DIFFERENTIAL SUBSTRATE UTILIZATION IN TUMOR AND HOST

肿瘤和宿主中底物利用的差异

• 批准号: 3460786
• 负责人: LAURI O BYERLEY
• 金额: $ 10.03万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460786
• 关键词: cachexia; carbon; deficient growth media; dietary lipid; fatty acids; glycolysis; host neoplasm interaction; laboratory rat; lactates; lipid metabolism; lipolysis; metabolism; neoplastic cell; neoplastic growth; nutrition aspect of cancer; nutrition related tag; protein metabolism; radiotracer; stable isotope

Cancer cachexia is wasting syndrome characterized in its early stages by a loss of host fat and protein stores without a concurrent change in food intake followed in its later stages with metabolic abnormalities. The cachectic syndrome is imposed by the tumor since weight gain and reversal of the metabolic abnormalities occurs when the tumor is removed. Tumor cells, like other cells, can not survive without substrate (carbon sources) from the host, and the intracellular metabolism of the tumor should reflect the availability of host-derived carbon sources. Differences in tumor metabolism have been reported which include increased glycolysis, lactogenesis and cholesterolgenesis. Do the differences in cellular metabolism between non-neoplastic and neoplastic tissue give tumor cells an advantage over the host that leads to loss of host fat stores? The answer can only be determined from quantitating production and utilization of substrate by the tumor and host separately, which has not been done. This study will focus on host and tumor metabolism in vivo separately and simultaneously to determined if the competition for substrate by tumor tissue to support its rapid and unregulated growth leads o the increased catabolism of the host's fat stores. These investigations will use [U13C] glucose and mass isotopomer technology to measure tumor, liver, muscle and fat intracellular metabolism; the tumor tissue-isolate model to measure substrate utilization of the tumor; and isotope tracers to measure host production of substrate (glucose production/6-3H-glucose, and lipolysis/1-14C-palmitate and [2H5] glycerol). Intracellular metabolism will focus on two active metabolic pathways: 1) glucose carbon recycling including lactate production and Krebs cycle parameters, and 2) glucose carbon channeling to lipid metabolites (cholesterol synthesis). The relative enrichments between precursor and labeled product will be used to estimate lactate production from labeling in lactate, Krebs cycle parameters from labeling in glutamate, aspartate, alanine, cholesterol synthesis from labeling in cholesterol, and ribose synthesis from labeling in ribose. Loss of substrate from the host to the tumor will be determined from the difference n host production of substrate and tumor utilization of substrate. After the intterelationship between tumor and host metabolism is known, I will investigate the effect of dietary fatty acids on host and tumor metabolism to determine if a specific diet can slow down or prevent the cancer cachexia process. In summary, results from this research will determine f substrate needs of the tumor deplete the host's substrate pool and if manipulation of dietary fat can alter tumor metabolism to benefit the host.

癌症恶病质正在浪费综合症，以此来表征其早期阶段 宿主脂肪和蛋白质存储的损失而没有同时变化 食物摄入后期的阶段随着代谢异常。 缓存综合征是由肿瘤施加的，因为体重增加和 当肿瘤为时发生代谢异常的逆转 删除。像其他细胞一样，肿瘤细胞无法生存 宿主的底物（碳源）和细胞内 肿瘤的代谢应反映宿主衍生的可用性 碳源。据报道，肿瘤代谢的差异 包括增加糖酵解，泌乳发生和胆固醇。做 非塑性和非塑性和 肿瘤组织使肿瘤细胞优于宿主 损失主机脂肪储存？答案只能从中确定 定量肿瘤对底物的生产和利用 主机分开，尚未完成。这项研究将重点放在宿主上 分别和同时确定的体内肿瘤代谢 如果通过肿瘤组织竞争底物以支持其快速 不受管制的增长导致o宿主的分解代谢增加 脂肪存储。这些研究将使用[U13C]葡萄糖和质量 测量肿瘤，肝脏，肌肉和脂肪的同位素技术 细胞内代谢；肿瘤组织分析模型测量 肿瘤的底物利用；和同位素示踪剂以测量主机 底物的产生（葡萄糖产生/6-3H-葡萄糖，以及 脂解/1-14C-钙木酸盐和[2H5]甘油）。细胞内代谢 将专注于两个主动代谢途径：1）葡萄糖碳回收 包括乳酸产生和克雷布斯循环参数，以及2）葡萄糖 碳传递到脂质代谢产物（胆固醇合成）。这 将使用前体和标记产品之间的相对富集 估计乳酸在乳酸上的标记，克雷布斯循环的乳酸产生 在谷氨酸，天冬氨酸，丙氨酸，胆固醇中标记的参数 来自胆固醇标记的合成，以及核糖合成 在核糖中标记。从宿主到肿瘤的底物损失将是 从差异n宿主产生的底物和肿瘤确定 利用底物。肿瘤和 宿主代谢是已知的，我将研究饮食脂肪的影响 宿主和肿瘤代谢上的酸，以确定特定饮食是否可以 减慢或预防癌症恶病质过程。总而言之，结果 通过这项研究将确定肿瘤耗尽的F底物需求 宿主的底物池以及饮食脂肪的操纵是否会改变 肿瘤代谢使宿主受益。