The Role of Fat in Tumor Formation

摘要 肥胖是一个全球性的公共卫生问题。据估计，68%的美国成年人 超重或肥胖，导致显著的发病率和死亡率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增强了癌症 发展知之甚少。早期的研究表明，给老鼠喂食高脂肪食物 增强的紫外线B（UVB）诱导的皮肤癌和减少子宫旁脂肪（腹部脂肪周围的 子宫）通过运动或脂肪切除术减弱UVB诱导的皮肤肿瘤形成。这导致我们 建立了一个模型，以评估脂肪在表皮皮肤细胞转化中的作用，通过JB 6 P+细胞测量 (an启动小鼠表皮细胞系）在软琼脂中生长。JB 6 P+模型是一个特征良好的模型， 对肿瘤促进剂如12-O-十四酰基佛波醇-13-乙酸酯的肿瘤转化反应， 自发转化的背景很低。初步数据显示子宫旁脂肪 从喂食高脂肪饮食的小鼠中分离的一种细胞引起JB 6P+细胞的转化。显著降低转化率 用来自喂食低脂肪食物的小鼠的子宫旁脂肪观察到活性。子宫旁脂肪含有大量 具有刺激增殖、抑制凋亡和诱导细胞产生 活性氧（ROS）和活性氮（RNS），这是生物体的标志性特征， 肿瘤促进剂许多具有刺激转化潜力的脂肪因子， 在喂食高脂肪食物的小鼠子宫旁脂肪垫中发现。这些脂肪因子要么不存在， 以较低的丰度存在于喂食低脂饮食的小鼠的子宫旁脂肪垫和其它脂肪库中 （腹股沟、腹膜后、皮下）。我们的论点是，肥胖症中的脂肪本质上不同于脂肪 从正常人的脂肪因子的生产概况。本申请的中心假设是， 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 物种这项研究的目的是：1）进一步表征脂肪刺激的肿瘤模型， 转换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 影响JB 6 P+和HaCaT细胞转化3）确定宫旁脂肪刺激的机制 体外和体内UVB诱导的致癌模型中的转化，以及4）确定人类是否 从肥胖和正常受试者中分离的脂肪组织将刺激细胞转化。内部研究 这项提议将有助于确定脂肪在皮肤肿瘤形成中的作用，确定风险的分子生物标志物， 为今后的机械化工作铺平道路。

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.