The Role of Fat in Tumor Formation

脂肪在肿瘤形成中的作用

• 批准号: 9026753
• 负责人: Jamie J Bernard
• 金额: $ 24.08万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026753
• 关键词: Actinic keratosis; Adipose tissue; Adult; Agar; American; Apoptosis; Attenuated; Biological Markers; Body mass index; CCL2 gene; Calories; Cancer Etiology; Cancer Patient; Cell Line; Cell model; Cells; Characteristics; Data; Development; Diagnosis; Diet; Environmental Carcinogens; Epidemiologic Studies; Epithelial Cells; Exercise; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Future; Gene Expression; Genome; Goals; Growth; Human; Hysterectomy; In Vitro; Intake; Interleukin-6; Knockout Mice; Leptin; Lipectomy; Malignant Neoplasms; Measures; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplastic Cell Transformation; Nitrogen; Obesity; Overweight; Oxygen; Parametrial; Pathway interactions; Process; Production; Public Health; RNA Sequence Analysis; Reactive Nitrogen Species; Reactive Oxygen Species; Recombinant Proteins; Research; Retroperitoneal Space; Risk; Role; Serpins; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Sunlight; Testing; Tetradecanoylphorbol Acetate; Time; Tissue Inhibitor of Metalloproteinase-1; Tumor Promoters; Tumorigenicity; UVB induced; United States; Uterus; Visceral; Western Blotting; Woman; Work; abdominal fat; abstracting; adipokines; base; cancer risk; carcinogenesis; cell transformation; feeding; human subject; in vivo; in vivo Model; inhibitor/antagonist; keratinocyte; mortality; neutralizing antibody; obesity risk; physical property; response; subcutaneous; tumor; ultraviolet

Abstract Obesity is a world-wide public health concern. It has been estimated that 68% of American adults are overweight or obese, causing significant morbidity and mortality1. Recent research suggests that obesity can influence cancer risk. However, the molecular changes induced by obesity that actually enhance cancer development are poorly understood. Early research demonstrated that feeding a high fat diet to mice enhanced ultraviolet B (UVB)-induced skin cancer and that reducing parametrial fat (abdominal fat around the uterus) by either exercise or lipectomy attenuated UVB-induced skin tumor formation. This led us to establish a model to evaluate the role of fat in epidermal skin cell transformation as measured by JB6 P+ cell (an initiated mouse epidermal cell line) growth in soft agar. The JB6 P+ model is a well-characterized model for a neoplastic transformation response to tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate and has a low background of spontaneous transformation. Preliminary data demonstrated that parametrial fat isolated from mice fed a high fat diet caused transformation of JB6 P+ cells. Significantly lower transforming activity was observed with parametrial fat from mice fed a low fat chow diet. Parametrial fat contains a number of adipokines that have the potential to stimulate proliferation, inhibit apoptosis and induce cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are hallmark characteristics of tumor promoters. A number of these adipokines that have the potential to stimulate transformation were identified in the parametrial fat pads of mice fed a high fat diet. These adipokines were either absent or present in lower abundance in the parametrial fat pads of mice fed a low fat diet and in other fat depots (inguinal, retroperitoneal, subcutaneous). It is our contention that fat in obesity is intrinsically different from fat from normal subjects in its profile of adipokine production. The central hypothesis of this application is that adipose tissue, specifically parametrial fat, can transform initiated epidermal cells and stimulate carcinogenesis through the release of Serpin E1, TIMP-1 and other adipokines that stimulate reactive oxygen/nitrogen species. The goals of this proposed research are to 1) further characterize a model of fat-stimulated neoplastic transformation 2) determine if the number of calories from fat and the duration of feeding a high fat diet will influence JB6 P+ and HaCaT cell transformation 3) determine the mechanisms of parametrial fat-stimulated transformation both in vitro and in an in vivo model of UVB-induced carcinogenesis and 4) determine if human adipose tissue isolated from obese and normal subjects will stimulate cell transformation. The studies within this proposal will help define the role of fat in skin tumor formation, identify molecular biomarkers of risk and pave the way for future mechanistic work.

摘要 肥胖是一个世界性的公共卫生问题。据估计，68%的美国成年人是 超重或肥胖，导致严重的发病率和死亡率1。最近的研究表明，肥胖可能 影响癌症风险。然而，肥胖引起的分子变化实际上会加剧癌症 人们对发展知之甚少。早期研究表明，给小鼠喂食高脂肪食物 增强中波紫外线(UVB)诱导的皮肤癌和减少宫旁脂肪(腹部脂肪周围) 通过运动或脂肪切除来减少UVB诱导的皮肤肿瘤的形成。这让我们找到了 用JB6P+细胞建立评价脂肪在表皮细胞转化中作用的模型 (启动的小鼠表皮细胞系)在软琼脂中生长。JB6 P+模型是一个很好地刻画了 肿瘤转化反应对肿瘤促进剂，如12-O-十四酰佛波醇-13-乙酸酯和 具有较低的自发转化背景。初步数据显示宫旁脂肪 从喂食高脂饲料的小鼠中分离出的JB6P+细胞可引起转化。显著降低转化率 观察了喂食低脂饮食的小鼠子宫旁脂肪的活性。宫旁脂肪含有一个数字 脂肪因子具有刺激增殖、抑制细胞凋亡和诱导细胞产生 活性氧物种(ROS)和活性氮物种(RNS)，这是 肿瘤促进剂。这些有可能刺激转化的脂肪因子中有许多是 在喂食高脂饮食的小鼠子宫旁脂肪垫中发现。这些脂肪因子要么不存在，要么 在喂食低脂饮食的小鼠子宫旁脂肪垫和其他脂肪库中含量较低 (腹股沟、腹膜后、皮下)。我们的论点是肥胖中的脂肪与脂肪本质上是不同的 从正常受试者的脂肪因子产生情况来看。这个应用程序的中心假设是 脂肪组织，特别是子宫旁脂肪，可以转化启动的表皮细胞并刺激癌变。 通过释放Serpin E1、TIMP-1和其他刺激活性氧/氮的脂肪因子 物种。这项拟议研究的目标是：1)进一步描述脂肪刺激的肿瘤模型 转变2)确定来自脂肪的卡路里数量和喂食高脂肪饮食的持续时间是否会 对JB6、P+和HaCaT细胞转化的影响3)宫旁脂肪刺激的机制探讨 在体外和体内的UVB致癌模型中的转化以及4)确定人类是否 从肥胖者和正常人身上分离出的脂肪组织将刺激细胞转化。其中的研究 这项提议将有助于确定脂肪在皮肤肿瘤形成中的作用，识别风险的分子生物标记物和 为今后的机械化工作铺平道路。