The Role of Fat in Tumor Formation

脂肪在肿瘤形成中的作用

• 批准号: 8692048
• 负责人: Jamie J Bernard
• 金额: $ 8.86万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692048
• 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; Epidemiologic Studies; Epithelial Cells; Exercise; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Future; Gene Expression; Genome; Goals; Growth; Health; 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; United States; Uterus; Visceral; Western Blotting; Woman; Work; abdominal fat; 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

DESCRIPTION (provided by applicant): 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 understood2-4. 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 formation8,9. 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 intrinsicall 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.

描述（由申请人提供）：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，导致严重的发病率和死亡率1。最近的研究表明，肥胖会影响癌症风险。然而，人们对肥胖引起的实际上促进癌症发展的分子变化知之甚少2-4。早期研究表明，给小鼠喂食高脂肪饮食会增强紫外线 B (UVB) 诱发的皮肤癌，而通过运动或脂肪切除术减少宫旁脂肪（子宫周围的腹部脂肪）则可减弱 UVB 诱发的皮肤肿瘤的形成8,9。这促使我们建立了一个模型来评估脂肪在表皮细胞转化中的作用，通过软琼脂中 JB6 P+ 细胞（一种起始的小鼠表皮细胞系）生长来测量。 JB6 P+ 模型是针对肿瘤促进剂（例如 12-O-十四烷酰佛波醇-13-乙酸酯）的肿瘤转化反应的良好表征模型，并且具有较低的自发转化背景。初步数据表明，从喂食高脂肪饮食的小鼠中分离出的宫旁脂肪引起了 JB6 P+ 细胞的转化。观察到喂食低脂食物的小鼠的宫旁脂肪的转化活性显着降低。宫旁脂肪含有许多具有刺激增殖潜力的脂肪因子， 抑制细胞凋亡并诱导细胞产生活性氧（ROS）和活性氮（RNS），这是肿瘤促进剂的标志特征。在喂食高脂肪饮食的小鼠的宫旁脂肪垫中发现了许多具有刺激转化潜力的脂肪因子。这些脂肪因子在低脂饮食小鼠的宫旁脂肪垫和其他脂肪库（腹股沟、腹膜后、皮下）中要么不存在，要么含量较低。我们的论点是，肥胖者的脂肪在脂肪因子产生方面与正常人的脂肪有着本质上的不同。该应用的中心假设是脂肪组织，特别是宫旁脂肪，可以转化启动的表皮细胞，并通过释放丝氨酸蛋白酶抑制剂E1、TIMP-1和其他刺激活性氧/氮的脂肪因子来刺激癌发生。这项研究的目标是 1) 进一步表征脂肪刺激肿瘤转化的模型 2) 确定脂肪中的卡路里数量和高脂肪饮食的持续时间是否会影响 JB6 P+ 和 HaCaT 细胞转化 3) 确定体外和体内 UVB 诱导致癌模型中宫旁脂肪刺激转化的机制；4) 确定从肥胖和正常受试者中分离的人体脂肪组织是否会刺激细胞转化。该提案中的研究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，并为未来的机械工作铺平道路。

项目成果

Fibroblast growth factor receptor is a mechanistic link between visceral adiposity and cancer.

• DOI: 10.1038/onc.2017.278
• 发表时间: 2017-11-30
• 期刊: Oncogene
• 影响因子: 8
• 作者: Chakraborty D;Benham V;Bullard B;Kearney T;Hsia HC;Gibbon D;Demireva EY;Lunt SY;Bernard JJ
• 通讯作者: Bernard JJ