DJ-1蛋白对肺癌微环境的调节作用及其与EGCG防癌的关系
|
摘要
目的
肺癌在形成前经历了一系列形态学及分子水平的改变,从正常的支气管肺泡上皮细胞演变成为各种形态学表现的肺癌是一个复杂漫长的多阶段多步骤的癌变过程,支气管上皮细胞增殖／分化的控制失调是其中的根本原因。在致癌剂如苯并芘促进肺部细胞恶化和促进肿瘤成长的过程中,这些对于肺正常细胞如支气管上皮细胞的作用是潜移默化从量变向质变恶性转化进行时的。研究表明酚类等抗氧化剂可以拮抗这一作用。人们致力于寻找良好的化学预防策略及物质,干预致癌物代谢,不使其活化成完成致癌物或者抑制、防止致癌物与细胞DNA结合,抑制癌前病变演变成癌或使其逆转成正常细胞。在本课题组的前期研究中,证实3,4-苯并芘油剂经皮肺内注射构建大鼠肺肿瘤模型是一种简单可靠的肺肿瘤动物模型的构建方法,其中肿瘤的病理组织学类型以非小细胞肺癌为主。我们通过二维凝胶电泳获取未成瘤大鼠3,4-苯并芘注射旁肺组织与成瘤大鼠癌旁肺组织的差异表达蛋白质图谱,从而筛选大鼠肺组织微环境中与3,4-苯并芘诱导大鼠原发肺癌发生相关的蛋白质点。这些蛋白质点是包括DJ-1在内的9个质点,我们认为是与3,4-苯并芘肺内注射后未成瘤大鼠抑制肺癌形成相关的蛋白质点。提示肿瘤微环境中的DJ-1蛋白可以作为化学预防治疗癌症的靶点,化学预防可以在早期对致癌因素进行控制,通过对微环境中多种细胞及细胞因子的干预而影响肿瘤表型。肿瘤微环境靶点众多,从中挑选DJ-1作为分子靶点及寻找其定位细胞是第一步,弄清微环境中蛋白分子水平的变化对肿瘤细胞的影响,从而验证靶点蛋白及定位细胞的作用及与绿茶(酚类)肺癌预防的关系。
方法
实验第一部分,构建3,4-苯并芘油剂经皮肺内注射大鼠肺肿瘤模型,80只7-8周龄雌性SD大鼠,体重180-220g,随机分为2组,A组与B组各40只。A组接受3,4-苯并芘-玉米油肺内注射,B组接受玉米油肺内注射。两组大鼠采用相同普通饲料饲养,以水为饮料。32周处死大鼠,获取成瘤鼠和未成瘤鼠的苯并芘注射旁肺组织,验证肺组织抑制肺癌蛋白点DJ-1表达水平及主要定位细胞。DJ-1靶向siRNA转染人支气管上皮细胞,从mRNA水平和蛋白水平研究转染后DJ-1基因的表达下调的效应,检测转染DJ-1靶向siRNA转染HBE细胞对细胞增殖及凋亡的影响。实验第二部分,建立人支气管上皮细胞和肺腺癌细胞的共培养模型,分成三组,A组为单独肿瘤细胞培养组即空白组,B组为未处理的上皮细胞和肺腺癌细胞共培养组即对照组,C组为转染靶向DJ-1的siRNA后的上皮细胞和肺腺癌细胞共培养组即实验组。研究各组细胞生长增殖曲线及细胞周期凋亡水平及三组的裸鼠移植瘤实验。第三部分,构建3,4-苯并芘油剂经皮肺内注射大鼠肺肿瘤模型,60只7-8周龄雌性SD大鼠,体重180-220g,随机分为2组,A组与B组各30只。均接受3,4-苯并芘-玉米油肺内注射,两组大鼠采用相同普通饲料饲养,A组以1%绿茶为饮料,B组以水为饮料。16周处死大鼠,从mRNA水平和蛋白水平比较两组大鼠苯并芘注射旁肺组织的DJ-1基因表达差异。用绿茶有效成分(EGCG)处理支气管上皮细胞,从mRNA水平和蛋白水平测定上皮细胞中DJ-1基因表达的时间效应和剂量效应关系。
结果
成功构建3,4-苯并芘油剂经皮肺内注射大鼠肺肿瘤模型,免疫组化发现DJ-1主要表达于上皮细胞,且组间表达存在明显差异,未成瘤组肺组织表达水平较成瘤组明显降低。定位苯并芘促进肺癌发生过程中,大鼠肺组织微环境防癌作用的位于支气管上皮细胞的靶点DJ-1蛋白。DJ-1靶向siRNA转染HBE细胞,能有效的从mRNA水平和蛋白水平下调DJ-1基因的表达,在一定转染浓度对HBE细胞的增值及凋亡无明显影响。第二部分细胞实验,C组中肺腺癌细胞的增殖受到增殖抑制,细胞周期阻滞及凋亡水平较前2组增高。各组裸鼠移植瘤实验提示C组与A组的成瘤时间及成瘤体积存在差异,C组肿瘤的平均体积指数小于A组。第三部分,A组苯并芘注射旁肺组织DJ-1基因mRNA水平和蛋白水平较B组明显降低。绿茶有效成分(EGCG)能有效地下调支气管上皮细胞中的DJ-1蛋白的表达水平,并呈一定剂量和时间效应。
结论
苯并芘肺内注射构建大鼠原发肺肿瘤过程中,位于支气管上皮细胞DJ-1蛋白可能是大鼠肺组织微环境抑制肺癌的靶点蛋白之一。下调支气管上皮细胞中的的DJ-1蛋白的表达水平,对共培养的肺腺癌细胞增殖及成瘤性有抑制作用。上皮细胞中这个蛋白水平的改变可能参与抗促癌剂(茶酚类)拮抗促癌剂肺癌预防作用。
OBJECTIVE
Before the formation of lung cancer experienced a series of morphological and molecular changes, Bronchoalveolar lavage from normal epithelial cells turn into various morphological features of lung cancer is a complex and lengthy multi-stage multi-step carcinogenesis,and Bronchial epithelial cell proliferation/differentiation control disorders are among the root causes. In the cancer-causing agents such as benzo (a) pyrene compounds for lung cancer process to promote tumor growth, These normal cells, such as the lung bronchial epithelial cells, From quantitative to qualitative change is imperceptible to the time of malignant transformation. Studies show that the polyphenols and other antioxidants could antagonize the effect. People dedicated to finding prevention strategies and excellent chemical substances, interfere with metabolism of carcinogens, do not make it into a complete carcinogen activation or inhibition、prevention of carcinogen DNA binding and cell, Inhibiting cancer or precancerous lesions evolving into its reversal to normal cells. In the previous studies, study confirmed 3,4-benzo (a) pyrene in oil injection percutaneous pulmonary rat lung tumor model building is a simple and reliable animal model of lung cancer method comfirmed, one type of tumor pathology mainly in non-small cell lung cancer. In our study, By unpaired two-dimensional gel electrophoresis to obtain tumors in rats 3,4-Benzo (a) pyrene injection into the tumor adjacent lung tissue and adjacent lung tissue in rats differentially expressed protein profiles, To screening in lung tissue microenvironment and 3,4-benzo (a) pyrene induced lung cancer associated with primary protein points. These proteins include the DJ-1, including nine particle, We believe that with 3,4-benzo (a) pyrene in lung tumors after injection of immature rats inhibited the formation of lung cancer-related proteins. Tumor microenvironment suggest DJ-1 protein can serve as a target for cancer chemoprevention, Chemoprevention against cancer-causing factors in the early control, micro-environment through a variety of cells and cytokines affect tumor phenotype intervention. Many targets the tumor microenvironment, Selecting the DJ-1 as a molecular target and find its place cells is the first step, Understand the micro-environment, changes in the level of protein molecules on tumor cells, To verify the target protein and localization of cells and with green tea (polyphenols) the relationship between lung cancer prevention.
METHODS AND RESULTS
The study was carried out in three parts.In the first part,80 female SD rats were randomized into two groups(each group has 40 rats).40 rats(group A)were treated with 3,4-benzopyrene-corn oil(2mg 3,4-benzopyrene,dissolved in 0.2mL corn oil);meanwhile 40 rats(group B)were treated with corn oil only.The injection were given in every 2 weeks for 8 weeks through left middle-chest percutaneous puncture.All rats received deionized water as their sole source of drinking fluid.After 32 weeks following the first injection,the rats were killed.In group A,the rats those developed lung tumors were separated into group C and the others were separated into group D.Portions of tumor-adjacent lung tissues(group C)and 3,4-benzopyrene injection-adjacent lung tissues(group D) which might be associated with the carcinogenesis process of lung cancer. Verified by immunohistochemistry in lung tissue of lung cancer proteins inhibit the expression levels of DJ-1 and the main place cells. DJ-1 targeted siRNA transfection of human bronchial epithelial cells, from the mRNA level and protein level of DJ-1 after transfection reduced the effect of gene expression, detected by the DJ-1 HBE cells transfected with targeted siRNA on cell proliferation and apoptosis. In the second part, the establishment of human bronchial epithelial cells and lung adenocarcinoma cells were co-cultured model. Divided into three groups, group A of tumor cell culture as a separate group or the control group, group B untreated epithelial cells and lung adenocarcinoma cells were cultured group that controls, group C transfected with the siRNA targeting DJ-1 and lung epithelial cells after co-culture group of cancer cells that the experimental group. Proliferation of cell growth curve of each group and the level of cell cycle and apoptosis in three groups of nude mice experiments. In the third part, construction of 3,4-benzo (a) pyrene in oil percutaneous injection of rat lung tumor model of lung,60 female SD rats were randomized into two groups(each group has 30 rats),one for green tea(group A),and the other for control(group B).All rats were treated with 3,4-benzopyrene-corn oil(as described in Experment 1).16 weeks, rats were killed and protein from the mRNA levels were compared in rats of benzo (a) pyrene injected next to the lung tissue of DJ-1 gene expression differences. With the active ingredients of green tea (EGCG) treatment of bronchial epithelial cells, mRNA and protein levels from the determination of epithelial cells in DJ-1 gene expression in time and dose-response relationship. Successfully constructed and 3,4-benzo (a) pyrene in oil percutaneous injection of rat lung tumor model of lung, immunohistochemistry showed that DJ-1 was mainly expressed in bronchial epithelial cells, and the expression of significant differences between groups, immature lung tumor tissue levels of tumor was significantly lower than that. Location benzo (a) pyrene in the process of promoting lung cancer, lung tissue micro-environment in the anti-cancer effect of bronchial epithelial cells in DJ-1 protein target. DJ-1 HBE cells transfected with siRNA targeting, effective from the mRNA level and reduced levels of DJ-1 protein expression, a certain concentration of HBE cells transfected with the value-added and no significant effect on apoptosis. The second part of the cell experiments, group C, lung cancer cell proliferation was inhibited, the level of cell cycle arrest and apoptosis increased over the previous 2 groups. Nude mice in each group experiment indicated, group C and group A of tumor formation time and tumor volume differences, group C, the average tumor size of less than group A of indices. In the third part, group A of benzo (a) pyrene injected next to the lung tissue levels of DJ-1 gene mRNA and protein levels were significantly lower than group B. Active ingredients of green tea (EGCG) effectively reduced bronchial epithelial cells the expression of DJ-1 protein levels, and a dose and time effect.
