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

描述（申请人提供）：尽管最近的研究表明，欧米茄-6（n-6）与欧米茄-3之间的比例（n-3）脂肪酸和癌症风险，问题是是否高n-6/n-3比率（>15），如在大多数西方人中发现的，促进肿瘤发生，或者平衡的n-6/n-3脂肪酸比例是否可以减少癌症发展，仍有待于在合格的实验动物模型中阐明。我的实验室最近创造了一种新的转基因小鼠模型，表达C。elegans fat-1基因能够将n-6脂肪酸转化为n-3脂肪酸，这在野生型小鼠中不存在。这些转基因动物的特征在于其组织和器官中丰富的n-3脂肪酸和平衡的n-6/n-3脂肪酸比率（1：1），而野生型小鼠在维持高n-6和缺乏n-3脂肪酸的相同饮食时具有> 30的比率。使用这些转基因动物可以避免饮食的潜在混杂因素，并将为n-3脂肪酸和n-6/n-3比例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转基因小鼠之间B16黑色素瘤的肿瘤形成和生长存在显著差异。这一令人兴奋的观察结果使我们假设，平衡的n-6/n-3脂肪酸比例可能对癌症发展具有保护作用，并且这种抗癌作用是由某些类花生酸或脂质介质介导的癌症相关基因表达的变化引起的。具体目标是：1）确定植入fat-1转基因和野生型小鼠中的B16黑素瘤细胞的致瘤性和转移性; 2）使用微阵列技术表征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;和3）确定类花生酸生物合成的变化是否负责对基因表达和肿瘤生长的影响。包括微阵列和脂质组学在内的几种方法将用于识别所涉及的介质。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.