Adipose Tissue Extracellular Vesicles in Colorectal Tumorigenesis

截至2017年，78%的美国退伍军人超重或肥胖，食用西方饮食，其特点是高 饱和脂肪的摄入。众所周知，肥胖与结直肠癌风险增加有关。 癌症是退伍军人事务部医疗保健系统中第三大最常诊断的癌症。脂肪组织 是产生和分泌细胞外囊泡（EV）的最大内分泌器官，所述细胞外囊泡携带分子货物， 可以被受体细胞吸收，导致器官内的通讯。我们的初步数据表明，EV 来自肥胖人和小鼠的脂肪组织的分泌增加。此外，肥胖脂肪组织EV 富含参与脂肪酸（FA）代谢过程的酶。脂肪酸β-氧化（FAO）是一种 线粒体中的分解代谢途径对癌细胞氧化磷酸化产生ATP至关重要 生存和成长。结肠直肠癌的发生和发展被认为涉及 主要在Lgr 5+结肠隐窝基底柱状（CBC）干细胞中的基因突变， 优势和扩展。然而，粮农组织在Lgr5 + CBCs中的作用仍然未知， 尚未研究组织来源的EV对结肠Lgr5 + CBC的线粒体代谢或功能的影响。我们 初步数据表明，来自肥胖脂肪组织的EV增加了结肠Lgr 5+的持续性， 干/祖细胞功能依赖粮农组织。我们还表明，肥胖脂肪EV诱导的FAO 增加β-连环蛋白转录激活，这对CBC干性和隐窝至关重要 增殖来源于肥胖小鼠脂肪组织的EV增加依赖于FAO的结肠类肿瘤生长。 我们将检验起源于脂肪组织的EV刺激远端CBC干细胞的假设， 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。到 确定从肥胖脂肪组织脱落的EV是否含有改变结肠CBC代谢的货物，CBC 功能和上皮稳态;目的2.定义肥胖脂肪EV驱动CBC的机制 增强肿瘤发生的功能变化;以及目标3。定义靶向通路的抗肿瘤反应 在CRC中被脂肪EV改变。我们的长期目标是确定是否靶向脂肪EV诱导 结肠中的信号通路是在肥胖期间对抗结肠直肠癌的有效治疗策略。

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.