CONCLUSION
Benzo (a) pyrene in rat lungs injected construct during the primary lung tumor, DJ-1 protein in the bronchial epithelial cells may be inhibited in lung tissue micro-environment of the target protein of lung cancer. Reduced bronchial epithelial cells of the DJ-1 protein expression, On the co-cultured lung cancer cell proliferation and tumorigenesis was inhibited. Epithelial cells, the protein level may be involved in anti-tumor promotion agents (tea polyphenols) against cancer-promoting agent of lung cancer prevention.
肺癌在形成前经历了一系列形态学及分子水平的改变,从正常的支气管肺泡上皮细胞演变成为各种形态学表现的肺癌是一个复杂漫长的多阶段多步骤的癌变过程,支气管上皮细胞增殖／分化的控制失调是其中的根本原因。在致癌剂如苯并芘促进肺部细胞恶化和促进肿瘤成长的过程中,这些对于肺正常细胞如支气管上皮细胞的作用是潜移默化从量变向质变恶性转化进行时的。研究表明酚类等抗氧化剂可以拮抗这一作用。人们致力于寻找良好的化学预防策略及物质,干预致癌物代谢,不使其活化成完成致癌物或者抑制、防止致癌物与细胞DNA结合,抑制癌前病变演变成癌或使其逆转成正常细胞。在本课题组的前期研究中,证实3,4-苯并芘油剂经皮肺内注射构建大鼠肺肿瘤模型是一种简单可靠的肺肿瘤动物模型的构建方法,其中肿瘤的病理组织学类型以非小细胞肺癌为主。我们通过二维凝胶电泳获取未成瘤大鼠3,4-苯并芘注射旁肺组织与成瘤大鼠癌旁肺组织的差异表达蛋白质图谱,从而筛选大鼠肺组织微环境中与3,4-苯并芘诱导大鼠原发肺癌发生相关的蛋白质点。这些蛋白质点是包括DJ-1在内的9个质点,我们认为是与3,4-苯并芘肺内注射后未成瘤大鼠抑制肺癌形成相关的蛋白质点。提示肿瘤微环境中的DJ-1蛋白可以作为化学预防治疗癌症的靶点,化学预防可以在早期对致癌因素进行控制,通过对微环境中多种细胞及细胞因子的干预而影响肿瘤表型。肿瘤微环境靶点众多,从中挑选DJ-1作为分子靶点及寻找其定位细胞是第一步,弄清微环境中蛋白分子水平的变化对肿瘤细胞的影响,从而验证靶点蛋白及定位细胞的作用及与绿茶(酚类)肺癌预防的关系。
方法
实验第一部分,构建3,4-苯并芘油剂经皮肺内注射大鼠肺肿瘤模型,80只7-8周龄雌性SD大鼠,体重180-220g,随机分为2组,A组与B组各40只。A组接受3,4-苯并芘-玉米油肺内注射,B组接受玉米油肺内注射。两组大鼠采用相同普通饲料饲养,以水为饮料。32周处死大鼠,获取成瘤鼠和未成瘤鼠的苯并芘注射旁肺组织,验证肺组织抑制肺癌蛋白点DJ-1表达水平及主要定位细胞。DJ-1靶向siRNA转染人支气管上皮细胞,从mRNA水平和蛋白水平研究转染后DJ-1基因的表达下调的效应,检测转染DJ-1靶向siRNA转染HBE细胞对细胞增殖及凋亡的影响。实验第二部分,建立人支气管上皮细胞和肺腺癌细胞的共培养模型,分成三组,A组为单独肿瘤细胞培养组即空白组,B组为未处理的上皮细胞和肺腺癌细胞共培养组即对照组,C组为转染靶向DJ-1的siRNA后的上皮细胞和肺腺癌细胞共培养组即实验组。研究各组细胞生长增殖曲线及细胞周期凋亡水平及三组的裸鼠移植瘤实验。第三部分,构建3,4-苯并芘油剂经皮肺内注射大鼠肺肿瘤模型,60只7-8周龄雌性SD大鼠,体重180-220g,随机分为2组,A组与B组各30只。均接受3,4-苯并芘-玉米油肺内注射,两组大鼠采用相同普通饲料饲养,A组以1%绿茶为饮料,B组以水为饮料。16周处死大鼠,从mRNA水平和蛋白水平比较两组大鼠苯并芘注射旁肺组织的DJ-1基因表达差异。用绿茶有效成分(EGCG)处理支气管上皮细胞,从mRNA水平和蛋白水平测定上皮细胞中DJ-1基因表达的时间效应和剂量效应关系。
结果
成功构建3,4-苯并芘油剂经皮肺内注射大鼠肺肿瘤模型,免疫组化发现DJ-1主要表达于上皮细胞,且组间表达存在明显差异,未成瘤组肺组织表达水平较成瘤组明显降低。定位苯并芘促进肺癌发生过程中,大鼠肺组织微环境防癌作用的位于支气管上皮细胞的靶点DJ-1蛋白。DJ-1靶向siRNA转染HBE细胞,能有效的从mRNA水平和蛋白水平下调DJ-1基因的表达,在一定转染浓度对HBE细胞的增值及凋亡无明显影响。第二部分细胞实验,C组中肺腺癌细胞的增殖受到增殖抑制,细胞周期阻滞及凋亡水平较前2组增高。各组裸鼠移植瘤实验提示C组与A组的成瘤时间及成瘤体积存在差异,C组肿瘤的平均体积指数小于A组。第三部分,A组苯并芘注射旁肺组织DJ-1基因mRNA水平和蛋白水平较B组明显降低。绿茶有效成分(EGCG)能有效地下调支气管上皮细胞中的DJ-1蛋白的表达水平,并呈一定剂量和时间效应。
结论
苯并芘肺内注射构建大鼠原发肺肿瘤过程中,位于支气管上皮细胞DJ-1蛋白可能是大鼠肺组织微环境抑制肺癌的靶点蛋白之一。下调支气管上皮细胞中的的DJ-1蛋白的表达水平,对共培养的肺腺癌细胞增殖及成瘤性有抑制作用。上皮细胞中这个蛋白水平的改变可能参与抗促癌剂(茶酚类)拮抗促癌剂肺癌预防作用。
OBJECTIVE
Before the formation of lung cancer experienced a series of morphological and molecular changes, Bronchoalveolar lavage from normal epithelial cells turn into various morphological features of lung cancer is a complex and lengthy multi-stage multi-step carcinogenesis,and Bronchial epithelial cell proliferation/differentiation control disorders are among the root causes. In the cancer-causing agents such as benzo (a) pyrene compounds for lung cancer process to promote tumor growth, These normal cells, such as the lung bronchial epithelial cells, From quantitative to qualitative change is imperceptible to the time of malignant transformation. Studies show that the polyphenols and other antioxidants could antagonize the effect. People dedicated to finding prevention strategies and excellent chemical substances, interfere with metabolism of carcinogens, do not make it into a complete carcinogen activation or inhibition、prevention of carcinogen DNA binding and cell, Inhibiting cancer or precancerous lesions evolving into its reversal to normal cells. In the previous studies, study confirmed 3,4-benzo (a) pyrene in oil injection percutaneous pulmonary rat lung tumor model building is a simple and reliable animal model of lung cancer method comfirmed, one type of tumor pathology mainly in non-small cell lung cancer. In our study, By unpaired two-dimensional gel electrophoresis to obtain tumors in rats 3,4-Benzo (a) pyrene injection into the tumor adjacent lung tissue and adjacent lung tissue in rats differentially expressed protein profiles, To screening in lung tissue microenvironment and 3,4-benzo (a) pyrene induced lung cancer associated with primary protein points. These proteins include the DJ-1, including nine particle, We believe that with 3,4-benzo (a) pyrene in lung tumors after injection of immature rats inhibited the formation of lung cancer-related proteins. Tumor microenvironment suggest DJ-1 protein can serve as a target for cancer chemoprevention, Chemoprevention against cancer-causing factors in the early control, micro-environment through a variety of cells and cytokines affect tumor phenotype intervention. Many targets the tumor microenvironment, Selecting the DJ-1 as a molecular target and find its place cells is the first step, Understand the micro-environment, changes in the level of protein molecules on tumor cells, To verify the target protein and localization of cells and with green tea (polyphenols) the relationship between lung cancer prevention.
METHODS AND RESULTS
The study was carried out in three parts.In the first part,80 female SD rats were randomized into two groups(each group has 40 rats).40 rats(group A)were treated with 3,4-benzopyrene-corn oil(2mg 3,4-benzopyrene,dissolved in 0.2mL corn oil);meanwhile 40 rats(group B)were treated with corn oil only.The injection were given in every 2 weeks for 8 weeks through left middle-chest percutaneous puncture.All rats received deionized water as their sole source of drinking fluid.After 32 weeks following the first injection,the rats were killed.In group A,the rats those developed lung tumors were separated into group C and the others were separated into group D.Portions of tumor-adjacent lung tissues(group C)and 3,4-benzopyrene injection-adjacent lung tissues(group D) which might be associated with the carcinogenesis process of lung cancer. Verified by immunohistochemistry in lung tissue of lung cancer proteins inhibit the expression levels of DJ-1 and the main place cells. DJ-1 targeted siRNA transfection of human bronchial epithelial cells, from the mRNA level and protein level of DJ-1 after transfection reduced the effect of gene expression, detected by the DJ-1 HBE cells transfected with targeted siRNA on cell proliferation and apoptosis. In the second part, the establishment of human bronchial epithelial cells and lung adenocarcinoma cells were co-cultured model. Divided into three groups, group A of tumor cell culture as a separate group or the control group, group B untreated epithelial cells and lung adenocarcinoma cells were cultured group that controls, group C transfected with the siRNA targeting DJ-1 and lung epithelial cells after co-culture group of cancer cells that the experimental group. Proliferation of cell growth curve of each group and the level of cell cycle and apoptosis in three groups of nude mice experiments. In the third part, construction of 3,4-benzo (a) pyrene in oil percutaneous injection of rat lung tumor model of lung,60 female SD rats were randomized into two groups(each group has 30 rats),one for green tea(group A),and the other for control(group B).All rats were treated with 3,4-benzopyrene-corn oil(as described in Experment 1).16 weeks, rats were killed and protein from the mRNA levels were compared in rats of benzo (a) pyrene injected next to the lung tissue of DJ-1 gene expression differences. With the active ingredients of green tea (EGCG) treatment of bronchial epithelial cells, mRNA and protein levels from the determination of epithelial cells in DJ-1 gene expression in time and dose-response relationship. Successfully constructed and 3,4-benzo (a) pyrene in oil percutaneous injection of rat lung tumor model of lung, immunohistochemistry showed that DJ-1 was mainly expressed in bronchial epithelial cells, and the expression of significant differences between groups, immature lung tumor tissue levels of tumor was significantly lower than that. Location benzo (a) pyrene in the process of promoting lung cancer, lung tissue micro-environment in the anti-cancer effect of bronchial epithelial cells in DJ-1 protein target. DJ-1 HBE cells transfected with siRNA targeting, effective from the mRNA level and reduced levels of DJ-1 protein expression, a certain concentration of HBE cells transfected with the value-added and no significant effect on apoptosis. The second part of the cell experiments, group C, lung cancer cell proliferation was inhibited, the level of cell cycle arrest and apoptosis increased over the previous 2 groups. Nude mice in each group experiment indicated, group C and group A of tumor formation time and tumor volume differences, group C, the average tumor size of less than group A of indices. In the third part, group A of benzo (a) pyrene injected next to the lung tissue levels of DJ-1 gene mRNA and protein levels were significantly lower than group B. Active ingredients of green tea (EGCG) effectively reduced bronchial epithelial cells the expression of DJ-1 protein levels, and a dose and time effect.
