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

基本信息

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
项目类别：
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

项目摘要

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.

在美国，肺癌的死亡率是所有癌症中最高的。肺癌 (LC) 发展的复杂性表明需要结合多种方法来理解 LC 生物学机制以及肿瘤细胞与肿瘤微环境中的其他细胞（例如免疫细胞）的相互作用。这 “癌症免疫编辑”的概念认识到肿瘤与肿瘤之间复杂且动态的相互作用。肿瘤发生、进展和转移过程中的宿主。尽管免疫系统如何发挥作用人类非小细胞肺癌（NSCLC）的发生和进展仍然难以捉摸，是先天的 NSCLC 肿瘤中巨噬细胞丰富。这些巨噬细胞属于免疫抑制性 M2 表型，促进肿瘤血管生成和转移并限制非小细胞肺癌化疗的疗效。 β-葡聚糖是多种来源的多糖，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表明，体外β-葡聚糖治疗可将免疫抑制性M2巨噬细胞转化为杀肿瘤M1表型，并显着降低肿瘤相关巨噬细胞（TAM）介导的对CD4和CDS T细胞的免疫抑制。使用稳定同位素解析代谢组学（SIRM）方法，我们表明当免疫抑制性M2巨噬细胞转化为M1表型时，谷氨酰胺（Gin）摄取以及随后代谢为葡萄糖、谷胱甘肽和乳酸的能力得到增强。该提议的中心假设是，不同的人类 NSCLC 亚型可能具有不同的代谢特征，β-葡聚糖治疗调节 TAM 活性和代谢，导致 NSCLC 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组分析 (META) 来定义人 NSCLC 体内的关键代谢成分，并研究 β-葡聚糖治疗如何影响 TAM 表型、功能、代谢以及随后的肿瘤微环境代谢事件。提出了三个具体目标来确定： 1 异种移植中人类 NSCLC 细胞的具体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) 人类原代生化和表型特征响应β-葡聚糖给药，将肿瘤植入 N0D/SCID/IL-2gcNULL 小鼠中。这些调查将增进我们对非小细胞肺癌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。