节拍性化疗在胃癌裸鼠模型中抗肿瘤机制的研究
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摘要
背景
胃癌是全世界最常见的恶性肿瘤之一,其发病率位于恶性肿瘤第四位,居癌症死因的第二位。手术切除是早期胃癌的标准治疗,可是,80%至90%患者确诊时已是晚期,不能手术根治,全身化疗是晚期胃癌患者的主要治疗手段。虽然随机临床研究已证实化疗可以为晚期胃癌患者带来生存益处,但标准化疗常有严重的不良反应,从而降低患者的生活质量,也严重限制了化疗的使用。
为了避免传统化疗引起的问题,研究者开始寻找新的用药方式,旨在提高抗肿瘤和/或抗转移效果,降低毒性。血管生成(angiogenesis)对维持原发肿瘤的生长和转移至关重要。自1971年Folkman首次提出针对肿瘤血管生成的治疗以来,血管生成已成为癌症治疗一个靶点。研究发现,某些细胞毒性药物的确能抑制血管生成,尤其是以小剂量、高频率给药时。与最大耐受剂量(maximum tolerable dose,MTD)化疗相比,小剂量、高频率或持续给药对肿瘤血管内皮的靶向作用更强。这种化疗方案称为“节拍性化疗”(metronomic chemotherapy)或“抗血管生成化疗”(antiangiogenicchemotherapy)。由于节拍性化疗以肿瘤血管内基因稳定、活化的内皮细胞为治疗靶点,降低了耐药性的发生,提高了治疗效果,又因其剂量较低,还能降低化疗的毒副作用。为了探讨胃癌治疗治疗新方法,本课题以MKN-45荷瘤裸鼠为模型,研究节拍性化疗的抗肿瘤血管生成作用。
研究证实,血管生成并不是肿瘤获得微循环的唯一机制。肿瘤细胞在行为上与胚胎干细胞类似。肿瘤细胞可模拟其他类型细胞,对微环境变化作出适应性应答。肿瘤细胞表达多种细胞表型基因的能力,称为肿瘤细胞可塑性。肿瘤细胞表达内皮细胞相关基因,形成输送液体的管道结构,即称为血管生成拟态(vasculogenic mimicry,VM),其是肿瘤可塑性的一种表现。研究证实,人胃癌细胞系可表达一系列与上皮细胞生理相关的基因,如Von Willebrand因子、CD31、VE-钙粘蛋白(VE-cadherin),表明胃癌细胞具有肿瘤细胞可塑性,提示胃癌中可能存在血管生成拟态。基于以上研究的启示,本课题拟在荷瘤裸鼠中研究MKN-45肿瘤细胞是否具有形成VM的能力,以及节拍性化疗对VM是否具有抑制作用。
目的
确定优福定(UFT)节拍性化疗的最佳生物学剂量(optimum biologic dose,OBD),以及在MKN-45荷瘤裸鼠中检测UFT节拍性化疗抗血管生成效应和抑制血管生成拟态作用,并比较UFT节拍性化疗与MTD UFT和CTX节拍性化疗的疗效。
材料与方法
1.MKN-45、SGC-7901人胃癌细胞系、Huh-7人肝癌细胞系和U87人神经胶质瘤细胞系接种至裸鼠皮下形成皮下移植瘤。移植后3周处死裸鼠,三色流式细胞术检测MKN-45、SGC-7901、Huh-7和U87荷瘤裸鼠外周血内皮祖细胞(circulatingendothelial progenitor cells,CEPs)。使用小鼠内皮VEGF受体2(flk-1)、Sca-1和CD117来定义CEP。以0、5、10、15、20、25mg/kg/d UFT治疗MKN-45荷瘤裸鼠,治疗3周处死,流式细胞术检测CEPs。
2.将未荷瘤裸鼠作为空白组,MKN-45荷瘤裸鼠用生理盐水组、UFT节拍性化疗(20mg/kg/d),MTD UFT(50mg/kg,5天连续使用)和CTX节拍性化疗(20mg/kg/d)。治疗1周、2周和3周时,每组处死5只,流式细胞术检测CEPs。治疗3周后免疫组化检测肿瘤微血管密度(MVD)。
3.MKN-45荷瘤裸鼠分组为:生理盐水组(A)、UFT LMD(20mg/kg/d)组(B),UFTMTD(50mg/kg,5天连续使用)组(C)。UFT治疗1周、2周和3周时,每组处死5只。H&E和PAS染色肿瘤切片,显微镜观察,计数血管生成拟态(VM)。免疫组化检测CD31表达。采集第3周裸鼠血浆,ELISA法检测人血管内皮生长因子(VEGF)。
结果
1.SGC-7901、MKN-45、Huh-7和U87等动物模型中CEP水平升高。U87荷瘤裸鼠中CEPs数最高,而Huh-7荷瘤裸鼠中CEPs数最低。CEPs数与癌细胞系具有一致性。
2.使用CEPs作为标记物,确定UFT节拍性化疗的OBD为20mg/kg。
3.UFT节拍性化疗可抑制MKN-45荷瘤裸鼠中CEP和MVD,但CTX节拍性化疗却均未抑制CEP流动和MVD。
4.MKN-45肿瘤细胞在活体内可形成VM。UFT节拍性化疗抑制VM形成,而MTD UFT却没有。
结论
1.不同荷瘤裸鼠中外周血CEP水平是不同的。
2.外周血CEP检测确定UFT的OBD为20mg/kg。
3.UFT可通过抑制血管生成,对MKN-45胃癌产生抗肿瘤效应。
4.UFT节拍性化疗可抑制MKN-45胃癌的VM。
Backgroud
Gastric carcinoma remains a common disease worldwide.It represents the fourth most frequent malignancy and second leading cause of cancer-related death worldwide.Surgical resection is the standard treatment for patients with early-stage gastric cancer.Howerver, 80 to 90%of all patients are either diagnosed at an advanced stage when the tumour is inoperable.Patients with advanced disease are mainly treated with chemotherapy. Although several randomised trials have provided evidence that chemotherapy improves survival in these patients,the standard chemotherapeutic regimens often seriously impair the quality of life and cause serious side effects,which pose serious constraints on the use of chemotherapy.