CONCLUSION
Benzo (a) pyrene in rat lungs injected construct during the primary lung tumor, DJ-1 protein in the bronchial epithelial cells may be inhibited in lung tissue micro-environment of the target protein of lung cancer. Reduced bronchial epithelial cells of the DJ-1 protein expression, On the co-cultured lung cancer cell proliferation and tumorigenesis was inhibited. Epithelial cells, the protein level may be involved in anti-tumor promotion agents (tea polyphenols) against cancer-promoting agent of lung cancer prevention.
引文
[1]Sung SY,Hsieh CL,Wu D,et al.Tumor microenvironment promotes cancer progression,metastasis,and therapeutic resistance.Curr Probl Cancer,2007;31(2) 36-100.
[2]Joyce JA.Therapeutic targeting of the tumor microenvironment.Cancer Cell,20057:513-520.
[3]Albini A,Sporn MB.The tumor microenvironment as a target for chemoprevention.Nat Rev Cancer,2007;7:139-147.
[4]Bonfil R,Chinni S,Fridman R,et al.Proteases,growth factors,chemokines,and the microenvironment in prostate cancer bone metastasis[J].Urol Oncol,2007,25(5):407-411.
[5]Wita IP.Tumor-microenvironment interactions:the selectinselectin ligand axis in tumor-endothelium cross talk [J].Cancer Treat Res,2006,130(25):125-140.
[6]Fidler IJ.Seed and soil revisited:contribution of the organ microenvironment to cancer metastsis[J].Surg Oncol Clin N Am,2001,10(2):257-269.
[7]Scott AM,Wiseman G,Welt S,et al.A Phase I dose-es-calation study of sibrotuzumab in patients with advanced or metastatic fivroblast activation protein-positive cancer [J].Clin Cancer Res,2003,9(5):1639-1647.
[8]Gu Q, Hu C, Chen Q, et al. Development of a rat model by 3,4-benzopyrene intra-pulmonary injection and evaluation of the effect of green tea drinking on p53 and bcl-2 expression in lung carcinoma. Cancer Detect Prev. 2009;32(5-6):444-51
[9]Chengping HU,Min Li,Qihua Gu,et al.Proteomics-based identification of 9 proteins in tumor microenvironment as targets for lung cancer prevention by green tea.Respirology,2008; 13(S5):103
[10]Kelloff GJ,Crowell JA,Stelle VE,Lubet RA,Malone WA,Boone CW,Kopelovich L,Hawk ET,Lieberman R,Lawrence JA,Ali I,Viner JL,Sigman CC.Progerss in cancer chemoprevention:developmeng of diet-derived chemopreventive agents.J Nutr,2000;130(2S Suppl):467S-471S.
[11]Clark J,You M.Chemoprevention of lung cancer by tea.Mol Nurt Food Res,2006;50(2):144-51.
[12]Chung FL,Schwartz J,Herzog CR,Herzog,Yang YM.Tea and cancer pervention:studies in animal and humans.J Nutr,2003;133(10):3268S-3274S.
[13]Suganuma M,Okabe S,Sueoka N,Sueoka E,Matsuyama S,Imsi K,Nakachi K,Fujiki H.Green tea and cancer chemoprevention.Mutat Res,1999 428(1-2):339-44.
[14]Yang CS,Liao J,Yang GY,Lu G.Inhibitiong of lung tumorigenesis by tea.Exp Lung Res,2005;31(1):135-44.
[15]Fujiki H.Green tea:Health benefits as cancer preventive for humans.Chem Rec,2005;5(3):119-32.
[16]Suganuma M,Okabe S,Sueoka N,Sueoka E,Matsuyama S,Imsi K,Nakachi K,Fujiki H.Green tea and cancer chemoprevention.Mutat Res,1999 428(1-2):339-44.
[17]Okabe S,Fujimoto N,Sueoka N,Suganuma M,Fujiki H.Modulation of gene expression by (-)-epigallocatechin gallate in PC-9 cells using a cDNA experssion array.Biol PharmBull.2001;24(8):883-6.
[18]Suganuma M,Okabe S,Kai Y,Sueoka N,Sueoka E,Fujiki H.Synergistic effects of (--)-epigallocatechin gallate with (--)-epicatechin,sulindac,or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9.Cancer Res.1999;59(1):44-7.
[19]Nagakubo D,Taira T,Kitaura H,et al.DJ-l,a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras [J].Biochem Biophys Res,1997,231(2):509-513.
[20]Bonifati V,Rizzu P,Van Baren M J.et al.Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism [J].Science,2003,299(5604) 256-259.
[21]Le Naour F,Misek DE,Krause MC,et al. Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer. Clin Cancer Res. 2001 Nov;7(11):3328-35.
[22]Pardo M,Garcia A,Thomas B, et al.The characterization of the invasion phenotype of uveal melanoma tumor cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker,Int J Cancer,2006,119:1014-1022
[23]Clements CM,McNally RS,Conti BJ,et al.DJ-l,a cancer-and Parkindon's disease-associated protein,stabilizes the antioxidant transcriptional master regulator Nrf2.Proc Natl Acad Sci US A,2006,103:15091-15096.
[24]Taira T,Saito Y,Niki T,et al.DJ-1 has a role in antioxidative stress to prevent cell death.EMBO Rep,2004,5:213-218.
[25]Junn E,Taniguchi H,Jeong BS,et al.Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.Proc Natl Acad Sci USA,2005,102:9691-9696.
[26]Kim RH,Peter M,Jang Y,et al.DJ-1, a novel regulator of the tumor suppressor PTEN.Cancer Cell,2005,7:263-273.
[27]Pin-Pin Lin,Ming-Hui Yang,Pao-Chi Liao,et al.Proteomic analysis of proteins associated with t,t-DDE induced toxicity in BEAS-2B cells.Biochemical and Biophysical Research Communications.376(2008) 519-524.
[28][28]Wang Y.Public health goal for benzo(a)pyrene in drinking water.California,OEHHA.1997,12:5-8.
[29]蒋义国,陈家堃,陈学敏苯并(a)芘代谢物反式二羟环氧苯并芘诱发人支气管上皮细胞恶性转化卫生研究2001,30(3)：129-130
[30]World Cancer Research Fund/American Institute for Cancer Research.Food,Nutrition,Physical Activity,and the Prevention of Cancer:a Global Perspective.Washington,DC:AICR,2007.
[31]肿瘤化学预防及药物治疗韩锐主编北京医科大学中国协和医科大学联合出版社出版.1991.1253-61.
[32]Hishii M,Kurnick JT,Ramirez-Montagut T,et al.Studies of the mechanism of cytolysis by tumor-infiltrating lymphocytes.Clin Exp Immunol,1999;116 388-394.
[33]Rosenberg SA,Spiess P,Lafrenier R.A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating Lymphocytes.Science,1986 233:131.
[34]Elzaouk L,Moelling K,Pavlovic J.Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma model.Exp Dermatol,2006; 15(11) 865-874.
[35]Chaudhry UI,Kingham TP,Plitas G.Combined stimulation with interleukin-18 and CpG induces murine natural killer dendritic cells to produce IFN-gamma and inhibit tumor growth.Cancer Res,2006;66(21):10497-10504.
[36]龚选举,阎玉虎,吴建平。肺癌组织中肿瘤浸润树突状细胞对预后的影响.中华肿瘤杂志,2000；22(2)：135-137.
[37]杨新静,黄建安,雷伟等共培养的树突细胞和CIK细胞对肺癌的体内外抑制作用癌症,2006；25(11)：1329-1333.
[38]Hede K.Environmental protection:studies highlight importance of tumor microenvironment [J]. J Natl Cancer Inst,2004,96(15):1120-1121.
[39]Brown JM. Tumor microenvironment and the response to anticancer therapy[J]. Cancer Biol Ther,2002, 1(5):453-458.
[40]Mohla S. Tumor microenvironment [J]. J Cell Biochem,2007,101(4):801-804.
[41]Sung SY, Chung LW. Prostate tumor-stroma interaction:molecular mechanisms and opportunities for therapeutic targeting [J]. Differentiation,2002, 70(9-10):506-521.
[42]Gupta GP, Massague J. Cancer metastasis:building a framework [J]. Cell, 2006,127(4):679-695.
[43]Coussens LM, Werb Z. Inflammation and cancer [J]. Nature,2002, 420(6917):860-867.
[44]De Wever, Mareel M. Role of tissue stroma in cancer cell invasion [J].J Pathol, 2003,200(4):429-447.
[45]Manabe Y, Toda S, Miyazaki K, et al. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions [J]. J Pathol,2003,201 (2):221-228.
[46]Kalluri R, Zeisberg M. Fibroblasts in cancer [J]. Nat Rev Cancer,2006, 6(5):392-401.
[47]Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation [J]. Exp Cell Res,2001,264(1):169-184.
[48]Gruber G, Greiner RH, Hlushchuk R, et al. Hypoxia-inducible factor 1 alpha in high-risk breast cancer:an independent prognostic parameter? [J]. Breast Cancer Res,2004,6(3):R191-198.
[49]Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha in normal human tissues, cancers, and tumor-associated macrophages [J]. Am J Pathol,2000, 157(2):411-421.
[50]Kitano H. Cancer as a robust system:implications for anticancer therapy [J]. Nat Rev Cancer,2004,4(3):227-235.
[51]Kell BD, Hackett SF, Hirota K, et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active aorm of aypoxia-inducible aactor 1 [J].Circ Res,2003,11 (93):1074-1081.
[52]Melillo G, Semenza GL. Meeting report:exploiting the tumor microenv ironment for therapeutics[J]. Cancer Res,2006,66(9):4558-4560.
[53]Postovit L M,Margaryan N V,Seftor E A,Kirschmann D A,Lipavsky A,Wheaton W W,et al.Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype f aggressive cancer cells[J].Proc Natl Acad Sci USA.2008.105:4329-4334.
[54]Sneddon J B,Zhen H H,Montgomery K,van de Rijn M,Tward A D,West R,et al.Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation[J].Proc Natl Acad Sci USA.2006.103:14842-14847.
[55]Illmensee K,Mintz B,Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts[J].Proc Natl Acad Sci.USA.1976,73:549-553.
[56]Cucina A,Biava P M,D'Anselmi F,Coluccia P,Conti F,di Clemente R,et al.Zebrafish embryo proteins induce apoptosis in human colon cancer cell(Caco2)[J].Apoptosis.2006.11:1615-1628.
[57]Lee L M,Seftor E A,Bonde G,Cornell R A,Hendrix M J.The fate of human malignant melanoma cells transplanted into zebrafish embryos:Assessment of migration and cell division in the absence of tumor formation[J].Dev Dyn.2005.233:1560-1570.
