Adipose Tissue Extracellular Vesicles in Colorectal Tumorigenesis

脂肪组织细胞外囊泡在结直肠肿瘤发生中的作用

• 批准号: 10655305
• 负责人: ARIANNE L THEISS
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655305
• 关键词: Adipocytes; Adipose tissue; Antitumor Response; Automobile Driving; Body mass index; Breast Cancer Model; Cell Survival; Cells; Colon; Colorectal Cancer; Communication; Consumption; DNA Sequence Alteration; Data; Distant; Endocrine Glands; Environment; Enzymes; Epithelium; Exhibits; Fatty Acids; Fatty acid glycerol esters; Fostering; Genetic Transcription; Goals; Growth; Healthcare Systems; Homeostasis; Human; Intake; LGR5 gene; Lipids; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Metabolism; MicroRNAs; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Non obese; Obese Mice; Obesity; Oncoproteins; Organ; Organoids; Overweight; Oxidative Phosphorylation; Pathway interactions; Patients; Phenotype; Production; Proliferating; Proteins; Risk; Role; Signal Induction; Signal Pathway; Signal Transduction; Surface; System; Testing; Transcriptional Activation; United States; Up-Regulation; Veterans; Veterans Health Administration; Visceral; base; beta catenin; cancer cell; cancer diagnosis; cell growth; cell type; colon tumorigenesis; colonic crypt; colorectal cancer progression; combat; exosome; experimental study; extracellular vesicles; fatty acid metabolism; inhibitor; intestinal epithelium; malignant breast neoplasm; military veteran; mitochondrial metabolism; mouse model; obese patients; obese person; oxidation; progenitor; receptor; saturated fat; src-Family Kinases; stem; stem cells; stemness; subcutaneous; therapeutically effective; translational study; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis; uptake; vesicular release; western diet

As of 2017, 78% of US Veterans are overweight or obese consuming a Western diet characterized by a high intake of saturated fat. It is well-established that obesity is associated with increased risk of developing colorectal cancer, the third most commonly diagnosed cancer in the Veterans Affairs Health Care System. Adipose tissue is the largest endocrine organ producing and secreting extracellular vesicles (EVs) carrying molecular cargo that can be taken up by recipient cells, resulting in intra-organ communication. Our preliminary data suggest that EV secretion is increased from adipose tissue from obese humans and mice. Additionally, obese adipose tissue EVs are enriched with enzymes involved in the fatty acid (FA) metabolic process. Fatty acid β-oxidation (FAO) is a catabolic pathway in the mitochondria crucial for ATP production by oxidative phosphorylation for cancer cell survival and growth. Initiation and progression of colorectal cancer is thought to involve an accumulation of genetic mutations predominantly in Lgr5+ colonic crypt base columnar (CBC) stem cells that confer a clonal advantage and expansion. However, the role of FAO in Lgr5+ CBCs remains unknown and the effect of adipose tissue-derived EVs on mitochondrial metabolism or function of colonic Lgr5+ CBCs has not been studied. Our preliminary data suggest that EVs derived from obese adipose tissue increase persistence of colonic Lgr5+ stem/progenitor function that is dependent on FAO. We also show that obese adipose EV-induced FAO increases β-Catenin transcriptional activation, which is crucially important for CBC stemness and crypt proliferation. EVs derived from adipose tissue of obese mice increase colon tumoroid growth dependent on FAO. We will test the hypothesis that EVs originating in the adipose tissue stimulate distant CBC stem cells, and in obese individuals, favor the progression to CRC. We propose 3 specific aims to test this hypothesis: Aim 1. To determine whether EVs shed from obese adipose tissue contain cargos that alter colonic CBC metabolism, CBC function, and epithelial homeostasis; Aim 2. Define the mechanism whereby obese adipose EVs drive CBC functional changes to enhance tumorigenesis; and Aim 3. Define the anti-tumor response of targeting pathways altered by adipose EVs in CRC. Our long-term goal is to determine whether targeting adipose EV-induced signaling pathways in the colon is an effective therapeutic strategy to combat colorectal cancer during obesity.

截至2017年，有78％的美国退伍军人超重或肥胖，消费西方饮食，其特征是 摄入饱和脂肪。公认的是，肥胖与发展结直肠的风险增加有关 癌症是退伍军人事务医疗系统中第三大通常被诊断出的癌症。脂肪组织 是携带分子货物的最大的内分泌器官生产和分泌细胞外蔬菜（EV） 可以用受体细胞吸收，从而导致器质内通信。我们的初步数据表明EV 分泌来自肥胖人和小鼠的脂肪组织。此外，肥胖的脂肪组织EV 富含参与脂肪酸（FA）代谢过程的酶。脂肪酸β-氧化（FAO）是 线粒体中的分解代谢途径对于通过氧化磷酸化的癌细胞产生ATP至关重要 生存和成长。结直肠癌的起始和进展被认为涉及 遗传突变主要在LGR5+结肠隐窝底座（CBC）干细胞中，该干细胞会遇到克隆 优势和扩展。但是，粮农组织在LGR5+ CBC中的作用尚不清楚，脂肪的影响 组织衍生的EV在线粒体代谢或结肠LGR5+ CBC的功能上尚未研究。我们的 初步数据表明，来自肥胖脂肪组织的电动汽车增加了结肠LGR5+的持久性 依赖粮农组织的茎/祖细胞功能。我们还表明肥胖的脂肪EV引起的粮农组织 增加β-catenin转录激活，这对于CBC茎和加密至关重要 增殖。源自肥胖小鼠的脂肪组织的电动汽车会增加结肠肿瘤的生长，取决于粮农组织。 我们将检验以下假设，即源自脂肪组织中的EV刺激遥远的CBC干细胞，并在 肥胖的个体，赞成向CRC的发展。我们提出了3个特定旨在检验这一假设的特定目标：目的1。 确定电动汽车是否从肥胖的脂肪组织中脱离，这些脂肪组织含有改变结肠CBC代谢的赤道 功能和上皮稳态；目标2。定义肥胖脂肪EVS驱动CBC的机制 功能变化以增强肿瘤发生；和目标3。定义靶向途径的抗肿瘤响应 在CRC中被脂肪电动汽车改变。我们的长期目标是确定是否针对脂肪EV诱导 结肠中的信号通路是在肥胖期间对抗大肠癌的有效治疗策略。