In order to avoid the problems caused by traditional chemotherapeutic treatments, several researchers began to search for new modalities of drug administration oriented towards a more efficient and non-toxic antitumoral and/or antimetastic therapy. Angogenesis is necessary to sustain the growth of both the primary tumor and the development of metastases.Therapeutic targeting of tumor angiogenesis was first proposed by Folkman in 1971.From then on,the concept of angiogenesis as a therapeutic target in cancer has gained considerable momentum.Experiments had shown that some cytoxic drugs inhibited angiogenesis effectively,especially when administered more frequently and at lower dosage.Compared to maximum tolerable dose(MTD) chemotherapy,drugs being given at lower doses more frequently have stronger target effects on tumor vessel endothelial cells.This type of regimen is called metronomic chemotherapy or antiangiogenic chemotherapy.The metronomic chemotherapy affects the actively dividing and genetically stable endothelial cells,thereby reducing the chances of drug resistance to minimum.Because of its lower dosage,and more frequent schedule,it has lower toxicity. To develop a new approach for the treatment of gastric cancer,we want to explore whether antiangiogenic effect will be seen in nude mice bearing gastic cancer cells with this therapeutic approaches.
Recent evidences suggest that angiogenesis may not be the only mechanism by which tumors acquire a microcirculation.Tumour cells are able to behave like stem cells. Therefore,cancer cells can mimic other cell types and can adapt to microenvironmental changes.Tumour cell plasticity refers to the ability of tumour cells to express genes associated with multiple cellular phenotypes.Vasculogenic mimicry,in which tumour cells express genes associated with endothelial cells and form fluid-conducting channels,is an example of this plasticity.Some evidences suggested that gastric carcinoma cell lines expressed a set of genes,many of which had been implicated in epithelial cell biology, such as Von Willebrand factor,CD31,VE-cadherin.That means gastric carcinoma cells may be have tumor cell plasticity,and form VM in vivo.Based on these evidences,we want to explore wethere MKN-45 tumor cells can form VM in vivo and the effect of metronomic chemotherapy on VM.
Object
To assess endothelial progenitor cells(EPCs) in the peripheral blood of SGC 7901, MKN45,Huh-7 and U87 xenograft in BALB/c nude mice,to determined the optimum biologic dose(OBD) of metronomic LIFT,and to assess antiangiogenic effect and its effect on vasculogenic mimicry of metronomic UFT in human MKN-45 gastric cancer,compare its efficacy with MTD chemotherapy and metronomic CTX.
Materials and Methods
1.MKN-45 and SGC-7901 human gastric carcinoma cell lines,Huh-7 human hepatoma cell lines and U87 human glioblastoma cell lines were inoculated subcutaneously in nude mice to develop s.c.growing tumors.Nude mice were sacrificed at the 3th week after tumor implantation,EPCs in the peripheral blood of SGC-7901, MKN-45,Huh-7 and U87 xenograft in BALB/c nude mice were measured by 3-color flow cytometry.CEP(EPC in the peripheral blood) subset were depicted using the endothelial murine markers VEGF receptor 2 fetal liver kinase 1(flk-1),Sca-1,and CD117.After nude mice bearing MKN-45 human gastric cancer cell lines were treated with 0,5,10,15,20, 25mg/kg/d UFT,mice were sacrificed at 3th week,evaluation of CEPs was carried out on blood by flow cytometry.
2.Except for blank group,which was tumor-free nude mice,xenografts of MKN-45 gastric cancer cell lines were subjected to either continuous treatment with normal saline, low doses of UFT(20mg/kg/d),maximum tolerable doses of UFT(50mg/kg,5 consecutive days) and low doses of cyclophosphamide(CTX,20mg/kg/d).At the 1th,2th,3th week after the treatment,5 in each group were sacrificed,and evaluation of CEPs was carried out on blood by flow cytometry.Tumor microvessel density was evaluated by immunohistochemistry at the 3th week after the treatment.
3.Nude mice bearing MKN-45 human gastric carcinoma cell lines were deviding into three group:control group(A),UFT LMD(20mg/kg/d) group(B),UFT MTD (50mg/kg,5 consecutive days) group(C).At the 1th,2th,3th week after the treatment with normal saline or UFT,5 in each group were sacrificed.The morphological characteristics of slides of tumor specimens stained with H&E and PAS were examined in microscope, and counted the numbers of vasculogenic mimicry(VM).Immunohistochemical staining was used to analyze the expression of CD31.At 3th week after the treatment,the mouse sera were collected and measured for human VEGF by ELISA.
Results
1.In immunodeficient mice bearing MKN-45 and SGC 7901 human gastric carcinoma cell lines,Huh-7 human hepatoma cell lines and U87 human glioblastoma cell lines,increases in the levels of CEPs were observed.Nude mice bearing U87 human glioblastoma cell lines expressed the highest numbers of CEPs.In contrast,nude mice bearing Huh-7 human hepatoma cell lines were found to have much lowest numbers of CEPs.Moreover,we also observed a correlation between the number of CEPs and cancer cell lines.Using CEPs as a biomarker,we determined that the OBD of metronomic UFT administered daily was 20mg/kg.
2.In immunodeficient mice bearing MKN-45 human gastric carcinoma cell lines, metronomic UFT inhibited the mobilization of CEPs and reduced MVD,but metronomic CTX didn't,although in group CTX LMD,inhibiton rate of tumor was higher than in group UFT LMD.We observed a correlation between the number of CEPs and MVD.
3.MKN-45 tumor cells were ability to form VM in vivo.We found metronomic UFT inhibited the VM formations by MKN-45 gastric cancer cells,but MTD UFT didn't.
Conclusion
1.There are different levels of CEPs in the nude mice bearing different cancer cells.
2.We determine the OBD of metronomic UFT by detection of CEPs was 20mg/kg.
3.Metronomic UFT has antiangiogenic effect in human MKN-45 gastric cancer.
4.Metronomic UFT can inhibited VM formations by MKN-45 gastric cancer cells.