[58]LaBarge MA, Petersen OW, Bissell MJ. Of microenvironments and mammary stem cells[J]. Stem Cell Rev,2007,3(2):137-146.
[59]Kuperwasser C,Chavarria T,Wu M, et al.Reconstruction of functionally normal and malignant human breast tissues in mice [J].Proc Natl Acad Sci U S A, 2004,101(14):4723-4724.
[60]WH Zhu,Nicosia RF. The thin prep rat aortic ring assay:A modified method for the characterization of angiogenesis in whole mounts [J].Angio-genesis 2002,5(1/2)81-86.
[61]Donovan D, Brown NJ, Bishop ET, et al. Comparison of three in vitro human' angiogenesis'assays with capillaries formed in vivo[J]. Angiogenesis,2001,4(2) 113-121.
[62]Hu M, Yao, J, Carroll DK, Weremowicz S, Chen H, Carrassco DE, Richardson AL, Violette S, Nikolskaya T, Nikolsky Y, Bauerlein EL, William C. Hahn WC, Gelman RS, Allred C, Bissell MJ, Schnitt SJ, Polyak K. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 2008; 13:394-406
[63]Khan N, Adhami VM, Mukhtar H. Green tea polyphenols in chemoprevention of prostate cancer:preclinical and clinical studies. Nutr Cancer. 2009;61(6):836-41.
[64]Johnson JJ, Bailey HH, Mukhtar H. Green tea polyphenols for prostate cancer chemoprevention:a translational perspective. Phytomedicine.2010;17(1):3-13.
[65]Adachi S, Shimizu M, Shirakami Y,et al. (-)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAPK in colon cancer cells. Carcinogenesis.2009;30(9):1544-52.
[66]Fu H, He J, Mei F,et al. Lung cancer inhibitory effect of epigallocatechin-3-gallate is dependent on its presence in a complex mixture (polyphenon E). Cancer Prev Res (Phila Pa).2009;2(6):531-7.
[67]Tachibana H. Molecular basis for cancer chemoprevention by green tea polyphenol EGCG.Forum Nutr.2009;61:156-69..
[68]Nanqun Zhu,Tzou-Chi Huang,Younong Yu,et al.Indentification of oxidation produnts of (-)-Epigallocatechin gallate and (-)-Epigallocatechin with H2O2 J.J
A gtic Food,2000,48:979-981
[69]Yang B,Kotani A,Arai K,et al.Relationship of electrochemical oxidant of catechinson their antioxidant activity in microsomal lipid peroxidation J.Chem Pharm Bull (Tokyo),2001,49(6):747-751
[70]Osada K,Takahashi M,Hoshina S,et al.Tea catechins inhibit cholesterol oxidation accompanying oxidation of low density lipoprotein in vitro J.Com p Biochem Physiol C Toxicol Pharmacol,2001,128(2):153-164.
[71]吴志鸿,王冕蓉,阎启昌等彗星法分析紫外线诱导的人晶状体上皮细胞DNA的损伤及抗氧化剂对DNA损伤的拮抗作用中华眼科杂志2006；42(11)：1002-7
[72]Jang S, Jeong HS, Park JS,et al. Neuroprotective effects of (-)-epigallocatechin-3-gallate against quinolinic acid-induced excitotoxicity via PI3K pathway and NO inhibition. Brain Res.2010(8);1313:25-33.
[73]Zhang ZM, Yang XY, Yuan JH,et al. Modulation of NRF2 and UGT1A expression by epigallocatechin-3-gallate in colon cancer cells and BALB/c mice. Chin Med J (Engl).2009;122(14):1660-5
[74]Hauber I, Hohenberg H, Holstermann B,et al. The main green tea polyphenol epigallocatechin-3-gallate counteracts semen-mediated enhancement of HIV infection. Proc Natl Acad Sci U S A.2009106(22):9033-8.
[75]Patra SK, Rizzi F, Silva A,et al. Molecular targets of (-)-epigallocatechin-3-gallate (EGCG):specificity and interaction with membrane lipid rafts. J Physiol Pharmacol.2008 59 Suppl 9:217-35
[76]Heo J, Lee BR, Koh JW. Protective effects of epigallocatechin gallate after UV irradiation of cultured human lens epithelial cells. Korean J Ophthalmol. 2008;22(3):183-6.
[77]Shim JH, Choi HS, Pugliese A,et al. (-)-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. J Biol Chem.2008;283(42):28370-9.
[78]Morse MA, Kresty LA, Steele VE,et al. Effects of theaflavins on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis. Nutr Cancer. 1997;29(1):7-12.
[79]Li ZG, Shimada Y, Sato F,et al. Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Int J Oncol.2002;21(6):1275-83.
[80]Li ZG, Shimada Y, Sato F,et al. Promotion effects of hot water on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Oncol Rep.2003;10(2):421-6.
[81]Chiang WC, Wong YK, Lin SC,et al. Increase of MMP-13 expression in multi-stage oral carcinogenesis and epigallocatechin-3-gallate suppress MMP-13 expression. Oral Dis.2006;12(1):27-33.
[82]Lambert JD, Sang S, Hong J,et al. Peracetylation as a means of enhancing in vitro bioactivity and bioavailability of epigallocatechin-3-gallate. Drug Metab Dispos.2006;34(12):2111-6.
[83]Hou Z, Sang S, You H, Lee MJ,et al. Mechanism of action of (-)-epigallocatechin-3-gallate:auto-oxidation-dependent inactivation of epidermal growth factor receptor and direct effects on growth inhibition in human esophageal cancer KYSE 150 cells. Cancer Res.2005 Sep 1;65(17):8049-56.
[84]Muto S,Fujita K,Yamazaki Y,et al.Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450J.Mutat Res,2001,479(1-2):197-206.
[85]Hong J,Smith TJ,Ho CT,et al.Effects of purified green and black tea pollyphenols on cyclooxygenase and lipoxugenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues J.Biochem Pharmacol,2001,62(9):1175-1183.
[86]Mataunaga K,Klein TW,Friedman H,et al.Legionella pneumophila replication in macrophages inhibited by selective immumodulatory effects on cytokine formation by epigallocatechin gallate,a major form of tea catechins J.Infect Immun,2001,69(6):3947-3953.
[87]Katiyar SK,Mukhtar H,Green tea polyphenol (-)-epigallocatechin-3-gallate treatment to mouse skin prevents UVB-induced infiltration of leukocytes,depletion of antigen-presenting cells,and oxidative stress J.J Leukoc Biol,2001,69(5):719-726.
[88]Cutter H, Wu LY, Kim C,et al. Is the cancer protective effect correlated with growth inhibitions by green tea (-)-epigallocatechin gallate mediated through an antioxidant mechanism? Cancer Lett.200126;162(2):149-54.
[89]Morre DJ, Morre DM, Sun H,et al. Tea catechin synergies in inhibition of cancer cell proliferation and of a cancer specific cell surface oxidase (ECTO-NOX). Pharmacol Toxicol.2003;92(5):234-41.
[90]Chueh PJ, Wu LY, Morre DM,et al. tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate. Biofactors.2004;20(4):235-49.
[91]梁钢,黄仁彬,黄志明等,表没食子儿茶素没食子酸酯抗肿瘤作用的研究广西医科大学学报,2000,17(2)：176
[92]Yang GY,Liao Y,Kim K,et al.Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols.Carcino genesis,1998,19(4):611-616.
[93]Krul C,Luiten-Schuite A,Tenfelde A,et al.Antimutagenic activity of green tea and black tea extracts studied in dynamic in vitro gastro intestinal model.Mutat Res,2001,474(1-2):71-85.
[94]梁钢,符麟军表没食子儿茶素没食子酸酯抗突变的实验研究广西预防医学,2000,6(4)：201-204.
[95]Sakagami H,Arakawa H,Maeda M,et al.Production of hydrogen peroxide and methionine sulfoxide by epigallocatechin gallate and antioxidants.Anticancer Res,2001,21(4A):2633-2641
[96]Tosetti F,Ferrari N,De Flora S,et al.Angioprevention:angiogenesis is a common and key target for cancer chemopreventive agents.FASEBJ,2002,16(1):2-14.
[97]Imad N,Hiroyuki S,Takashi T.Telamerase inhibition,telomere shortening,and senescence of cancer cells by tea catechins J.Biochem and Bio phy Res Commu,1998,249:391-396.
[98]Lamy S,Gingras D,Beliveau R,et al.Green tea catechins inhibit vascular endothelial growth factor receptor phophorylation J.Cancer Res,2002,15,62(2):381-385
[99]Tsuchiya H.Atereospecificity in membrane effects of catechinsJ.Chem Biol Interact,2001,134(1):41-54.
[100]Kim RH, Peters M, Jang Y, et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 2005; 7:263-273.
[1]World Cancer Research Fund/American Institute for Cancer Research.Food,Nutrition,Physical Activity,and the Prevention of Cancer:a Global Perspective.Washington,DC:AICR,2007.
[2]肿瘤化学预防及药物治疗韩锐主编北京医科大学中国协和医科大学联合出版社出版.1991.12 53-61
[3]SAITOK,OKUT,ATAN,et al.Amodifiedandconvenient method for assessing tumor cell invasion and its application to screening for inhibitors J.Biol Pharm Bull,1997,204:345-348.
[4]ZHOU H,CALAF G M,HEI T K.Malignant transformation of human bronchial epithelial cells with the tobacco-specific nitrosamine,4-(methylnitro samino)-1-(3-pyridyl)-1-butanoneJ.IntJ Cancer,2003,106 (6):821-826
[5]SUI J L,AN J,SUN JF,et al.Spindle checkpoint and apoptotic response in alpha-particle transformed human bronchial epithelial cells J.Radiat Environ Biophys,2004,43(4):257-263.
[6]SUZUKI J,SHISHIDO T.Regulation of cellular transformation by oncogenic and normal Abl kinasesJ.J Biochem (Tokyo),2007,141(4):453-458.
[7]HUSSAIN S P,KENNEDY C H,AMMND P,et al.Radon and lung carcinogenesis:mutability of p53 codon 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells J.Carcinogen,1997,18(1):121-125.
[8]陈光宇,袁素波,马华智,等.环磷酰胺及塞替派诱导的人支气管上皮恶性转化细胞的细胞周期相关蛋白表达 J.中国药理学与毒理学杂志,2002,16(2)：138-142
[9]Fukano Y,Oishi M,Chibana F,Numazawa S,et ak,T. Analysisof the expression of heme oxygenase21 gene in human alveolar epithelial cells exposed to cigarette smoke condensate[J].JToxicol Sci,2006,31:992109.
[10]Nagaraj N S,Zacharias W. Cigarette smoke condensate increases cathepsin-mediated invasiveness of oral carcinoma cells[J].Toxicol Lett,2007,170:1342145.
[11]Ke Y,Reddel R R,Gerwin B I,Miyashita M,et al. Human bronchial epithelial cells with Integrated SV40 virus T antigen genes retain the ability to undergosquamous differentiation[J].Differentiation,1998,38:60266.
[12]王伦,刘晨.30%的癌症与吸烟有关[J].中国医药指南,2007,4：78279.
[13]Kurahashi N,Inoue M,Liu Y,et al. Passive smoking and lung cancer in Japanese non-smokingwomen:A prospective study[J]. Int J Cancer,2008,122:6532657.
