Omega-6/Omega-3 Fatty Acid Ratio and Tumorigenesis

描述(由申请人提供)：尽管最近的研究表明omega-6(n-6)和omega-3(n-3)脂肪酸的比率与癌症风险之间存在联系，但对于大多数西方人中发现的高n-6/n-3比率(&gt；15)是否会促进肿瘤发生，或者平衡的n-6/n-3脂肪酸比率是否可以减少癌症的发展，仍有待在合格的实验动物模型中得到澄清。我的实验室最近创造了一种新型的转基因小鼠模型，它表达了线虫脂肪-1基因，能够将n-6脂肪酸转化为n-3脂肪酸，这在野生型小鼠中是不存在的。这些转基因动物的特点是它们的组织和器官中含有丰富的n-3脂肪酸和平衡的n-6/n-3脂肪酸比例(1：1)，而野生型小鼠在相同的饮食中保持高n-6脂肪酸和缺乏n-3脂肪酸的比例为30。使用这些转基因动物可以避免潜在的饮食混杂因素，并将为n-3脂肪酸和n-6/n-3比率的影响提供更可靠的证据。我们的初步实验表明，野生型和FAT-1转基因小鼠在B16黑色素瘤的形成和生长方面存在显著差异。这一令人兴奋的观察使我们假设，平衡的n-6/n-3脂肪酸比率可能对癌症的发展具有保护作用，并且这种抗癌作用是由某些二十烷基类化合物或脂质介体介导的癌症相关基因表达的变化所诱导的。具体目的是：1)确定B16黑色素瘤细胞移植到FAT-1转基因和野生型小鼠体内的致瘤性和转移；2)利用基因芯片技术研究FAT-1转基因和野生型小鼠中肿瘤细胞和间质组织的基因表达模式；以及3)确定二十烷类化合物生物合成的变化是否与基因表达和肿瘤生长的影响有关。包括微阵列和脂质组学在内的几种方法将被用来鉴定涉及的介体。从这些研究中获得的信息将增加我们对n-3脂肪酸以及n-6/n-3脂肪酸比例在癌症预防中的重要性的理解，并有助于指导饮食建议。

DESCRIPTION (provided by applicant): Although recent research suggests a link between the ratio of omega-6 (n-6) to omega-3 (n-3] fatty acids and cancer risk, the question as to whether a high n-6/n-3 ratio (>15), as found in most Western people, promotes tumorigenesis or if a balanced n-6/n-3 fatty acid ratio can reduce cancer development remains to be clarified in well-qualified experimental animal models. My lab has recently generated a novel transgenic mouse model that expresses the C. elegans fat-1 gene capable of converting n-6 to n-3 fatty acids, which is absent in wild type mice. These transgenic animals are characterized by an abundance of n-3 fatty acids and a balanced n-6/n-3 fatty acid ratio (1:1) in their tissues and organs, whereas wild type mice have a ratio of > 30 when maintained on the same diet high in n-6 and deficient in n-3 fatty acids. Use of these transgenic animals can avoid potential confounding factors of diet and will provide more reliable evidence on the effects of n-3 fatty acids and n-6/n-3 ratio. Our pilot experiments showed a marked difference in tumor formation and growth of B16 melanoma between wild type and fat-1 transgenic mice. This exciting observation led us to hypothesize that a balanced n-6/n-3 fatty acid ratio may have a protective effect against cancer development, and that this anticancer effect is induced by changes in cancer-related gene expression mediated by certain eicosanoids or lipid mediators. Specific aims are: 1) To determine the tumorigenicity and metastasis of B16 melanoma cells implanted in the fat-1 transgenic and wild type mice; 2) To characterize gene expression patterns of the tumor cells and stromal tissues in the fat-1 transgenic and wild type mice using a microarray technology; and 3) To determine if changes in eicosanoid biosynthesis are responsible for the effects on gene expression and tumor growth. Several approaches including microarray and lipidomics will be used to identify the involved mediators. Information derived from these studies will increase our understanding of the importance of n-3 fatty acids as well as n-6/n-3 fatty acid ratio in cancer prevention and help guide dietary advice.