胃癌是全世界最常见的恶性肿瘤之一,其发病率位于恶性肿瘤第四位,居癌症死因的第二位。手术切除是早期胃癌的标准治疗,可是,80%至90%患者确诊时已是晚期,不能手术根治,全身化疗是晚期胃癌患者的主要治疗手段。虽然随机临床研究已证实化疗可以为晚期胃癌患者带来生存益处,但标准化疗常有严重的不良反应,从而降低患者的生活质量,也严重限制了化疗的使用。
为了避免传统化疗引起的问题,研究者开始寻找新的用药方式,旨在提高抗肿瘤和/或抗转移效果,降低毒性。血管生成(angiogenesis)对维持原发肿瘤的生长和转移至关重要。自1971年Folkman首次提出针对肿瘤血管生成的治疗以来,血管生成已成为癌症治疗一个靶点。研究发现,某些细胞毒性药物的确能抑制血管生成,尤其是以小剂量、高频率给药时。与最大耐受剂量(maximum tolerable dose,MTD)化疗相比,小剂量、高频率或持续给药对肿瘤血管内皮的靶向作用更强。这种化疗方案称为“节拍性化疗”(metronomic chemotherapy)或“抗血管生成化疗”(antiangiogenicchemotherapy)。由于节拍性化疗以肿瘤血管内基因稳定、活化的内皮细胞为治疗靶点,降低了耐药性的发生,提高了治疗效果,又因其剂量较低,还能降低化疗的毒副作用。为了探讨胃癌治疗治疗新方法,本课题以MKN-45荷瘤裸鼠为模型,研究节拍性化疗的抗肿瘤血管生成作用。
研究证实,血管生成并不是肿瘤获得微循环的唯一机制。肿瘤细胞在行为上与胚胎干细胞类似。肿瘤细胞可模拟其他类型细胞,对微环境变化作出适应性应答。肿瘤细胞表达多种细胞表型基因的能力,称为肿瘤细胞可塑性。肿瘤细胞表达内皮细胞相关基因,形成输送液体的管道结构,即称为血管生成拟态(vasculogenic mimicry,VM),其是肿瘤可塑性的一种表现。研究证实,人胃癌细胞系可表达一系列与上皮细胞生理相关的基因,如Von Willebrand因子、CD31、VE-钙粘蛋白(VE-cadherin),表明胃癌细胞具有肿瘤细胞可塑性,提示胃癌中可能存在血管生成拟态。基于以上研究的启示,本课题拟在荷瘤裸鼠中研究MKN-45肿瘤细胞是否具有形成VM的能力,以及节拍性化疗对VM是否具有抑制作用。
目的
确定优福定(UFT)节拍性化疗的最佳生物学剂量(optimum biologic dose,OBD),以及在MKN-45荷瘤裸鼠中检测UFT节拍性化疗抗血管生成效应和抑制血管生成拟态作用,并比较UFT节拍性化疗与MTD UFT和CTX节拍性化疗的疗效。
材料与方法
1.MKN-45、SGC-7901人胃癌细胞系、Huh-7人肝癌细胞系和U87人神经胶质瘤细胞系接种至裸鼠皮下形成皮下移植瘤。移植后3周处死裸鼠,三色流式细胞术检测MKN-45、SGC-7901、Huh-7和U87荷瘤裸鼠外周血内皮祖细胞(circulatingendothelial progenitor cells,CEPs)。使用小鼠内皮VEGF受体2(flk-1)、Sca-1和CD117来定义CEP。以0、5、10、15、20、25mg/kg/d UFT治疗MKN-45荷瘤裸鼠,治疗3周处死,流式细胞术检测CEPs。
2.将未荷瘤裸鼠作为空白组,MKN-45荷瘤裸鼠用生理盐水组、UFT节拍性化疗(20mg/kg/d),MTD UFT(50mg/kg,5天连续使用)和CTX节拍性化疗(20mg/kg/d)。治疗1周、2周和3周时,每组处死5只,流式细胞术检测CEPs。治疗3周后免疫组化检测肿瘤微血管密度(MVD)。
3.MKN-45荷瘤裸鼠分组为:生理盐水组(A)、UFT LMD(20mg/kg/d)组(B),UFTMTD(50mg/kg,5天连续使用)组(C)。UFT治疗1周、2周和3周时,每组处死5只。H&E和PAS染色肿瘤切片,显微镜观察,计数血管生成拟态(VM)。免疫组化检测CD31表达。采集第3周裸鼠血浆,ELISA法检测人血管内皮生长因子(VEGF)。
结果
1.SGC-7901、MKN-45、Huh-7和U87等动物模型中CEP水平升高。U87荷瘤裸鼠中CEPs数最高,而Huh-7荷瘤裸鼠中CEPs数最低。CEPs数与癌细胞系具有一致性。
2.使用CEPs作为标记物,确定UFT节拍性化疗的OBD为20mg/kg。
3.UFT节拍性化疗可抑制MKN-45荷瘤裸鼠中CEP和MVD,但CTX节拍性化疗却均未抑制CEP流动和MVD。
4.MKN-45肿瘤细胞在活体内可形成VM。UFT节拍性化疗抑制VM形成,而MTD UFT却没有。
结论
1.不同荷瘤裸鼠中外周血CEP水平是不同的。
2.外周血CEP检测确定UFT的OBD为20mg/kg。
3.UFT可通过抑制血管生成,对MKN-45胃癌产生抗肿瘤效应。
4.UFT节拍性化疗可抑制MKN-45胃癌的VM。
Backgroud
Gastric carcinoma remains a common disease worldwide.It represents the fourth most frequent malignancy and second leading cause of cancer-related death worldwide.Surgical resection is the standard treatment for patients with early-stage gastric cancer.Howerver, 80 to 90%of all patients are either diagnosed at an advanced stage when the tumour is inoperable.Patients with advanced disease are mainly treated with chemotherapy. Although several randomised trials have provided evidence that chemotherapy improves survival in these patients,the standard chemotherapeutic regimens often seriously impair the quality of life and cause serious side effects,which pose serious constraints on the use of chemotherapy.
In order to avoid the problems caused by traditional chemotherapeutic treatments, several researchers began to search for new modalities of drug administration oriented towards a more efficient and non-toxic antitumoral and/or antimetastic therapy. Angogenesis is necessary to sustain the growth of both the primary tumor and the development of metastases.Therapeutic targeting of tumor angiogenesis was first proposed by Folkman in 1971.From then on,the concept of angiogenesis as a therapeutic target in cancer has gained considerable momentum.Experiments had shown that some cytoxic drugs inhibited angiogenesis effectively,especially when administered more frequently and at lower dosage.Compared to maximum tolerable dose(MTD) chemotherapy,drugs being given at lower doses more frequently have stronger target effects on tumor vessel endothelial cells.This type of regimen is called metronomic chemotherapy or antiangiogenic chemotherapy.The metronomic chemotherapy affects the actively dividing and genetically stable endothelial cells,thereby reducing the chances of drug resistance to minimum.Because of its lower dosage,and more frequent schedule,it has lower toxicity. To develop a new approach for the treatment of gastric cancer,we want to explore whether antiangiogenic effect will be seen in nude mice bearing gastic cancer cells with this therapeutic approaches.