[14]Yang Z H,Fan B X,Lu Y,et al. Malignant transformation of human bronchial epithelial cell (BEAS-2B) induced by depleted uranium[J]. Ai Zheng,2002,21:944-948.
[15]Chen H J,Yu R A,He L F,et al.Inhibitory effects of selenium on telomerase activity andhTERT expression in cadmium-transformed 16HBE cells[J].Biomed Environ Sci,2007,20:3072312.
[16]KernJ A,Torney L,Weiner D,et al. Inhibition of human lung cancer cell line growth by an anti-p18HER2 antibody [J]. Ant J Respir Cell Mol Boil,1993,9:448-454.
[17]杨陟华,朱茂祥,龚诒芬,等.NNK诱发人支气管上皮细胞恶性转化及氧化损伤机理研究[J].癌变·畸变·突变,1999,11：1842187.
[18]Li H,Gu Y,MikiJ,Hukku B, et al. Malignant transformation of human benign prostate epithelial cells by high linear energy transfer alpha particles[J].2007,31:537-544.
[19]吕兰海,杨陟华,尤汉虎,等.卷烟烟气及其主要有害成分诱发细胞基因突变的研究[J].环境与健康杂志,2004,21：2862288.
[20]Richardson H L, Cunningham L. The inhibitory action of methylcholanthrene on rats fed the azo dye 3'methyl 4 dime thy laminobenzene [J].Cancer Res,1951,11(4):274.
[21]Richardson H L, Stier A R, Borsos nachtnebel E. Liver tumor inhibition and adrenal histologic responses in rats to which 3'methyl 4 dimethy-laminoazobenzene and 20-methylcholanthrene were simultaneously administered [J]. Cancer Res,1952,12(5):356-361.
[22]Talalay P, Fahey J W. Phytochemicals from cruciferous plants protectagainst cancer by modulating carcinogen metabolism [J]. J Nutr,2001,131(11 Suppl):3027S-3033S.
[23]Wolf C R. Chemoprevention:increased potential to bear fruit [J].Proc Natl Acad Sci,2001,98(6):2941-2943.
[24]Chen M F, Keng P C, Shau H, et al. Inhibition of lung tumor growth and augmentation of radio sensitivity by decreasing peroxiredoxin I expression [J]. Int J Radiat Oncol Biol Phys,2006,64(2):581-591.
[25]Sahoo S K, Sawa T, Fang J, et al. Pegylated zinc protoporphyrin:a water soluble heme oxygenase inhibitor with tumor targeting capacity [J] Bioconjug Chem,2002,13(5):1031-1038.
[26]Nioi P, McMahon M, Itoh K, et al. Identification of a novel Nrf2 regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene:reassessment of the ARE consensus sequence [J] Biochem J,2003,374(Pt 2):337-348.
[27]Iida K, Itoh K, Kumagai Y, et al. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis [J]. Cancer Res, 2004,64(18):6424-6431.
[28]Bonfil R,Chinni S,Fridman R,et al.Proteases,growth factors,chemokines,and the microenvironment in prostate cancer bone metastasis[J].Urol Oncol,2007,25(5):407-411.
[29]Wita IP.Tumor-microenvironment interactions:the selectinselectin ligand axis in tumor-endothelium cross talk [J].Cancer Treat Res,2006,130(25):125-140.
[30]Fidler IJ.Seed and soil revisited:contribution of the organ microenvironment to cancer metastsis[J].Surg Oncol Clin N Am,2001,10(2):257-269.
[31]Fidler IJ. The pathogenesis of cancer metastasis:the'seed and soil' hypothesis revisited [J]. Nat Rev Cancer,2003,3(6):453-458.
[32]Hede K.Environmental protection:studies highlight importance of tumor microenvironment [J]. J Natl Cancer Inst,2004,96(15):1120-1121.
[33]Brown JM. Tumor microenvironment and the response to anticancer therapy[J]. Cancer Biol Ther,2002, 1(5):453-458.
[34]Mohla S. Tumor microenvironment [J].J Cell Biochem,2007,101(4):801-804.
[35]Sung SY, Chung LW. Prostate tumor-stroma interaction:molecular mechanisms and opportunities for therapeutic targeting [J]. Differentiation,2002, 70(9-10):506-521.
[36]Gupta GP, Massague J. Cancer metastasis:building a framework [J]. Cell, 2006,127(4):679-695.
[37]Sung SY, Hsieh CL, Wu D, et al. Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance [J]. Curr Probl Cancer,2007, 31(2):36-100.
[38]Hanahan D, Weinberg RA. The hallmarks of cancer.Cell.2000;100(1):57-70.
[39]Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med.2004;10(8):789-99.
[40]Boland CR, Ricciardiello L. How many mutations does it take to make a tumor?Proc Natl Acad Sci U S A.199921;96(26):14675-7.
[41]Melillo G, Semenza GL. Meeting report:exploiting the tumor microenvironment for therapeutics.Cancer Res.2006 1;66(9):4558-60.
[42]Witz IP. Tumor-microenvironment interactions:the selectin-selectin ligand axis in tumor-endothelium cross talk.C ancer Treat Res.2006; 130:125-40.
[43]Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells.Nature.2001 1;414(6859):105-11.
[44]Trosko JE, Chang CC, Upham BL, Tai MH. Ignored hallmarks of carcinogenesis:stem cells and cell-cell communication.Ann N Y Acad Sci. 2004;1028:192-201.
[45]Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells:nature, biology, and potential applications. Stem Cells. 2001; 19(3):180-92.
[46]Pittenger MF, Mackay AM, Beck SC,et al. Multilineage potential of adult human mesenchymal stem cells. Science.1999;284(5411):143-7.
[47]Strauss E. Brain stem cells show their potential.Science.1999;283(5401):471.
[48]Li L, Xie T. Stem cell niche:structure and function.Annu Rev Cell Dev Biol. 2005;21:605-31.
[49]Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells:inferences for the localization of stem cell niches.Blood. 2001;97(8):2293-9.
[50]Schofield R The relationship between the spleen colony-forming cell and the haemopoietic stem cell.Blood Cells.1978;4(1-2):7-25.
[51]Spradling A, Drummond-Barbosa D, Kai T. Stem cells find their niche.Nature. 2001;414(6859):98-104.
[52]Lin H. The stem-cell niche theory:lessons from flies. Nat Rev Genet. 2002;3(12):931-40.
[53]Chepko G, Slack R, Carbott D,et al. Differential alteration of stem and other cell populations in ducts and lobules of TGFalpha and c-Myc transgenic mouse mammary epithelium.Tissue Cell.2005;37(5):393-412.
[54]Zhu Y, Ghosh P, Charnay P,et al. Neurofibromas in NF1:Schwann cell origin and role of tumor environment. Science.2002;296(5569):920-2.
[55]Sonnenschein C, Soto. AM Somatic mutation theory of carcinogenesis:why it should be dropped and replaced.Mol Carcinog.2000;29(4):205-11.
[56]Folkman J, Hahnfeldt P, Hlatky L. Cancer:looking outside the genome. Nat Rev Mol Cell Biol.2000;1(1):76-9.
[57]Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46-54.
[58]Thiery JP. Epithelial-mesenchymal transitions in tumour progression.Nat Rev Cancer.2002;2(6):442-54.
[59]Maffini MV, Soto AM, Calabro JM,et al. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci.2004;117(Pt 8):1495-502.
[60]Tsonis PA, Vergara MN, Spence JR,et al. A novel role of the hedgehog pathway in lens regeneration.Dev Biol.2004;267(2):450-61.
[61]Monga SP, Pediaditakis P, Mule K,et al. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration.Hepatology. 2001;33(5):1098-109.
[62]Surendran K, Simon TC. CNP gene expression is activated by Wnt signaling and correlates with Wnt4 expression during renal injury.Am J Physiol Renal Physiol.2003;284(4):F653-62.
[63]Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-7.
[64]Dvorak HF. Tumors:wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med.1986;315(26):1650-9.
[65]Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch [J]. Nat Rev Cancer,2003,3(6):401-410.
[66]Coussens LM, Werb Z. Inflammation and cancer [J]. Nature,2002, 420(6917):860-867.
[67]De Wever, Mareel M. Role of tissue stroma in cancer cell invasion [J].J Pathol, 2003,200(4):429-447.
[68]Manabe Y, Toda S, Miyazaki K, et al. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions [J]. J Pathol,2003,201(2):221-228.
[69]Kalluri R, Zeisberg M. Fibroblasts in cancer [J]. Nat Rev Cancer,2006, 6(5):392-401.
[70]Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation [J]. Exp Cell Res,2001,264(1):169-184.
[71]Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease [J]. Cancer Cell,2005, 7(3):211-217.
[72]Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis [J]. Nat Rev Cancer,2004,4(1):71-78.
[73]Hynes RO. A reevaluation of integrins as regulators of angiogenesis [J]. Nat Med,2002,8(9):918-921.
[74]Kacinski BM.CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract [J]. Mol Reprod Dev,1997,46(1):71-74.
[75]Braun B, Lange M, Oeckler R, et al. Expression of G-CSF and GM-CSF in human meningiomas correlates with increased tumor proliferation and vascularization [J]. J Neurooncol,2004,68(2):131-140.
[76]Mueller MM, Fusenig NE. Friends or foes-bipolar effects of the tumour stroma in cancer [J]. Nat Rev Cancer,2004,4(11):839-849.
[77]Sneddon JB, Zhen HH, Montgomery K,et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci U S A. 2006;103(40):14842-7.
[78]Schlappack OK, Zimmermann A, Hill RP. Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells[J]. Br J Cancer,1991,64(4):663-670.
[79]Aguirre-Ghiso J A,Estrad Y,Liu D,Ossowski L.ERK(MAPK) activity as a determinant of tumor growth and dormancy regulation by p38(SAPK)[J].Cancer Res,2003,63:1684-1695.
[80]Illmensee K,Mintz B,Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts[J].Proc Natl Acad Sci.USA.1976,73:549-553.
[81]Cucina A,Biava P M,D'Anselmi F,Coluccia P,Conti F,di Clemente R,et al.Zebrafish embryo proteins induce apoptosis in human colon cancer cell(Caco2)[J].Apoptosis.2006.11:1615-1628.
[82]Lee L M,Seftor E A,Bonde G,Cornell R A,Hendrix M J.The fate of human malignant melanoma cells transplanted into zebrafish embryos:Assessment of migration and cell division in the absence of tumor formation[J].Dev Dyn.2005.233:1560-1570.
[83]Postovit L M,Margaryan N V,Seftor E A,Kirschmann D A,Lipavsky A,Wheaton W W,et al.Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype f aggressive cancer cells[J].Proc Natl Acad Sci USA.2008.105:4329-4334.
[84]Hu M, Yao J, Carroll DK, Weremowicz S,et al. Regulation of in situ to invasive breast carcinoma transition.Cancer Cell.2008;13(5):394-406.
[85]Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention [J]. Nat Rev Cancer,2007,7(2):139-147.
[86]Joyce JA. Therapeutic targeting of the tumor microenvironment [J]. Cancer Cell,2005,7(6):513-520.
[87]LaBarge MA, Petersen OW, Bissell MJ. Of microenvironments and mammary stem cells[J]. Stem Cell Rev,2007,3(2):137-146.
