from lung cancer are the highest of all cancers in the US. The complexity of lung cancer (LC) development suggests that a combination of approaches is needed to understand the mechanism of LC biology and tumor cell interactions with other cells such as immune cells within the tumor microenvironment. The concept of "cancer immunoediting" recognizes the complex and dynamic interactions between the tumor and host during tumor development, progression and metastasis. Although how the immune system plays a role in development and progression of human non-small cell lung carcinoma (NSCLC) is still elusive, innate macrophages are abundant in the NSCLC tumors. These macrophages are of immune suppressive M2 phenotype, promote tumor angiogenesis and metastasis and limit efficacy of chemotherapy for NSCLC. beta-Glucans, polysaccharides derived from various sources, can stimulate both innate and adaptive immune responses. Our preliminary data further demonstrate that beta-glucan treatment in vitro converts immune suppressive M2 macrophages into tumoricidal M1 phenotype and significantly decreases tumor-associated macrophage (TAM)-mediated immune suppression on CD4 and CDS T cells. Using the stable isotope resolved metabolomics (SIRM) approach, we show that glutamine (Gin) uptake and subsequent metabolism to glucose, glutathiones and lactate are enhanced when immune suppressive M2 macrophages are converted into an Ml phenotype. The central hvpothesis of this proposal is that differential human NSCLC subtypes may have distinct metabolic profiles and p-glucan treatment modulates TAM activity and metabolism, leading to the alterations of metabolic networks in NSCLC. We will use stable isotopic (13C, 15N) nutrient tracers in combination with the SIRM approach and metabolomics-edited transcriptomic analysis (META) to define key metabolic components of human NSCLC in vivo and investigate how beta-glucan treatment influences TAM phenotype, function, metabolism and subsequently tumor microenvironmental metabolic events. Three Specific Aims are proposed to determine the: 1 specific metabolic patterns of human NSCLC cells in xenografted tumors in severe combined immunodeficient (SCID) mice; 2) biochemical mechanisms of beta-glucan action in murine lung carcinoma models; 3) biochemical and phenotypic characteristics of human primary tumors implanted in N0D/SCID/IL-2gcNULL mice in response to beta-glucan administration. These investigations will advance our understanding of the biochemical underpinnings of tumor microenvironment nutrient utilization by NSCLC and how these processes are related to tumor immune evasion and immunomodulation.

肺癌是美国所有癌症中死亡率最高的。肺癌（LC）发展的复杂性 表明，需要结合各种方法来了解LC生物学机制 以及肿瘤细胞与肿瘤微环境中的其他细胞如免疫细胞的相互作用。的 “癌症免疫编辑”的概念认识到肿瘤和肿瘤细胞之间复杂和动态的相互作用， 在肿瘤发生、发展和转移过程中宿主。尽管免疫系统如何发挥作用 在人类非小细胞肺癌（NSCLC）的发展和进展中， 巨噬细胞在NSCLC肿瘤中丰富。这些巨噬细胞具有免疫抑制性M2 表型，促进肿瘤血管生成和转移，限制NSCLC的化疗效果。β-葡聚糖是一种来自不同来源的多糖，可以刺激先天性和适应性免疫反应。我们的初步数据进一步证明，β-葡聚糖体外处理可将免疫抑制性M2巨噬细胞转化为杀肿瘤的M1表型，并显著降低肿瘤相关巨噬细胞（TAM）介导的对CD 4和CDS T细胞的免疫抑制。使用稳定同位素分辨代谢组学（SIRM）方法，我们表明当免疫抑制性M2巨噬细胞转化为Ml表型时，谷氨酰胺（Gln）摄取和随后代谢为葡萄糖、谷胱甘肽和乳酸盐增强。该建议的中心假设是，不同的人类NSCLC亚型可能具有不同的代谢特征，β-葡聚糖治疗可调节TAM活性和代谢，导致NSCLC中代谢网络的改变。我们将使用稳定同位素（13 C，15 N）营养示踪剂结合SIRM方法和代谢组学编辑转录组学分析（Meta）来确定体内人类NSCLC的关键代谢组分，并研究β-葡聚糖治疗如何影响TAM表型，功能，代谢和随后的肿瘤微环境代谢事件。提出了三个特定目的来确定：1异种移植中人NSCLC细胞的特定代谢模式 严重联合免疫缺陷（SCID）小鼠的肿瘤; 2）β-葡聚糖的生化机制 在小鼠肺癌模型中的作用; 3）人原发性肺癌的生物化学和表型特征 植入N 0 D/SCID/IL-2gcNULL小鼠的肿瘤对β-葡聚糖给药的反应。这些调查 将促进我们对NSCLC肿瘤微环境营养利用的生化基础以及这些过程如何与肿瘤免疫逃避和免疫调节相关的理解。