Recent evidences suggest that angiogenesis may not be the only mechanism by which tumors acquire a microcirculation.Tumour cells are able to behave like stem cells. Therefore,cancer cells can mimic other cell types and can adapt to microenvironmental changes.Tumour cell plasticity refers to the ability of tumour cells to express genes associated with multiple cellular phenotypes.Vasculogenic mimicry,in which tumour cells express genes associated with endothelial cells and form fluid-conducting channels,is an example of this plasticity.Some evidences suggested that gastric carcinoma cell lines expressed a set of genes,many of which had been implicated in epithelial cell biology, such as Von Willebrand factor,CD31,VE-cadherin.That means gastric carcinoma cells may be have tumor cell plasticity,and form VM in vivo.Based on these evidences,we want to explore wethere MKN-45 tumor cells can form VM in vivo and the effect of metronomic chemotherapy on VM.
Object
To assess endothelial progenitor cells(EPCs) in the peripheral blood of SGC 7901, MKN45,Huh-7 and U87 xenograft in BALB/c nude mice,to determined the optimum biologic dose(OBD) of metronomic LIFT,and to assess antiangiogenic effect and its effect on vasculogenic mimicry of metronomic UFT in human MKN-45 gastric cancer,compare its efficacy with MTD chemotherapy and metronomic CTX.
Materials and Methods
1.MKN-45 and SGC-7901 human gastric carcinoma cell lines,Huh-7 human hepatoma cell lines and U87 human glioblastoma cell lines were inoculated subcutaneously in nude mice to develop s.c.growing tumors.Nude mice were sacrificed at the 3th week after tumor implantation,EPCs in the peripheral blood of SGC-7901, MKN-45,Huh-7 and U87 xenograft in BALB/c nude mice were measured by 3-color flow cytometry.CEP(EPC in the peripheral blood) subset were depicted using the endothelial murine markers VEGF receptor 2 fetal liver kinase 1(flk-1),Sca-1,and CD117.After nude mice bearing MKN-45 human gastric cancer cell lines were treated with 0,5,10,15,20, 25mg/kg/d UFT,mice were sacrificed at 3th week,evaluation of CEPs was carried out on blood by flow cytometry.
2.Except for blank group,which was tumor-free nude mice,xenografts of MKN-45 gastric cancer cell lines were subjected to either continuous treatment with normal saline, low doses of UFT(20mg/kg/d),maximum tolerable doses of UFT(50mg/kg,5 consecutive days) and low doses of cyclophosphamide(CTX,20mg/kg/d).At the 1th,2th,3th week after the treatment,5 in each group were sacrificed,and evaluation of CEPs was carried out on blood by flow cytometry.Tumor microvessel density was evaluated by immunohistochemistry at the 3th week after the treatment.
3.Nude mice bearing MKN-45 human gastric carcinoma cell lines were deviding into three group:control group(A),UFT LMD(20mg/kg/d) group(B),UFT MTD (50mg/kg,5 consecutive days) group(C).At the 1th,2th,3th week after the treatment with normal saline or UFT,5 in each group were sacrificed.The morphological characteristics of slides of tumor specimens stained with H&E and PAS were examined in microscope, and counted the numbers of vasculogenic mimicry(VM).Immunohistochemical staining was used to analyze the expression of CD31.At 3th week after the treatment,the mouse sera were collected and measured for human VEGF by ELISA.
Results
1.In immunodeficient mice bearing MKN-45 and SGC 7901 human gastric carcinoma cell lines,Huh-7 human hepatoma cell lines and U87 human glioblastoma cell lines,increases in the levels of CEPs were observed.Nude mice bearing U87 human glioblastoma cell lines expressed the highest numbers of CEPs.In contrast,nude mice bearing Huh-7 human hepatoma cell lines were found to have much lowest numbers of CEPs.Moreover,we also observed a correlation between the number of CEPs and cancer cell lines.Using CEPs as a biomarker,we determined that the OBD of metronomic UFT administered daily was 20mg/kg.
2.In immunodeficient mice bearing MKN-45 human gastric carcinoma cell lines, metronomic UFT inhibited the mobilization of CEPs and reduced MVD,but metronomic CTX didn't,although in group CTX LMD,inhibiton rate of tumor was higher than in group UFT LMD.We observed a correlation between the number of CEPs and MVD.
3.MKN-45 tumor cells were ability to form VM in vivo.We found metronomic UFT inhibited the VM formations by MKN-45 gastric cancer cells,but MTD UFT didn't.
Conclusion
1.There are different levels of CEPs in the nude mice bearing different cancer cells.
2.We determine the OBD of metronomic UFT by detection of CEPs was 20mg/kg.
3.Metronomic UFT has antiangiogenic effect in human MKN-45 gastric cancer.
4.Metronomic UFT can inhibited VM formations by MKN-45 gastric cancer cells.
引文
1 Khan FA, Shukla AN. Pathogenesis and treatment of gastric carcinoma: "an up-date with brief review"[J]. J Cancer Res Ther, 2006,2(4): 196-9.
2 Folkman J. Angiogenesis[J]. Annu Rev Med, 2006,57:1-18.
3 Harlozinska A. Progress in molecular mechanisms of tumor metastasis and angiogenesis[J]. Anticancer Res, 2005,25(5):3327-33.
4 Semenza GL. Angiogenesis in ischemic and neoplastic disorders[J]. Annu Rev Med, 2003,54:17-28.
5 Whisenant J, Bergsland E. Anti-angiogenic strategies in gastrointestinal malignancies[J]. Curr Treat Options Oncol, 2005,6(5):411-21.
6 Miller KD, Sweeney CJ,Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics[J]. J Clin Oncol, 2001,19(4): 1195-206.
7 Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity[J]. J Clin Invest, 2000,105(8):R15-24.
8 Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer[J]. Cancer Res, 2000,60(7): 1878-86.
9 Bello L, Carrabba G, Giussani C, et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo[J]. Cancer Res, 2001,61(20):7501-6.
10 Kamat AA, Kim TJ, Landen CN Jr, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer[J]. Cancer Res, 2007,67(1):281-8.
11 Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer[J]. J Clin Oncol, 2005,23(5):939-52.
12 Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water[J]. Cancer Res, 2002,62(10):2731-5.
13 Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with Her-2 positive metastatic breast cancer[J]. BMC Cancer, 2006,6(1):225.
