The Role of Fat in Tumor Formation

脂肪在肿瘤形成中的作用

基本信息

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
项目类别：
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

项目摘要

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.

抽象的肥胖是一个世界性的公共卫生问题。据估计，68%的美国成年人超重或肥胖，导致显着的发病率和死亡率1。最近的研究表明，肥胖可以影响癌症风险。然而，肥胖引起的分子变化实际上会增强癌症的发展了解甚少。早期研究表明，给小鼠喂食高脂肪饮食增强紫外线 B (UVB) 诱发的皮肤癌以及减少宫旁脂肪（子宫周围的腹部脂肪）子宫）通过运动或脂肪切除术减弱了 UVB 诱导的皮肤肿瘤的形成。这导致我们建立模型以评估脂肪在表皮细胞转化中的作用（通过 JB6 P+ 细胞测量）（一种起始的小鼠表皮细胞系）在软琼脂中生长。 JB6 P+ 型号是一款特性良好的型号，适用于对肿瘤促进剂（如 12-O-十四烷酰佛波醇-13-乙酸酯）的肿瘤转化反应自发转化的背景较低。初步数据表明，宫旁脂肪从喂食高脂肪饮食的小鼠中分离出来的 JB6 P+ 细胞引起了转化。显着降低转化率用低脂食物喂养的小鼠的宫旁脂肪观察到活性。宫旁脂肪含有多种具有刺激增殖、抑制细胞凋亡和诱导细胞产生脂肪因子的潜力活性氧（ROS）和活性氮（RNS），这是肿瘤促进剂。许多具有刺激转化潜力的脂肪因子是在喂食高脂肪饮食的小鼠的宫旁脂肪垫中发现。这些脂肪因子要么不存在，要么低脂饮食小鼠的宫旁脂肪垫和其他脂肪库中含量较低（腹股沟、腹膜后、皮下）。我们认为肥胖中的脂肪与脂肪有本质上的不同来自正常受试者的脂肪因子产生概况。该应用的中心假设是脂肪组织，特别是宫旁脂肪，可以转化起始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。这项研究的目标是 1) 进一步表征脂肪刺激肿瘤模型转化 2) 确定来自脂肪的卡路里数量和喂养高脂肪饮食的持续时间是否会影响JB6 P+和HaCaT细胞转化3）确定宫旁脂肪刺激机制 UVB 诱导的致癌作用的体外和体内模型的转化，以及 4) 确定人类是否从肥胖者和正常受试者中分离的脂肪组织将刺激细胞转化。内的研究该提案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志物以及为以后的机械工作铺平道路。