[88]Kuperwasser C,Chavarria T,Wu M, et al.Reconstruction of functionally normal and malignant human breast tissues in mice [J].Proc Natl Acad Sci U S A, 2004,101(14):4723-4724.
[89]WH Zhu,Nicosia RF.The thin prep rat aortic ring assay:A modified method for the characterization of angiogenesis in whole mounts [J].Angiog-enesis 2002,5(1/2)81-86.
[90]Donovan D, Brown NJ, Bishop ET, et al. Comparison of three in vitro human' angiogenesis'assays with capillaries formed in vivo[J]. Angiogenesis,2001,4(2) 113-121.
[2]Joyce JA.Therapeutic targeting of the tumor microenvironment.Cancer Cell,20057:513-520.
[3]Albini A,Sporn MB.The tumor microenvironment as a target for chemoprevention.Nat Rev Cancer,2007;7:139-147.
[4]Bonfil R,Chinni S,Fridman R,et al.Proteases,growth factors,chemokines,and the microenvironment in prostate cancer bone metastasis[J].Urol Oncol,2007,25(5):407-411.
[5]Wita IP.Tumor-microenvironment interactions:the selectinselectin ligand axis in tumor-endothelium cross talk [J].Cancer Treat Res,2006,130(25):125-140.
[6]Fidler IJ.Seed and soil revisited:contribution of the organ microenvironment to cancer metastsis[J].Surg Oncol Clin N Am,2001,10(2):257-269.
[7]Scott AM,Wiseman G,Welt S,et al.A Phase I dose-es-calation study of sibrotuzumab in patients with advanced or metastatic fivroblast activation protein-positive cancer [J].Clin Cancer Res,2003,9(5):1639-1647.
[8]Gu Q, Hu C, Chen Q, et al. Development of a rat model by 3,4-benzopyrene intra-pulmonary injection and evaluation of the effect of green tea drinking on p53 and bcl-2 expression in lung carcinoma. Cancer Detect Prev. 2009;32(5-6):444-51
[9]Chengping HU,Min Li,Qihua Gu,et al.Proteomics-based identification of 9 proteins in tumor microenvironment as targets for lung cancer prevention by green tea.Respirology,2008; 13(S5):103
[10]Kelloff GJ,Crowell JA,Stelle VE,Lubet RA,Malone WA,Boone CW,Kopelovich L,Hawk ET,Lieberman R,Lawrence JA,Ali I,Viner JL,Sigman CC.Progerss in cancer chemoprevention:developmeng of diet-derived chemopreventive agents.J Nutr,2000;130(2S Suppl):467S-471S.
[11]Clark J,You M.Chemoprevention of lung cancer by tea.Mol Nurt Food Res,2006;50(2):144-51.
[12]Chung FL,Schwartz J,Herzog CR,Herzog,Yang YM.Tea and cancer pervention:studies in animal and humans.J Nutr,2003;133(10):3268S-3274S.
[13]Suganuma M,Okabe S,Sueoka N,Sueoka E,Matsuyama S,Imsi K,Nakachi K,Fujiki H.Green tea and cancer chemoprevention.Mutat Res,1999 428(1-2):339-44.
[14]Yang CS,Liao J,Yang GY,Lu G.Inhibitiong of lung tumorigenesis by tea.Exp Lung Res,2005;31(1):135-44.
[15]Fujiki H.Green tea:Health benefits as cancer preventive for humans.Chem Rec,2005;5(3):119-32.
[16]Suganuma M,Okabe S,Sueoka N,Sueoka E,Matsuyama S,Imsi K,Nakachi K,Fujiki H.Green tea and cancer chemoprevention.Mutat Res,1999 428(1-2):339-44.
[17]Okabe S,Fujimoto N,Sueoka N,Suganuma M,Fujiki H.Modulation of gene expression by (-)-epigallocatechin gallate in PC-9 cells using a cDNA experssion array.Biol PharmBull.2001;24(8):883-6.
[18]Suganuma M,Okabe S,Kai Y,Sueoka N,Sueoka E,Fujiki H.Synergistic effects of (--)-epigallocatechin gallate with (--)-epicatechin,sulindac,or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9.Cancer Res.1999;59(1):44-7.
[19]Nagakubo D,Taira T,Kitaura H,et al.DJ-l,a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras [J].Biochem Biophys Res,1997,231(2):509-513.
[20]Bonifati V,Rizzu P,Van Baren M J.et al.Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism [J].Science,2003,299(5604) 256-259.
[21]Le Naour F,Misek DE,Krause MC,et al. Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer. Clin Cancer Res. 2001 Nov;7(11):3328-35.
[22]Pardo M,Garcia A,Thomas B, et al.The characterization of the invasion phenotype of uveal melanoma tumor cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker,Int J Cancer,2006,119:1014-1022
[23]Clements CM,McNally RS,Conti BJ,et al.DJ-l,a cancer-and Parkindon's disease-associated protein,stabilizes the antioxidant transcriptional master regulator Nrf2.Proc Natl Acad Sci US A,2006,103:15091-15096.
[24]Taira T,Saito Y,Niki T,et al.DJ-1 has a role in antioxidative stress to prevent cell death.EMBO Rep,2004,5:213-218.
[25]Junn E,Taniguchi H,Jeong BS,et al.Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.Proc Natl Acad Sci USA,2005,102:9691-9696.
[26]Kim RH,Peter M,Jang Y,et al.DJ-1, a novel regulator of the tumor suppressor PTEN.Cancer Cell,2005,7:263-273.
[27]Pin-Pin Lin,Ming-Hui Yang,Pao-Chi Liao,et al.Proteomic analysis of proteins associated with t,t-DDE induced toxicity in BEAS-2B cells.Biochemical and Biophysical Research Communications.376(2008) 519-524.
[28][28]Wang Y.Public health goal for benzo(a)pyrene in drinking water.California,OEHHA.1997,12:5-8.
[29]蒋义国,陈家堃,陈学敏苯并(a)芘代谢物反式二羟环氧苯并芘诱发人支气管上皮细胞恶性转化卫生研究2001,30(3)：129-130
[30]World Cancer Research Fund/American Institute for Cancer Research.Food,Nutrition,Physical Activity,and the Prevention of Cancer:a Global Perspective.Washington,DC:AICR,2007.
[31]肿瘤化学预防及药物治疗韩锐主编北京医科大学中国协和医科大学联合出版社出版.1991.1253-61.
[32]Hishii M,Kurnick JT,Ramirez-Montagut T,et al.Studies of the mechanism of cytolysis by tumor-infiltrating lymphocytes.Clin Exp Immunol,1999;116 388-394.
[33]Rosenberg SA,Spiess P,Lafrenier R.A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating Lymphocytes.Science,1986 233:131.
[34]Elzaouk L,Moelling K,Pavlovic J.Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma model.Exp Dermatol,2006; 15(11) 865-874.
[35]Chaudhry UI,Kingham TP,Plitas G.Combined stimulation with interleukin-18 and CpG induces murine natural killer dendritic cells to produce IFN-gamma and inhibit tumor growth.Cancer Res,2006;66(21):10497-10504.
[36]龚选举,阎玉虎,吴建平。肺癌组织中肿瘤浸润树突状细胞对预后的影响.中华肿瘤杂志,2000；22(2)：135-137.
[37]杨新静,黄建安,雷伟等共培养的树突细胞和CIK细胞对肺癌的体内外抑制作用癌症,2006；25(11)：1329-1333.
[38]Hede K.Environmental protection:studies highlight importance of tumor microenvironment [J]. J Natl Cancer Inst,2004,96(15):1120-1121.
[39]Brown JM. Tumor microenvironment and the response to anticancer therapy[J]. Cancer Biol Ther,2002, 1(5):453-458.
[40]Mohla S. Tumor microenvironment [J]. J Cell Biochem,2007,101(4):801-804.
[41]Sung SY, Chung LW. Prostate tumor-stroma interaction:molecular mechanisms and opportunities for therapeutic targeting [J]. Differentiation,2002, 70(9-10):506-521.
[42]Gupta GP, Massague J. Cancer metastasis:building a framework [J]. Cell, 2006,127(4):679-695.
[43]Coussens LM, Werb Z. Inflammation and cancer [J]. Nature,2002, 420(6917):860-867.
[44]De Wever, Mareel M. Role of tissue stroma in cancer cell invasion [J].J Pathol, 2003,200(4):429-447.
[45]Manabe Y, Toda S, Miyazaki K, et al. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions [J]. J Pathol,2003,201 (2):221-228.
[46]Kalluri R, Zeisberg M. Fibroblasts in cancer [J]. Nat Rev Cancer,2006, 6(5):392-401.
[47]Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation [J]. Exp Cell Res,2001,264(1):169-184.
[48]Gruber G, Greiner RH, Hlushchuk R, et al. Hypoxia-inducible factor 1 alpha in high-risk breast cancer:an independent prognostic parameter? [J]. Breast Cancer Res,2004,6(3):R191-198.
[49]Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha in normal human tissues, cancers, and tumor-associated macrophages [J]. Am J Pathol,2000, 157(2):411-421.
[50]Kitano H. Cancer as a robust system:implications for anticancer therapy [J]. Nat Rev Cancer,2004,4(3):227-235.
[51]Kell BD, Hackett SF, Hirota K, et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active aorm of aypoxia-inducible aactor 1 [J].Circ Res,2003,11 (93):1074-1081.
[52]Melillo G, Semenza GL. Meeting report:exploiting the tumor microenv ironment for therapeutics[J]. Cancer Res,2006,66(9):4558-4560.
[53]Postovit L M,Margaryan N V,Seftor E A,Kirschmann D A,Lipavsky A,Wheaton W W,et al.Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype f aggressive cancer cells[J].Proc Natl Acad Sci USA.2008.105:4329-4334.
[54]Sneddon J B,Zhen H H,Montgomery K,van de Rijn M,Tward A D,West R,et al.Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation[J].Proc Natl Acad Sci USA.2006.103:14842-14847.
[55]Illmensee K,Mintz B,Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts[J].Proc Natl Acad Sci.USA.1976,73:549-553.
[56]Cucina A,Biava P M,D'Anselmi F,Coluccia P,Conti F,di Clemente R,et al.Zebrafish embryo proteins induce apoptosis in human colon cancer cell(Caco2)[J].Apoptosis.2006.11:1615-1628.
[57]Lee L M,Seftor E A,Bonde G,Cornell R A,Hendrix M J.The fate of human malignant melanoma cells transplanted into zebrafish embryos:Assessment of migration and cell division in the absence of tumor formation[J].Dev Dyn.2005.233:1560-1570.
[58]LaBarge MA, Petersen OW, Bissell MJ. Of microenvironments and mammary stem cells[J]. Stem Cell Rev,2007,3(2):137-146.
[59]Kuperwasser C,Chavarria T,Wu M, et al.Reconstruction of functionally normal and malignant human breast tissues in mice [J].Proc Natl Acad Sci U S A, 2004,101(14):4723-4724.
[60]WH Zhu,Nicosia RF. The thin prep rat aortic ring assay:A modified method for the characterization of angiogenesis in whole mounts [J].Angio-genesis 2002,5(1/2)81-86.