14 Dome B, Dobos J, Tovari J, et al. Circulating bone marrow-derived endothelial progenitor cells: characterization, mobilization, and therapeutic considerations in malignant disease[J]. Cytometry A, 2008,73(3):186-93.
15 Khakoo AY, Finkel T. Endothelial progenitor cells[J]. Annu Rev Med, 2005,56:79-101.
16 Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer[J]. Nat Med, 2004,10(2): 145-7.
17 Mancuso P, Colleoni M, Called A, et al. Circulating endothelial cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemo therapy [J]. Blood, 2006,108(2):452-59.
18 Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity[J]. Blood, 2005,106(9):3058-61.
19 Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry[J]. Am J Pathol, 1999,155(3):739-52.
20 Suvannasankha A, Fausel C, Juliar BE, et al. Final Report of Toxicity and Efficacy of a Phase II Study of Oral Cyclophosphamide, Thalidomide, and Prednisone for Patients with Relapsed or Refractory Multiple Myeloma: A Hoosier Oncology Group Trial, HEM01-21[J]. Oncologist, 2007,12(1):99-106.
21 Clarijs R, van Dijk M, Ruiter DJ, et al. Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2005,46(9):3013-20.
22 Clarijs R, Otte-Holler I, Ruiter DJ, et al. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2002,43(4):912-8.
23 Folberg R, Maniotis AJ. Vasculogenic mimicry[J]. APMIS, 2004,112(7-8):508-25.
24 Hendrix MJ, Seftor EA, Hess AR, et al. Molecular plasticity of human melanoma cells[J]. Oncogene, 2003,22(20):3070-5.
25 Ji J, Chen X, Leung SY, et al. Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines[J]. Oncogene, 2002,21(42):6549-56.
26 Shimizu K, Asai T,Oku N. Antineovascular therapy, a novel antiangiogenic approach[J]. Expert Opin Ther Targets, 2005,9(1):63-76.
1 Goon PK, Boos CJ, Stonelake PS, et al. Circulating endothelial cells in malignant disease[J]. Fut Oncol, 2005,1(6):813-20.
2 Goon PK, Lip GY, Boos CJ, et al. Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer[J]. Neoplasia, 2006,8(2):79-88.
3 Bertolini F, Shaked Y, Mancuso P, et al. The multifaceted circulating endothelial cell in cancer: towards marker and target identification[J]. Nat Rev Cancer, 2006,6(11):835-45.
4 Schneider M, Tjwa M,Carmeliet P. A surrogate marker to monitor angiogenesis at last[J]. Cancer Cell, 2005,7(1):3-4.
5 Dome B, Dobos J, Tovari J, et al. Circulating bone marrow-derived endothelial progenitor cells: characterization, mobilization, and therapeutic considerations in malignant disease[J]. Cytometry A, 2008,73(3):186-93.
6 Khakoo AY, Finkel T. Endothelial progenitor cells[J]. Annu Rev Med, 2005,56:79-101.
7 Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer[J]. Nat Med, 2004,10(2):145-7.
8 Munoz R, Shaked Y, Bertolini F, et al. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy [J]. Breast, 2005,14(6):466-79.
9 Mancuso P, Colleoni M, Calleri A, et al. Circulating endothelial cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemo therapy [J]. Blood, 2006,108(2):452-59.
10 Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity[J]. Blood, 2005,106(9):3058-61.
11 Basaki Y, Chikahisa L, Aoyagi K, et al. gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor[J]. Angiogenesis, 2001,4(3):163-73.
12 Khan SS, Solomon MA,McCoy JP Jr. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry[J]. Cytometry B Clin Cytom, 2005,64(1): 1-8.
13 Li TS, Hamano K, Nishida M, et al. CDl 17+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation[J]. Am J Physiol Heart Circ Physiol, 2003,285(3):H931-7.
14 Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration[J]. Nat Med, 2003,9(6):702-12.
15 Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells[J]. EMBO J, 1999,18(14):3964-72.
16 Goon PK, Boos CJ, Stonelake PS, et al. Detection and quantification of mature circulating endothelial cells using flow cytometry and immunomagnetic beads: a methodological comparison[J]. Thromb Haemost, 2006,96(1):45-52.
17 Del Papa N, Colombo G, Fracchiolla N, et al. Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis[J]. Arthritis Rheum, 2004,50(4): 1296-304.
18 Mancuso P, Burlini A, Pruneri G, et al. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients[J]. Blood, 2001,97(11):3658-61.
19 Kurosaka D, Yasuda J, Yoshida K, et al. Kinetics of circulating endothelial progenitor cells in mice with type II collagen arthritis[J]. Blood Cells Mol Dis, 2005,35(2):236-40.
20 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy [J]. Nat Rev Cancer, 2004,4(6):423-36.
21 Yonekura K, Basaki Y, Chikahisa L, et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice[J]. Clin Cancer Res, 1999,5(8):2185-91.
22 Celik I, Surucu O, Dietz C, et al. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve[J]. Cancer Res, 2005,65(23): 11044-50.
1. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy [J]. Nat Rev Cancer, 2004,4(6):423-36.
2. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003,3(6):401-10.
3. Whisenant J, Bergsland E. Anti-angiogenic strategies in gastrointestinal malignancies[J], Curr Treat Options Oncol, 2005,6(5):411-21.
4. Hanahan D, Bergers G,Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice[J]. J Clin Invest, 2000,105(8):1045-7.
5. Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer[J]. Cancer Res, 2000,60(7): 1878-86.
6. Bello L, Carrabba G, Giussani C, et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo[J]. Cancer Res, 2001,61(20):7501-6.
7. Kamat AA, Kim TJ, Landen CN Jr, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer[J]. Cancer Res, 2007,67(1):281-8.
8. Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer[J]. J Clin Oncol, 2005,23(5):939-52.
9. Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water[J]. Cancer Res, 2002,62(10):2731-5.
10. Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with Her-2 positive metastatic breast cancer[J]. BMC Cancer, 2006,6(1):225.
11. Yonekura K, Basaki Y, Chikahisa L, et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice[J]. Clin Cancer Res, 1999,5(8):2185-91.
12. Maehara Y, Kusumoto T, Kusumoto H, et al. 5-Fluorouracil and UFT-sensitive gastric carcinoma has a high level of thymidylate synthase[J]. Cancer, 1989,63(9):1693-6.
13. Bertolini F, Paul S, Mancuso P, et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells[J]. Cancer Res, 2003,63(15):4342-6.
