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.

肺癌的死亡率是美国所有癌症中最高的。肺癌(LC)发展的复杂性 提示需要多种方法的结合来理解LC生物学的机制 以及肿瘤细胞与肿瘤微环境中的免疫细胞等其他细胞的相互作用。这个 癌症免疫编辑的概念认识到肿瘤和肿瘤之间复杂而动态的相互作用 宿主参与肿瘤的发生、发展和转移。尽管免疫系统是如何发挥作用的 在人类非小细胞肺癌(NSCLC)的发生和发展中，先天的、难以捉摸的 非小细胞肺癌肿瘤中巨噬细胞丰富。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，限制非小细胞肺癌的化疗疗效。β-葡聚糖是一种来源于各种来源的多糖，可以刺激先天和获得性免疫反应。我们的初步数据进一步表明，体外β-葡聚糖处理可以将免疫抑制的M2巨噬细胞转化为杀瘤的M1表型，并显著降低肿瘤相关巨噬细胞()介导的对CD_4和CDS_T细胞的免疫抑制。利用稳定同位素分解代谢组学(SIRM)方法，我们发现当免疫抑制的M2巨噬细胞转变为M1表型时，谷氨酰胺(Gin)摄取以及随后对葡萄糖、谷胱甘肽和乳酸的代谢增强。这一建议的核心观点是，不同的人非小细胞肺癌亚型可能具有不同的代谢谱，而β-葡聚糖治疗调节的活动和代谢，导致非小细胞肺癌代谢网络的改变。我们将使用稳定同位素(13C，15N)营养示踪剂，结合SIRM方法和代谢组学编辑的转录分析(META)来确定体内人非小细胞肺癌的关键代谢成分，并研究β-葡聚糖治疗如何影响的表型、功能、代谢以及随后的肿瘤微环境代谢事件。提出了三个特定的目标来确定：1人非小细胞肺癌细胞在异种移植中的特定代谢模式 严重联合免疫缺陷(SCID)小鼠肿瘤；2)β-葡聚糖的生化机制 在小鼠肺癌模型中的作用；3)人原代细胞的生化和表型特征 N0D/SCID/IL-2gcNULL小鼠移植肿瘤对注射β-葡聚糖的反应。这些调查 将促进我们对非小细胞肺癌肿瘤微环境营养利用的生化基础的理解，以及这些过程是如何与肿瘤免疫逃避和免疫调节相关的。