[61]Donovan D, Brown NJ, Bishop ET, et al. Comparison of three in vitro human' angiogenesis'assays with capillaries formed in vivo[J]. Angiogenesis,2001,4(2) 113-121.
[62]Hu M, Yao, J, Carroll DK, Weremowicz S, Chen H, Carrassco DE, Richardson AL, Violette S, Nikolskaya T, Nikolsky Y, Bauerlein EL, William C. Hahn WC, Gelman RS, Allred C, Bissell MJ, Schnitt SJ, Polyak K. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 2008; 13:394-406
[63]Khan N, Adhami VM, Mukhtar H. Green tea polyphenols in chemoprevention of prostate cancer:preclinical and clinical studies. Nutr Cancer. 2009;61(6):836-41.
[64]Johnson JJ, Bailey HH, Mukhtar H. Green tea polyphenols for prostate cancer chemoprevention:a translational perspective. Phytomedicine.2010;17(1):3-13.
[65]Adachi S, Shimizu M, Shirakami Y,et al. (-)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAPK in colon cancer cells. Carcinogenesis.2009;30(9):1544-52.
[66]Fu H, He J, Mei F,et al. Lung cancer inhibitory effect of epigallocatechin-3-gallate is dependent on its presence in a complex mixture (polyphenon E). Cancer Prev Res (Phila Pa).2009;2(6):531-7.
[67]Tachibana H. Molecular basis for cancer chemoprevention by green tea polyphenol EGCG.Forum Nutr.2009;61:156-69..
[68]Nanqun Zhu,Tzou-Chi Huang,Younong Yu,et al.Indentification of oxidation produnts of (-)-Epigallocatechin gallate and (-)-Epigallocatechin with H2O2 J.J
A gtic Food,2000,48:979-981
[69]Yang B,Kotani A,Arai K,et al.Relationship of electrochemical oxidant of catechinson their antioxidant activity in microsomal lipid peroxidation J.Chem Pharm Bull (Tokyo),2001,49(6):747-751
[70]Osada K,Takahashi M,Hoshina S,et al.Tea catechins inhibit cholesterol oxidation accompanying oxidation of low density lipoprotein in vitro J.Com p Biochem Physiol C Toxicol Pharmacol,2001,128(2):153-164.
[71]吴志鸿,王冕蓉,阎启昌等彗星法分析紫外线诱导的人晶状体上皮细胞DNA的损伤及抗氧化剂对DNA损伤的拮抗作用中华眼科杂志2006；42(11)：1002-7
[72]Jang S, Jeong HS, Park JS,et al. Neuroprotective effects of (-)-epigallocatechin-3-gallate against quinolinic acid-induced excitotoxicity via PI3K pathway and NO inhibition. Brain Res.2010(8);1313:25-33.
[73]Zhang ZM, Yang XY, Yuan JH,et al. Modulation of NRF2 and UGT1A expression by epigallocatechin-3-gallate in colon cancer cells and BALB/c mice. Chin Med J (Engl).2009;122(14):1660-5
[74]Hauber I, Hohenberg H, Holstermann B,et al. The main green tea polyphenol epigallocatechin-3-gallate counteracts semen-mediated enhancement of HIV infection. Proc Natl Acad Sci U S A.2009106(22):9033-8.
[75]Patra SK, Rizzi F, Silva A,et al. Molecular targets of (-)-epigallocatechin-3-gallate (EGCG):specificity and interaction with membrane lipid rafts. J Physiol Pharmacol.2008 59 Suppl 9:217-35
[76]Heo J, Lee BR, Koh JW. Protective effects of epigallocatechin gallate after UV irradiation of cultured human lens epithelial cells. Korean J Ophthalmol. 2008;22(3):183-6.
[77]Shim JH, Choi HS, Pugliese A,et al. (-)-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. J Biol Chem.2008;283(42):28370-9.
[78]Morse MA, Kresty LA, Steele VE,et al. Effects of theaflavins on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis. Nutr Cancer. 1997;29(1):7-12.
[79]Li ZG, Shimada Y, Sato F,et al. Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Int J Oncol.2002;21(6):1275-83.
[80]Li ZG, Shimada Y, Sato F,et al. Promotion effects of hot water on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Oncol Rep.2003;10(2):421-6.
[81]Chiang WC, Wong YK, Lin SC,et al. Increase of MMP-13 expression in multi-stage oral carcinogenesis and epigallocatechin-3-gallate suppress MMP-13 expression. Oral Dis.2006;12(1):27-33.
[82]Lambert JD, Sang S, Hong J,et al. Peracetylation as a means of enhancing in vitro bioactivity and bioavailability of epigallocatechin-3-gallate. Drug Metab Dispos.2006;34(12):2111-6.
[83]Hou Z, Sang S, You H, Lee MJ,et al. Mechanism of action of (-)-epigallocatechin-3-gallate:auto-oxidation-dependent inactivation of epidermal growth factor receptor and direct effects on growth inhibition in human esophageal cancer KYSE 150 cells. Cancer Res.2005 Sep 1;65(17):8049-56.
[84]Muto S,Fujita K,Yamazaki Y,et al.Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450J.Mutat Res,2001,479(1-2):197-206.
[85]Hong J,Smith TJ,Ho CT,et al.Effects of purified green and black tea pollyphenols on cyclooxygenase and lipoxugenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues J.Biochem Pharmacol,2001,62(9):1175-1183.
[86]Mataunaga K,Klein TW,Friedman H,et al.Legionella pneumophila replication in macrophages inhibited by selective immumodulatory effects on cytokine formation by epigallocatechin gallate,a major form of tea catechins J.Infect Immun,2001,69(6):3947-3953.
[87]Katiyar SK,Mukhtar H,Green tea polyphenol (-)-epigallocatechin-3-gallate treatment to mouse skin prevents UVB-induced infiltration of leukocytes,depletion of antigen-presenting cells,and oxidative stress J.J Leukoc Biol,2001,69(5):719-726.
[88]Cutter H, Wu LY, Kim C,et al. Is the cancer protective effect correlated with growth inhibitions by green tea (-)-epigallocatechin gallate mediated through an antioxidant mechanism? Cancer Lett.200126;162(2):149-54.
[89]Morre DJ, Morre DM, Sun H,et al. Tea catechin synergies in inhibition of cancer cell proliferation and of a cancer specific cell surface oxidase (ECTO-NOX). Pharmacol Toxicol.2003;92(5):234-41.
[90]Chueh PJ, Wu LY, Morre DM,et al. tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate. Biofactors.2004;20(4):235-49.
[91]梁钢,黄仁彬,黄志明等,表没食子儿茶素没食子酸酯抗肿瘤作用的研究广西医科大学学报,2000,17(2)：176
[92]Yang GY,Liao Y,Kim K,et al.Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols.Carcino genesis,1998,19(4):611-616.
[93]Krul C,Luiten-Schuite A,Tenfelde A,et al.Antimutagenic activity of green tea and black tea extracts studied in dynamic in vitro gastro intestinal model.Mutat Res,2001,474(1-2):71-85.
[94]梁钢,符麟军表没食子儿茶素没食子酸酯抗突变的实验研究广西预防医学,2000,6(4)：201-204.
[95]Sakagami H,Arakawa H,Maeda M,et al.Production of hydrogen peroxide and methionine sulfoxide by epigallocatechin gallate and antioxidants.Anticancer Res,2001,21(4A):2633-2641
[96]Tosetti F,Ferrari N,De Flora S,et al.Angioprevention:angiogenesis is a common and key target for cancer chemopreventive agents.FASEBJ,2002,16(1):2-14.
[97]Imad N,Hiroyuki S,Takashi T.Telamerase inhibition,telomere shortening,and senescence of cancer cells by tea catechins J.Biochem and Bio phy Res Commu,1998,249:391-396.
[98]Lamy S,Gingras D,Beliveau R,et al.Green tea catechins inhibit vascular endothelial growth factor receptor phophorylation J.Cancer Res,2002,15,62(2):381-385
[99]Tsuchiya H.Atereospecificity in membrane effects of catechinsJ.Chem Biol Interact,2001,134(1):41-54.
[100]Kim RH, Peters M, Jang Y, et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 2005; 7:263-273.
[1]World Cancer Research Fund/American Institute for Cancer Research.Food,Nutrition,Physical Activity,and the Prevention of Cancer:a Global Perspective.Washington,DC:AICR,2007.
[2]肿瘤化学预防及药物治疗韩锐主编北京医科大学中国协和医科大学联合出版社出版.1991.12 53-61
[3]SAITOK,OKUT,ATAN,et al.Amodifiedandconvenient method for assessing tumor cell invasion and its application to screening for inhibitors J.Biol Pharm Bull,1997,204:345-348.
[4]ZHOU H,CALAF G M,HEI T K.Malignant transformation of human bronchial epithelial cells with the tobacco-specific nitrosamine,4-(methylnitro samino)-1-(3-pyridyl)-1-butanoneJ.IntJ Cancer,2003,106 (6):821-826
[5]SUI J L,AN J,SUN JF,et al.Spindle checkpoint and apoptotic response in alpha-particle transformed human bronchial epithelial cells J.Radiat Environ Biophys,2004,43(4):257-263.
[6]SUZUKI J,SHISHIDO T.Regulation of cellular transformation by oncogenic and normal Abl kinasesJ.J Biochem (Tokyo),2007,141(4):453-458.
[7]HUSSAIN S P,KENNEDY C H,AMMND P,et al.Radon and lung carcinogenesis:mutability of p53 codon 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells J.Carcinogen,1997,18(1):121-125.
[8]陈光宇,袁素波,马华智,等.环磷酰胺及塞替派诱导的人支气管上皮恶性转化细胞的细胞周期相关蛋白表达 J.中国药理学与毒理学杂志,2002,16(2)：138-142
[9]Fukano Y,Oishi M,Chibana F,Numazawa S,et ak,T. Analysisof the expression of heme oxygenase21 gene in human alveolar epithelial cells exposed to cigarette smoke condensate[J].JToxicol Sci,2006,31:992109.
[10]Nagaraj N S,Zacharias W. Cigarette smoke condensate increases cathepsin-mediated invasiveness of oral carcinoma cells[J].Toxicol Lett,2007,170:1342145.
[11]Ke Y,Reddel R R,Gerwin B I,Miyashita M,et al. Human bronchial epithelial cells with Integrated SV40 virus T antigen genes retain the ability to undergosquamous differentiation[J].Differentiation,1998,38:60266.
[12]王伦,刘晨.30%的癌症与吸烟有关[J].中国医药指南,2007,4：78279.
[13]Kurahashi N,Inoue M,Liu Y,et al. Passive smoking and lung cancer in Japanese non-smokingwomen:A prospective study[J]. Int J Cancer,2008,122:6532657.
[14]Yang Z H,Fan B X,Lu Y,et al. Malignant transformation of human bronchial epithelial cell (BEAS-2B) induced by depleted uranium[J]. Ai Zheng,2002,21:944-948.
[15]Chen H J,Yu R A,He L F,et al.Inhibitory effects of selenium on telomerase activity andhTERT expression in cadmium-transformed 16HBE cells[J].Biomed Environ Sci,2007,20:3072312.
[16]KernJ A,Torney L,Weiner D,et al. Inhibition of human lung cancer cell line growth by an anti-p18HER2 antibody [J]. Ant J Respir Cell Mol Boil,1993,9:448-454.