14. Gately S, Kerbel R. Antiangiogenic scheduling of lower dose cancer chemotherapy[J]. Cancer J, 2001,7(5):427-36.
15. Lamont EB, Schilsky RL. The oral fluoropyrimidines in cancer chemotherapy[J]. Clin Cancer Res, 1999,5(9):2289-96.
16. Miller KD, Sweeney CJ,Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics[J]. J Clin Oncol, 2001,19(4):1195-206.
17. Bocci G, Nicolaou KC,Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs[J]. Cancer Res, 2002,62(23):6938-43.
1. Dome B, Hendrix MJ, Paku S, et al. Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications[J]. Am J Pathol, 2007,170(1): 1-15.
2. Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry[J]. Am J Pathol, 1999,155(3):739-52.
3. McDonald DM, Munn L,Jain RK. Vasculogenic mimicry: how convincing, how novel, and how significant?[J]. Am J Pathol, 2000,156(2):383-8.
4. Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond[J]. Cancer Metastasis Rev, 2007,26(3-4):489-502.
5. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003,3(6):401-10.
6. Clarijs R, van Dijk M, Ruiter DJ, et al. Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2005,46(9):3013-20.
7. Clarijs R, Otte-Holler I, Ruiter DJ, et al. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2002,43(4):912-8.
8. Folberg R, Maniotis AJ. Vasculogenic mimicry[J]. APMIS, 2004,112(7-8):508-25.
9. Hendrix MJ, Seftor EA, Hess AR, et al. Molecular plasticity of human melanoma cells[J]. Oncogene, 2003,22(20):3070-5.
10. Hendrix MJ, Seftor EA, Seftor RE, et al. Reprogramming metastatic tumour cells with embryonic microenvironments[J]. Nat Rev Cancer, 2007,7(4):246-55.
11. Ji J, Chen X, Leung SY, et al. Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines[J]. Oncogene, 2002,21 (42) :6549-56.
12. Shimizu K, Asai T,Oku N. Antineovascular therapy, a novel antiangiogenic approach[J]. Expert Opin Ther Targets, 2005,9(1):63-76.
13. Pisacane AM, Picciotto F,Risio M. CD31 and CD34 expression as immunohistochemical markers of endothelial transdifferentiation in human cutaneous melanoma[J]. Cell Oncol, 2007,29(1):59-66.
14. Bissell MJ. Tumor plasticity allows vasculogenic mimicry, a novel form of angiogenic switch. A rose by any other name?[J]. Am J Pathol, 1999,155(3):675-9.
15. Vartanian AA, Burova OS, Stepanova EV, et al. Melanoma vasculogenic mimicry is strongly related to reactive oxygen species level[J]. Melanoma Res, 2007,17(6):370-9.
16. van der Schaft DW, Seftor RE, Seftor EA, et al. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells[J]. J Natl Cancer Inst, 2004,96(19):1473-7.
17. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy[J]. Nat Rev Cancer, 2004,4(6):423-36.
18. Folkins C, Man S, Xu P, et al. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors[J]. Cancer Res, 2007,67(8):3560-4.
19. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer[J]. J Clin Oncol, 2001,19(3):843-50.
20. Nakamura R, Kataoka H, Sato N, et al. EPHA2/EFNA1 expression in human gastric cancer[J]. Cancer Sci, 2005,96(1):42-7.
21. Hendrix MJ, Seftor EA, Hess AR, et al. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma[J]. Nat Rev Cancer, 2003,3(6):411-21.
22. Vihanto MM, Plock J, Erni D, et al. Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin[J]. FASEB J, 2005,19(12):1689-91.
1 Hanahan D, Bergers G,Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice[J]. J Clin Invest, 2000,105(8):1045-7.
2 Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer[J]. Cancer Res, 2000,60(7):1878-86.
3 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy[J]. Nat Rev Cancer, 2004,4(6):423-36.
4 Vacca A, Iurlaro M, Ribatti D, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine[J]. Blood, 1999,94(12):4143-55.
5 Wang J, Lou P, Lesniewski R, et al. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly[J]. Anticancer Drugs, 2003,14(1):13-9.
6 Bocci G, Nicolaou KC,Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs[J]. Cancer Res, 2002,62(23):6938-43.
7 Bocci G, Francia G, Man S, et al. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy[J]. Proc Natl Acad Sci U S A, 2003,100(22):12917-22.
8 Hamano Y, Sugimoto H, Soubasakos MA, et al. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression[J]. Cancer Res, 2004,64(5): 1570-4.
9 Dawson DW, Pearce SF, Zhong R, et al. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells[J]. J Cell Biol, 1997,138(3):707-17.
10 Jimenez B, Volpert OV, Crawford SE, et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1[J]. Nat Med, 2000,6(1):41-8.
11 Gupta K, Gupta P, Wild R, et al. Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis[J]. Angiogenesis, 1999,3(2):147-58.
12 Lam T, Hetherington JW, Greenman J, et al. From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials[J]. Anticancer Drugs, 2006,17(2): 113-21.
13 Shaked Y, Bertolini F, Man S, et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis[J]. Cancer Cell, 2005,7(1):101-11.
14 Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water[J]. Cancer Res, 2002,62(10):2731-5.
15 Klement G, Huang P, Mayer B, et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts[J]. Clin Cancer Res, 2002,8(1):221-32.
16 Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity [J]. J Clin Invest, 2000,105(8):R15-24.
17 Kim ES, Soffer SZ, Huang J, et al. Distinct response of experimental neuroblastoma to combination antiangiogenic strategies [J]. J Pediatr Surg, 2002,37(3):518-22.
18 Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer[J]. J Clin Oncol, 2005,23(5):939-52.
19 Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels[J]. Ann Oncol, 2002,13(1):73-80.
20 Tuettenberg J, Grobholz R, Korn T, et al. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme[J]. J Cancer Res Clin Oncol, 2005,131(1):31-40.
1 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases[J]. Nature, 2000,407(6801):249-57.
2 Martin A, Komada MR,Sane DC. Abnormal angiogenesis in diabetes mellitus[J]. Med Res Rev, 2003,23(2): 117-45.
3 Koch AE. Angiogenesis as a target in rheumatoid arthritis[J]. Ann Rheum Dis, 2003,62 Suppl 2:ii60-7.
4 Carmeliet P. Angiogenesis in life, disease and medicine[J]. Nature, 2005,438(7070):932-6.
5 Hanahan D, Weinberg RA. The hallmarks of cancer[J]. Cell, 2000,100(1):57-70.
6 Ferrara N, Gerber HP,LeCouter J. The biology of VEGF and its receptors[J]. Nat Med, 2003,9(6):669-76.
7 Hurwitz H, Kabbinavar F. Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer[J]. Oncology, 2005,69 Suppl 3:17-24.
8 Burri PH, Hlushchuk R,Djonov V. Intussusceptive angiogenesis: its emergence, its characteristics, and its significance[J]. Dev Dyn, 2004,231(3):474-88.
