DIETARY SOYBEAN COMPONENTS AFFECT ON PROSTATE CANCER PRO

这项应用的长期目标是检验大豆活性成分抑制前列腺癌(CAP)生长和转移的假设。其具体目的是：1)评价大豆成分对雄激素敏感的PSA产生的人CAP细胞系LNCaP和晚期转移的人CAP细胞系PC-3体内生长和转移的影响；2)确定大豆活性成分通过抑制肿瘤血管生成而抑制CAP肿瘤的生长和转移。雄性SCID小鼠将被前列腺接种LNCaP或PC-3细胞，并被分配到五种含大豆成分的日粮中：1)AIN-93M为对照日粮；2)AIN-93为去异黄酮型大豆分离蛋白；3)AIN-93中含有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毫克大豆苷元当量/公斤饲料；4)AIN-93饲料中含有800毫克染料木素当量的糖基化产物；或5)AIN-93饲料中添加770毫克大豆苷元当量/公斤饲料。实验结束后，测量原发肿瘤重量，以确定前列腺癌的生长率。我们将量化饮食治疗对前列腺内肿瘤生长和转移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，这在以前的研究中显示出与微血管密度相关的特定模式的变化(第八因子染色)。我们将确定以大豆为基础的饮食是否抑制了血管生成因子，一种受雄激素调节的血管生成因子，与前列腺癌的进展有关。我们将确定大豆治疗是否抑制循环中的IGF-1和雄激素，这两种激素都可以调节肿瘤血管生成和生长。本课程将检测肿瘤转移和血管生成的关键调节因子--肿瘤金属蛋白酶的表达和活性。本研究将对以下问题进行统计分析：1)大豆异黄酮是否是抑制前列腺癌生长和转移的主要生物活性成分；2)去异黄酮大豆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与血管生成相关生物标志物和/或其他生物标志物的调控有关。拟议的研究将提供关于大豆生物活性成分抑制CAP进展的能力的新见解。预计拟议项目的结果将转化为未来关于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.