DIETARY SOYBEAN COMPONENTS AFFECT ON PROSTATE CANCER PRO

这项应用的长期目标是验证大豆生物活性成分抑制前列腺癌（CaP）生长和转移的假设。具体目的是：1)在体内评价大豆成分对雄激素敏感的、产生psa的人CaP细胞株LNCaP和晚期转移的人CaP细胞株PC-3生长和转移的影响；2)确定大豆生物活性成分通过抑制肿瘤血管生成来抑制CaP肿瘤的生长和转移。雄性SCID小鼠在前列腺内接种LNCaP或PC-3细胞，并分配给5种含大豆成分的饲料中的一种：1)AIN-93M作为对照饲料；2) AIN-93与去异黄酮大豆分离蛋白，3)AIN-93与0.7%的大豆植物化学浓缩物，提供800毫克染料木素当量和770毫克大豆黄素当量/kg日粮，4)AIN-93日粮与800毫克糖基化形式的染料木黄素当量，或5)AIN-93日粮与770毫克大豆黄素当量/kg日粮。实验结束时测量原发肿瘤重量，测定前列腺肿瘤生长速率。我们将量化饮食治疗对前列腺内肿瘤生长和转移扩散到淋巴结或肺部的影响。我们将首先量化肿瘤增殖指数和凋亡指数，它们在先前的研究中显示了相对于微血管密度的特定变化模式（因子VIII染色）。我们将确定以大豆为基础的饮食是否会抑制VEGF（一种由雄激素调节并与前列腺癌进展相关的血管生成因子）。我们将确定循环中的IGF-1和雄激素是否被大豆治疗抑制，这两种物质都可能调节肿瘤血管生成和生长。肿瘤金属蛋白酶的表达和活性是肿瘤转移和血管生成的关键调节因子。统计分析将回答以下问题：1)大豆异黄酮是否是抑制前列腺肿瘤生长和转移的主要生物活性成分；2)大豆异黄酮缺失蛋白是否对肿瘤生长和转移有抑制作用；3)其他大豆植物化学物质是否对肿瘤生长和转移有影响；4)大豆生物活性成分是否抑制前列腺肿瘤的生长和/或转移与血管生成相关的生物标志物和/或其他生物标志物的调节有关。提出的研究将为大豆生物活性成分抑制CaP进展的能力提供新的见解。预计拟议项目的结果将转化为未来CaP预防/干预的临床试验。

The long-term objective of this application is to test the hypothesis that soybeans bioactive components inhibit the growth and metastasis of prostate cancer (CaP). The specific aims are: 1) to evaluate the effects of soybean components on the growth and metastasis of an androgen-sensitive and PSA-producing human CaP cell line LNCaP, and an advanced and metastatic human CaP cell line PC-3 in vivo, and 2) To determine that soybean bioactive components inhibit the growth and metastasis of CaP tumors via inhibition of tumor angiogenesis. Male SCID mice will be inoculated intraprostatically with LNCaP or PC-3 cells, and assigned to one of the five soybean components-containing diets: 1) AIN-93M as control diet; 2) AIN-93 with isoflavone-depleted soy protein isolate, 3) AIN-93 with 0.7 percent of soy phytochemical concentrate, providing 800 mg genistein equivalents and 770mg daidzein equivalents/kg diet, 4) AIN-93 diet with 800mg genistein equivalents in the glycosylated form typically found in foods, or 5) AIN-93 diet with 770 mg daidzein equivalents/kg diet. At the end of experiment, primary tumor weight will be measured to determine prostatic tumor growth rate. We will quantitate the effects of dietary treatment on intraprostatic tumor growth and metastatic spread to the lymph nodes or lungs. We will first quantitate tumor proliferation index and apoptotic index which in prior studies show specific patterns of changes relative to microvessel density (factor VIII stainig). We will determine if VEGF, an angiogenic factor regulated by androgens and associated with prostate cancer progression, is inhibited by soy based diets. We will determine if circulating IGF-1 and androgens, both of which may modulate tumor angiogenesis and growth, are inhibited by soy treatments. Expression and activity of tumor metalloproteinases, critical regulators of tumor metastasis and angiogensis will be examined. Statistical analyses will be performed to answer the following questions: 1) if soy isoflavones are the major bioactive components inhibiting the growth and metastasis of prostate tumors; 2) if isoflavone-depleted soy protein has inhibitory effects on tumor growth and metastasis; 3) if other soybean phytochemicals have effects on tumor growth and metastasis; 4) if soybean bioactive components inhibit growth and/or metastasis of prostate tumors associated with regulations of angiogenesis-related biomarkers and/or other biomarkers. The proposed studies will provide new insight concerning the ability of bioactive components of soy to inhibit CaP progression. It is expencted that the results from proposed project will be translated to future clinical trials on CaP prevention/intervention.