9 Patan S, Munn LL,Jain RK. Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis[J]. Microvasc Res, 1996,51(2):260-72.
10 Asahara T, Kawamoto A. Endothelial progenitor cells for postnatal vasculogenesis[J]. Am J Physiol Cell Physiol, 2004,287(3):C572-9.
11 Garmy-Susini B, Varner JA. Circulating endothelial progenitor cells[J]. Br J Cancer, 2005,93(8):855-8.
12 Urbich C, Aicher A, Heeschen C, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells[J]. J Mol Cell Cardiol, 2005,39(5):733-42.
13 Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth[J]. Nat Med, 2001,7(11):1194-201.
14 Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche[J]. Nature, 2005,438(7069):820-7.
15 Leenders WP, Kusters B,de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis[J]. Endothelium, 2002,9(2):83-7.
16 Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF[J]. Science, 1999,284(5422):1994-8.
17 Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis[J]. Science, 1997,277(5322):55-60.
18 Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry[J]. Am J Pathol, 1999,155(3):739-52.
19 Hendrix MJ, Seftor EA, Hess AR, et al. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma[J]. Nat Rev Cancer, 2003,3(6):411-21.
20 Seftor EA, Brown KM, Chin L, et al. Epigenetic transdifferentiation of normal melanocytes by a metastatic melanoma microenvironment[J]. Cancer Res, 2005,65(22): 10164-9.
21 Postovit LM, Seftor EA, Seftor RE, et al. Influence of the microenvironment on melanoma cell fate determination and phenotype[J]. Cancer Res, 2006,66(16):7833-6,
22 Sun B, Zhang D, Zhang S, et al. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma[J]. Cancer Lett, 2007,249(2): 188-97.
23 Clarijs R, Otte-Holler I, Ruiter DJ, et al. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2002,43(4):912-8.
24 Shirakawa K, Kobayashi H, Heike Y, et al. Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft[J]. Cancer Res, 2002,62(2):560-6.
25 Frenkel S, Barzel I, Levy J, et al. Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography[J], Eye, 2007.
26 Folberg R, Maniotis AJ. Vasculogenic mimicry[J]. APMIS, 2004,112(7-8):508-25.
27 Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy[J], Science, 2005,307(5706):58-62.
2 Folkman J. Angiogenesis[J]. Annu Rev Med, 2006,57:1-18.
3 Harlozinska A. Progress in molecular mechanisms of tumor metastasis and angiogenesis[J]. Anticancer Res, 2005,25(5):3327-33.
4 Semenza GL. Angiogenesis in ischemic and neoplastic disorders[J]. Annu Rev Med, 2003,54:17-28.
5 Whisenant J, Bergsland E. Anti-angiogenic strategies in gastrointestinal malignancies[J]. Curr Treat Options Oncol, 2005,6(5):411-21.
6 Miller KD, Sweeney CJ,Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics[J]. J Clin Oncol, 2001,19(4): 1195-206.
7 Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity[J]. J Clin Invest, 2000,105(8):R15-24.
8 Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer[J]. Cancer Res, 2000,60(7): 1878-86.
9 Bello L, Carrabba G, Giussani C, et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo[J]. Cancer Res, 2001,61(20):7501-6.
10 Kamat AA, Kim TJ, Landen CN Jr, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer[J]. Cancer Res, 2007,67(1):281-8.
11 Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer[J]. J Clin Oncol, 2005,23(5):939-52.
12 Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water[J]. Cancer Res, 2002,62(10):2731-5.
13 Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with Her-2 positive metastatic breast cancer[J]. BMC Cancer, 2006,6(1):225.
14 Dome B, Dobos J, Tovari J, et al. Circulating bone marrow-derived endothelial progenitor cells: characterization, mobilization, and therapeutic considerations in malignant disease[J]. Cytometry A, 2008,73(3):186-93.
15 Khakoo AY, Finkel T. Endothelial progenitor cells[J]. Annu Rev Med, 2005,56:79-101.
16 Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer[J]. Nat Med, 2004,10(2): 145-7.
17 Mancuso P, Colleoni M, Called A, et al. Circulating endothelial cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemo therapy [J]. Blood, 2006,108(2):452-59.
18 Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity[J]. Blood, 2005,106(9):3058-61.
19 Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry[J]. Am J Pathol, 1999,155(3):739-52.
20 Suvannasankha A, Fausel C, Juliar BE, et al. Final Report of Toxicity and Efficacy of a Phase II Study of Oral Cyclophosphamide, Thalidomide, and Prednisone for Patients with Relapsed or Refractory Multiple Myeloma: A Hoosier Oncology Group Trial, HEM01-21[J]. Oncologist, 2007,12(1):99-106.
21 Clarijs R, van Dijk M, Ruiter DJ, et al. Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2005,46(9):3013-20.
22 Clarijs R, Otte-Holler I, Ruiter DJ, et al. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2002,43(4):912-8.
23 Folberg R, Maniotis AJ. Vasculogenic mimicry[J]. APMIS, 2004,112(7-8):508-25.
24 Hendrix MJ, Seftor EA, Hess AR, et al. Molecular plasticity of human melanoma cells[J]. Oncogene, 2003,22(20):3070-5.
25 Ji J, Chen X, Leung SY, et al. Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines[J]. Oncogene, 2002,21(42):6549-56.
26 Shimizu K, Asai T,Oku N. Antineovascular therapy, a novel antiangiogenic approach[J]. Expert Opin Ther Targets, 2005,9(1):63-76.
1 Goon PK, Boos CJ, Stonelake PS, et al. Circulating endothelial cells in malignant disease[J]. Fut Oncol, 2005,1(6):813-20.
2 Goon PK, Lip GY, Boos CJ, et al. Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer[J]. Neoplasia, 2006,8(2):79-88.
3 Bertolini F, Shaked Y, Mancuso P, et al. The multifaceted circulating endothelial cell in cancer: towards marker and target identification[J]. Nat Rev Cancer, 2006,6(11):835-45.
