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，78% 的美国退伍军人超重或肥胖，其饮食特点是高脂肪饮食 众所周知，肥胖与结直肠癌风险增加有关。 癌症，退伍军人事务医疗保健系统中第三种最常见的癌症。 是最大的内分泌器官，产生和分泌携带分子货物的细胞外囊泡（EV） 我们的初步数据表明，EV 可以被受体细胞吸收，从而产生器官内通讯。 肥胖人和小鼠的脂肪组织的分泌增加。 富含参与脂肪酸 (FA) 代谢过程的酶 脂肪酸 β-氧化 (FAO) 是一种酶。 线粒体中的分解代谢途径对于癌细胞通过氧化磷酸化产生 ATP 至关重要 结直肠癌的发生和发展被认为涉及结直肠癌的积累。 主要发生在 Lgr5+ 结肠隐窝基底柱状 (CBC) 干细胞中的基因突变，赋予克隆性 然而，FAO 在 Lgr5+ CBC 中的作用以及脂肪的作用仍不清楚。 组织源性 EV 对结肠 Lgr5+ CBC 线粒体代谢或功能的影响尚未进行研究。 初步数据表明，源自肥胖脂肪组织的 EV 增加了结肠 Lgr5+ 的持久性 依赖于FAO的干细胞/祖细胞功能我们还表明肥胖脂肪EV诱导的FAO。 增加 β-Catenin 转录激活，这对于 CBC 干性和隐窝至关重要 源自肥胖小鼠脂肪组织的 EV 会增加依赖于FAO的结肠肿瘤生长。 我们将检验以下假设：源自脂肪组织的 EV 会刺激远处的 CBC 干细胞，并且 肥胖个体有利于进展为 CRC。我们提出了 3 个具体目标来检验这一假设： 目标 1. 目标 确定从肥胖脂肪组织中脱落的 EV 是否含有改变结肠 CBC 代谢的物质，CBC 功能和上皮稳态；目标 2. 明确肥胖脂肪 EV 驱动 CBC 的机制 功能改变以增强肿瘤发生；目标 3. 定义靶向途径的抗肿瘤反应 我们的长期目标是确定是否针对脂肪 EV 诱导的结直肠癌。 结肠信号通路是对抗肥胖期间结直肠癌的有效治疗策略。