Adipose Tissue Extracellular Vesicles in Colorectal Tumorigenesis

截至2017年，78%的美国退伍军人超重或肥胖，食用以高热量为特征的西方饮食 摄入饱和脂肪。众所周知，肥胖与患结直肠癌的风险增加有关。 癌症是退伍军人事务部医疗保健系统中第三种最常见的癌症。脂肪组织 是产生和分泌细胞外小泡(EVS)的最大内分泌器官，携带的分子货物 可以被受体细胞摄取，导致器官内的通讯。我们的初步数据表明，电动汽车 肥胖的人类和小鼠的脂肪组织分泌增加。此外，肥胖的脂肪组织EVS 富含参与脂肪酸(FA)代谢过程的酶。脂肪酸氧化(β-Oxation，FAO)是一种 线粒体的分解代谢途径对癌细胞氧化磷酸化产生三磷酸腺苷至关重要 生存和成长。结直肠癌的发生和发展被认为涉及一种积聚的 主要发生在Lgr5+结肠隐窝基柱状(CBC)干细胞中的基因突变 优势和扩张。然而，粮农组织在Lgr5+CBCs中的作用尚不清楚，脂肪的影响尚不清楚 组织源性EV对结肠Lgr5+CBCs线粒体代谢或功能的影响尚未见报道。我们的 初步数据表明，来自肥胖脂肪组织的EVS增加了结肠Lgr5+的持久性 依赖于粮农组织的干/祖细胞功能。我们还表明，肥胖脂肪EV诱导的粮农组织 增加β-连环蛋白的转录活性，这对血细胞的干细胞和隐窝至关重要 扩散。来自肥胖小鼠脂肪组织的EVS依赖于粮农组织增加结肠肿瘤样生长。 我们将测试这一假设，即源自脂肪组织的EV刺激远处的CBC干细胞，并且在 肥胖者，倾向于进展为结直肠癌。我们提出了三个具体目标来检验这一假设：目标1。 确定从肥胖脂肪组织中脱落的EVS是否含有改变结肠CBC代谢的货物 功能和上皮内稳态；目标2.确定肥胖脂肪EV驱动CBC的机制 功能改变以增强肿瘤的发生；以及目标3.确定靶向通路的抗肿瘤反应 在结直肠癌中被脂肪电动车改变。我们的长期目标是确定靶向脂肪EV诱导的 结肠中的信号通路是对抗肥胖期间结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.