[17]杨陟华,朱茂祥,龚诒芬,等.NNK诱发人支气管上皮细胞恶性转化及氧化损伤机理研究[J].癌变·畸变·突变,1999,11：1842187.
[18]Li H,Gu Y,MikiJ,Hukku B, et al. Malignant transformation of human benign prostate epithelial cells by high linear energy transfer alpha particles[J].2007,31:537-544.
[19]吕兰海,杨陟华,尤汉虎,等.卷烟烟气及其主要有害成分诱发细胞基因突变的研究[J].环境与健康杂志,2004,21：2862288.
[20]Richardson H L, Cunningham L. The inhibitory action of methylcholanthrene on rats fed the azo dye 3'methyl 4 dime thy laminobenzene [J].Cancer Res,1951,11(4):274.
[21]Richardson H L, Stier A R, Borsos nachtnebel E. Liver tumor inhibition and adrenal histologic responses in rats to which 3'methyl 4 dimethy-laminoazobenzene and 20-methylcholanthrene were simultaneously administered [J]. Cancer Res,1952,12(5):356-361.
[22]Talalay P, Fahey J W. Phytochemicals from cruciferous plants protectagainst cancer by modulating carcinogen metabolism [J]. J Nutr,2001,131(11 Suppl):3027S-3033S.
[23]Wolf C R. Chemoprevention:increased potential to bear fruit [J].Proc Natl Acad Sci,2001,98(6):2941-2943.
[24]Chen M F, Keng P C, Shau H, et al. Inhibition of lung tumor growth and augmentation of radio sensitivity by decreasing peroxiredoxin I expression [J]. Int J Radiat Oncol Biol Phys,2006,64(2):581-591.
[25]Sahoo S K, Sawa T, Fang J, et al. Pegylated zinc protoporphyrin:a water soluble heme oxygenase inhibitor with tumor targeting capacity [J] Bioconjug Chem,2002,13(5):1031-1038.
[26]Nioi P, McMahon M, Itoh K, et al. Identification of a novel Nrf2 regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene:reassessment of the ARE consensus sequence [J] Biochem J,2003,374(Pt 2):337-348.
[27]Iida K, Itoh K, Kumagai Y, et al. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis [J]. Cancer Res, 2004,64(18):6424-6431.
[28]Bonfil R,Chinni S,Fridman R,et al.Proteases,growth factors,chemokines,and the microenvironment in prostate cancer bone metastasis[J].Urol Oncol,2007,25(5):407-411.
[29]Wita IP.Tumor-microenvironment interactions:the selectinselectin ligand axis in tumor-endothelium cross talk [J].Cancer Treat Res,2006,130(25):125-140.
[30]Fidler IJ.Seed and soil revisited:contribution of the organ microenvironment to cancer metastsis[J].Surg Oncol Clin N Am,2001,10(2):257-269.
[31]Fidler IJ. The pathogenesis of cancer metastasis:the'seed and soil' hypothesis revisited [J]. Nat Rev Cancer,2003,3(6):453-458.
[32]Hede K.Environmental protection:studies highlight importance of tumor microenvironment [J]. J Natl Cancer Inst,2004,96(15):1120-1121.
[33]Brown JM. Tumor microenvironment and the response to anticancer therapy[J]. Cancer Biol Ther,2002, 1(5):453-458.
[34]Mohla S. Tumor microenvironment [J].J Cell Biochem,2007,101(4):801-804.
[35]Sung SY, Chung LW. Prostate tumor-stroma interaction:molecular mechanisms and opportunities for therapeutic targeting [J]. Differentiation,2002, 70(9-10):506-521.
[36]Gupta GP, Massague J. Cancer metastasis:building a framework [J]. Cell, 2006,127(4):679-695.
[37]Sung SY, Hsieh CL, Wu D, et al. Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance [J]. Curr Probl Cancer,2007, 31(2):36-100.
[38]Hanahan D, Weinberg RA. The hallmarks of cancer.Cell.2000;100(1):57-70.
[39]Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med.2004;10(8):789-99.
[40]Boland CR, Ricciardiello L. How many mutations does it take to make a tumor?Proc Natl Acad Sci U S A.199921;96(26):14675-7.
[41]Melillo G, Semenza GL. Meeting report:exploiting the tumor microenvironment for therapeutics.Cancer Res.2006 1;66(9):4558-60.
[42]Witz IP. Tumor-microenvironment interactions:the selectin-selectin ligand axis in tumor-endothelium cross talk.C ancer Treat Res.2006; 130:125-40.
[43]Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells.Nature.2001 1;414(6859):105-11.
[44]Trosko JE, Chang CC, Upham BL, Tai MH. Ignored hallmarks of carcinogenesis:stem cells and cell-cell communication.Ann N Y Acad Sci. 2004;1028:192-201.
[45]Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells:nature, biology, and potential applications. Stem Cells. 2001; 19(3):180-92.
[46]Pittenger MF, Mackay AM, Beck SC,et al. Multilineage potential of adult human mesenchymal stem cells. Science.1999;284(5411):143-7.
[47]Strauss E. Brain stem cells show their potential.Science.1999;283(5401):471.
[48]Li L, Xie T. Stem cell niche:structure and function.Annu Rev Cell Dev Biol. 2005;21:605-31.
[49]Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells:inferences for the localization of stem cell niches.Blood. 2001;97(8):2293-9.
[50]Schofield R The relationship between the spleen colony-forming cell and the haemopoietic stem cell.Blood Cells.1978;4(1-2):7-25.
[51]Spradling A, Drummond-Barbosa D, Kai T. Stem cells find their niche.Nature. 2001;414(6859):98-104.
[52]Lin H. The stem-cell niche theory:lessons from flies. Nat Rev Genet. 2002;3(12):931-40.
[53]Chepko G, Slack R, Carbott D,et al. Differential alteration of stem and other cell populations in ducts and lobules of TGFalpha and c-Myc transgenic mouse mammary epithelium.Tissue Cell.2005;37(5):393-412.
[54]Zhu Y, Ghosh P, Charnay P,et al. Neurofibromas in NF1:Schwann cell origin and role of tumor environment. Science.2002;296(5569):920-2.
[55]Sonnenschein C, Soto. AM Somatic mutation theory of carcinogenesis:why it should be dropped and replaced.Mol Carcinog.2000;29(4):205-11.
[56]Folkman J, Hahnfeldt P, Hlatky L. Cancer:looking outside the genome. Nat Rev Mol Cell Biol.2000;1(1):76-9.
[57]Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46-54.
[58]Thiery JP. Epithelial-mesenchymal transitions in tumour progression.Nat Rev Cancer.2002;2(6):442-54.
[59]Maffini MV, Soto AM, Calabro JM,et al. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci.2004;117(Pt 8):1495-502.
[60]Tsonis PA, Vergara MN, Spence JR,et al. A novel role of the hedgehog pathway in lens regeneration.Dev Biol.2004;267(2):450-61.
[61]Monga SP, Pediaditakis P, Mule K,et al. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration.Hepatology. 2001;33(5):1098-109.
[62]Surendran K, Simon TC. CNP gene expression is activated by Wnt signaling and correlates with Wnt4 expression during renal injury.Am J Physiol Renal Physiol.2003;284(4):F653-62.
[63]Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-7.
[64]Dvorak HF. Tumors:wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med.1986;315(26):1650-9.
[65]Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch [J]. Nat Rev Cancer,2003,3(6):401-410.
[66]Coussens LM, Werb Z. Inflammation and cancer [J]. Nature,2002, 420(6917):860-867.
[67]De Wever, Mareel M. Role of tissue stroma in cancer cell invasion [J].J Pathol, 2003,200(4):429-447.
[68]Manabe Y, Toda S, Miyazaki K, et al. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions [J]. J Pathol,2003,201(2):221-228.
[69]Kalluri R, Zeisberg M. Fibroblasts in cancer [J]. Nat Rev Cancer,2006, 6(5):392-401.
[70]Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation [J]. Exp Cell Res,2001,264(1):169-184.
[71]Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease [J]. Cancer Cell,2005, 7(3):211-217.
[72]Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis [J]. Nat Rev Cancer,2004,4(1):71-78.
[73]Hynes RO. A reevaluation of integrins as regulators of angiogenesis [J]. Nat Med,2002,8(9):918-921.
[74]Kacinski BM.CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract [J]. Mol Reprod Dev,1997,46(1):71-74.
[75]Braun B, Lange M, Oeckler R, et al. Expression of G-CSF and GM-CSF in human meningiomas correlates with increased tumor proliferation and vascularization [J]. J Neurooncol,2004,68(2):131-140.
[76]Mueller MM, Fusenig NE. Friends or foes-bipolar effects of the tumour stroma in cancer [J]. Nat Rev Cancer,2004,4(11):839-849.
[77]Sneddon JB, Zhen HH, Montgomery K,et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci U S A. 2006;103(40):14842-7.
[78]Schlappack OK, Zimmermann A, Hill RP. Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells[J]. Br J Cancer,1991,64(4):663-670.
[79]Aguirre-Ghiso J A,Estrad Y,Liu D,Ossowski L.ERK(MAPK) activity as a determinant of tumor growth and dormancy regulation by p38(SAPK)[J].Cancer Res,2003,63:1684-1695.
[80]Illmensee K,Mintz B,Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts[J].Proc Natl Acad Sci.USA.1976,73:549-553.
[81]Cucina A,Biava P M,D'Anselmi F,Coluccia P,Conti F,di Clemente R,et al.Zebrafish embryo proteins induce apoptosis in human colon cancer cell(Caco2)[J].Apoptosis.2006.11:1615-1628.
[82]Lee L M,Seftor E A,Bonde G,Cornell R A,Hendrix M J.The fate of human malignant melanoma cells transplanted into zebrafish embryos:Assessment of migration and cell division in the absence of tumor formation[J].Dev Dyn.2005.233:1560-1570.
[83]Postovit L M,Margaryan N V,Seftor E A,Kirschmann D A,Lipavsky A,Wheaton W W,et al.Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype f aggressive cancer cells[J].Proc Natl Acad Sci USA.2008.105:4329-4334.
[84]Hu M, Yao J, Carroll DK, Weremowicz S,et al. Regulation of in situ to invasive breast carcinoma transition.Cancer Cell.2008;13(5):394-406.
[85]Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention [J]. Nat Rev Cancer,2007,7(2):139-147.
[86]Joyce JA. Therapeutic targeting of the tumor microenvironment [J]. Cancer Cell,2005,7(6):513-520.
[87]LaBarge MA, Petersen OW, Bissell MJ. Of microenvironments and mammary stem cells[J]. Stem Cell Rev,2007,3(2):137-146.
[88]Kuperwasser C,Chavarria T,Wu M, et al.Reconstruction of functionally normal and malignant human breast tissues in mice [J].Proc Natl Acad Sci U S A, 2004,101(14):4723-4724.
[89]WH Zhu,Nicosia RF.The thin prep rat aortic ring assay:A modified method for the characterization of angiogenesis in whole mounts [J].Angiog-enesis 2002,5(1/2)81-86.
[90]Donovan D, Brown NJ, Bishop ET, et al. Comparison of three in vitro human' angiogenesis'assays with capillaries formed in vivo[J]. Angiogenesis,2001,4(2) 113-121.