Refined Fructose Promotes Pancreatic Cancer Growth

描述(由申请人提供)：体重、体力活动和营养改变了许多癌症的癌症风险和致癌过程，越来越多的证据表明，这些健康因素对癌症幸存者的癌症预后和生活质量的影响。在过去几十年里，随着总能源消耗的增加，美国人饮食中所消耗的营养素类型也发生了明显的转变。具体地说，果糖的消费量大幅增加，主要是因为高果糖饮料的消费量增加，以及其他用蔗糖和高果糖玉米糖浆(HFCS)加糖的食品的消费量增加。高碳水化合物摄入被认为是胰腺癌的危险因素，可能是由于游离胰岛素和胰岛素样生长因子-I水平的升高，以及果糖喂养诱导的胰岛素抵抗，主要是由于胰岛素抑制肝脏葡萄糖输出的能力减弱。然而，碳水化合物摄入与胰腺癌之间的关联可能是多因素的，除了胰岛素抵抗，血脂和甘油三酯水平也与胰腺癌风险增加有关。我们假设癌细胞本身可能能够区分并优先利用不同的碳水化合物，在一些癌症中已经描述了葡萄糖转运蛋白水平的改变。这项建议将描述不同碳水化合物影响胰腺癌增殖的潜在机制，重点是葡萄糖摄取和运输因子的作用，如GLUT-5。第二个目的是在胰腺癌动物模型中检测精制碳水化合物给药对肿瘤生长速度的影响。 公共卫生相关声明：胰腺癌是美国第四大死亡原因，尽管治疗有所改善，但5年生存率仅为5%，迫切需要新的策略来帮助早期诊断和治疗。饮食，特别是高精制碳水化合物摄入量在癌症中的重要作用越来越受到重视，我们将研究的精制果糖在胰腺癌中先前未知的增殖作用对胰腺癌患者具有直接的重要性。我们将GLUT-5确定为胰腺癌细胞优先利用果糖的分子机制中的关键，这可能为针对GLUT-5作用于胰腺癌的新的治疗方法铺平道路。

DESCRIPTION (provided by applicant): Weight, physical activity, and nutrition alter cancer risk and carcinogenesis for many cancers, and evidence is accumulating on the effect of these health factors on cancer prognosis and quality of life among cancer survivors. Along with an increase in total energy consumption over the past few decades, a clear shift in the types of nutrients consumed in the American diet has been highlighted. Specifically, the consumption of fructose has increased dramatically, primarily because of increased consumption of beverages that are high in fructose and the consumption of other foods sweetened with sucrose and high-fructose corn syrup (HFCS). High carbohydrate intake has been hypothesized to be a risk factor for pancreatic cancer, possibly mediated by elevated levels of free insulin and insulin-like growth factor-I, and fructose feeding-induces insulin resistance, mainly due to a diminished ability of insulin to suppress hepatic glucose output. However, the association between carbohydrate intake and pancreatic cancer is likely multifactorial, and in addition to insulin resistance, lipids and triglyceride levels have been associated with increased pancreatic cancer risk. We hypothesize that cancer cells themselves may be able to distinguish, and preferentially utilize different carbohydrates, and altered glucose transporter levels have been described in some cancers. This proposal will characterize the potential mechanisms by which different carbohydrates affect pancreatic cancer proliferation, focusing on the role of glucose uptake and transport factors, such as Glut-5. The second aim will examine the effects of refined carbohydrate administration on tumor growth rates in an animal model of pancreatic cancer. Public Health Relevance Statement: Pancreatic cancer is the fourth leading cause of US death, and despite some improvement in therapy, 5-year survival rate is only 5%, and novel strategies to aid early diagnosis and therapy are urgently needed. The important role that diet, and specifically high refined carbohydrate intake, plays in cancer is increasingly appreciated, and the previously unrecognized proliferative effects of refined fructose in pancreatic cancer that we will investigate are of immediate importance to patients with pancreatic cancer. Our identification of GLUT-5 as a key in the molecular mechanism by which pancreatic cancer cells preferentially utilize fructose may pave the way to novel therapeutic approaches targeting GLUT-5 action in pancreatic cancer.