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.

肺癌死亡是美国所有癌症中最高的。肺癌（LC）发育的复杂性 建议需要采用多种方法来了解LC生物学的机制 和肿瘤细胞与其他细胞（例如肿瘤微环境中的免疫细胞）的相互作用。这 “癌症免疫程序”的概念认识到肿瘤与 宿主在肿瘤发育，进展和转移过程中。虽然免疫系统如何发挥作用 人类非小细胞肺癌（NSCLC）的发展和进展仍然难以捉摸 NSCLC肿瘤中巨噬细胞丰富。这些巨噬细胞具有免疫抑制M2 表型，促进肿瘤血管生成和转移，并限制化学疗法对NSCLC的疗效。 β-葡聚糖是从各种来源得出的多糖，可以刺激先天和适应性免疫反应。我们的初步数据进一步表明，体外β-葡聚糖治疗将免疫抑制的M2巨噬细胞转化为肿瘤M1表型，并显着降低了与肿瘤相关的巨噬细胞（TAM）对CD4和CDS T细胞的免疫抑制。使用稳定的同位素分辨代谢组学（SIRM）方法，我们表明谷氨酰胺（GIN）的摄取和随后的代谢对葡萄糖，谷胱甘肽和乳酸的增强，当免疫抑制M2巨噬细胞转化为ML表型时，会增强谷胱甘肽和乳酸。该提案的中心HVPothesis是，差异人NSCLC亚型可能具有独特的代谢特征，而P-葡萄糖治疗调节TAM活性和代谢，从而导致NSCLC中代谢网络的改变。 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.提出了三个特定的目的，以确定异种移植中人NSCLC细胞的1个特定代谢模式 严重合并免疫缺陷（SCID）小鼠中的肿瘤； 2）β-葡聚糖的生化机制 在鼠肺癌模型中的作用； 3）人类主要的生化和表型特征 植入N0D/SCID/IL-2GCNULL小鼠中的肿瘤响应β-葡聚糖给药。这些调查 将促进我们对NSCLC肿瘤微环境养分利用的生化基础以及这些过程与肿瘤免疫逃避和免疫调节的关系。