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许多癌症的癌症风险和致癌作用，并且关于这些健康因素对癌症预后和癌症幸存者生活质量的影响的证据正在积累。 沿着过去几十年来总能量消耗的增加，美国人饮食中消耗的营养素类型的明显转变已经凸显出来。 具体来说，果糖的消费量急剧增加，主要是因为果糖含量高的饮料的消费量增加，以及用蔗糖和高果糖玉米糖浆（HFCS）增甜的其他食物的消费量增加。 高碳水化合物摄入被假设为胰腺癌的危险因素，可能由游离胰岛素和胰岛素样生长因子-I水平升高介导，果糖喂养诱导胰岛素抵抗，主要是由于胰岛素抑制肝葡萄糖输出的能力降低。 然而，碳水化合物摄入和胰腺癌之间的关联可能是多因素的，除了胰岛素抵抗，脂质和甘油三酯水平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，并且在某些癌症中已经描述了改变的葡萄糖转运蛋白水平。 该提案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转运因子（如Glut-5）的作用。 第二个目标将检查精制碳水化合物给药对胰腺癌动物模型中肿瘤生长速率的影响。 公共卫生相关性声明：胰腺癌是美国死亡的第四大原因，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的增殖作用对胰腺癌患者具有直接的重要性。 我们将GLUT-5鉴定为胰腺癌细胞优先利用果糖的分子机制的关键，这可能为靶向胰腺癌中GLUT-5作用的新治疗方法铺平道路。

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.