4 Schneider M, Tjwa M,Carmeliet P. A surrogate marker to monitor angiogenesis at last[J]. Cancer Cell, 2005,7(1):3-4.
5 Dome B, Dobos J, Tovari J, et al. Circulating bone marrow-derived endothelial progenitor cells: characterization, mobilization, and therapeutic considerations in malignant disease[J]. Cytometry A, 2008,73(3):186-93.
6 Khakoo AY, Finkel T. Endothelial progenitor cells[J]. Annu Rev Med, 2005,56:79-101.
7 Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer[J]. Nat Med, 2004,10(2):145-7.
8 Munoz R, Shaked Y, Bertolini F, et al. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy [J]. Breast, 2005,14(6):466-79.
9 Mancuso P, Colleoni M, Calleri A, et al. Circulating endothelial cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemo therapy [J]. Blood, 2006,108(2):452-59.
10 Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity[J]. Blood, 2005,106(9):3058-61.
11 Basaki Y, Chikahisa L, Aoyagi K, et al. gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor[J]. Angiogenesis, 2001,4(3):163-73.
12 Khan SS, Solomon MA,McCoy JP Jr. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry[J]. Cytometry B Clin Cytom, 2005,64(1): 1-8.
13 Li TS, Hamano K, Nishida M, et al. CDl 17+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation[J]. Am J Physiol Heart Circ Physiol, 2003,285(3):H931-7.
14 Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration[J]. Nat Med, 2003,9(6):702-12.
15 Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells[J]. EMBO J, 1999,18(14):3964-72.
16 Goon PK, Boos CJ, Stonelake PS, et al. Detection and quantification of mature circulating endothelial cells using flow cytometry and immunomagnetic beads: a methodological comparison[J]. Thromb Haemost, 2006,96(1):45-52.
17 Del Papa N, Colombo G, Fracchiolla N, et al. Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis[J]. Arthritis Rheum, 2004,50(4): 1296-304.
18 Mancuso P, Burlini A, Pruneri G, et al. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients[J]. Blood, 2001,97(11):3658-61.
19 Kurosaka D, Yasuda J, Yoshida K, et al. Kinetics of circulating endothelial progenitor cells in mice with type II collagen arthritis[J]. Blood Cells Mol Dis, 2005,35(2):236-40.
20 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy [J]. Nat Rev Cancer, 2004,4(6):423-36.
21 Yonekura K, Basaki Y, Chikahisa L, et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice[J]. Clin Cancer Res, 1999,5(8):2185-91.
22 Celik I, Surucu O, Dietz C, et al. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve[J]. Cancer Res, 2005,65(23): 11044-50.
1. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy [J]. Nat Rev Cancer, 2004,4(6):423-36.
2. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003,3(6):401-10.
3. Whisenant J, Bergsland E. Anti-angiogenic strategies in gastrointestinal malignancies[J], Curr Treat Options Oncol, 2005,6(5):411-21.
4. Hanahan D, Bergers G,Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice[J]. J Clin Invest, 2000,105(8):1045-7.
5. Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer[J]. Cancer Res, 2000,60(7): 1878-86.
6. Bello L, Carrabba G, Giussani C, et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo[J]. Cancer Res, 2001,61(20):7501-6.
7. Kamat AA, Kim TJ, Landen CN Jr, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer[J]. Cancer Res, 2007,67(1):281-8.
8. Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer[J]. J Clin Oncol, 2005,23(5):939-52.
9. Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water[J]. Cancer Res, 2002,62(10):2731-5.
10. Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with Her-2 positive metastatic breast cancer[J]. BMC Cancer, 2006,6(1):225.
11. Yonekura K, Basaki Y, Chikahisa L, et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice[J]. Clin Cancer Res, 1999,5(8):2185-91.
12. Maehara Y, Kusumoto T, Kusumoto H, et al. 5-Fluorouracil and UFT-sensitive gastric carcinoma has a high level of thymidylate synthase[J]. Cancer, 1989,63(9):1693-6.
13. Bertolini F, Paul S, Mancuso P, et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells[J]. Cancer Res, 2003,63(15):4342-6.
14. Gately S, Kerbel R. Antiangiogenic scheduling of lower dose cancer chemotherapy[J]. Cancer J, 2001,7(5):427-36.
15. Lamont EB, Schilsky RL. The oral fluoropyrimidines in cancer chemotherapy[J]. Clin Cancer Res, 1999,5(9):2289-96.
16. Miller KD, Sweeney CJ,Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics[J]. J Clin Oncol, 2001,19(4):1195-206.
17. Bocci G, Nicolaou KC,Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs[J]. Cancer Res, 2002,62(23):6938-43.
1. Dome B, Hendrix MJ, Paku S, et al. Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications[J]. Am J Pathol, 2007,170(1): 1-15.
2. Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry[J]. Am J Pathol, 1999,155(3):739-52.
3. McDonald DM, Munn L,Jain RK. Vasculogenic mimicry: how convincing, how novel, and how significant?[J]. Am J Pathol, 2000,156(2):383-8.
4. Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond[J]. Cancer Metastasis Rev, 2007,26(3-4):489-502.
5. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003,3(6):401-10.
6. Clarijs R, van Dijk M, Ruiter DJ, et al. Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2005,46(9):3013-20.
7. Clarijs R, Otte-Holler I, Ruiter DJ, et al. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2002,43(4):912-8.
8. Folberg R, Maniotis AJ. Vasculogenic mimicry[J]. APMIS, 2004,112(7-8):508-25.
9. Hendrix MJ, Seftor EA, Hess AR, et al. Molecular plasticity of human melanoma cells[J]. Oncogene, 2003,22(20):3070-5.
10. Hendrix MJ, Seftor EA, Seftor RE, et al. Reprogramming metastatic tumour cells with embryonic microenvironments[J]. Nat Rev Cancer, 2007,7(4):246-55.
11. Ji J, Chen X, Leung SY, et al. Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines[J]. Oncogene, 2002,21 (42) :6549-56.
12. Shimizu K, Asai T,Oku N. Antineovascular therapy, a novel antiangiogenic approach[J]. Expert Opin Ther Targets, 2005,9(1):63-76.
13. Pisacane AM, Picciotto F,Risio M. CD31 and CD34 expression as immunohistochemical markers of endothelial transdifferentiation in human cutaneous melanoma[J]. Cell Oncol, 2007,29(1):59-66.
14. Bissell MJ. Tumor plasticity allows vasculogenic mimicry, a novel form of angiogenic switch. A rose by any other name?[J]. Am J Pathol, 1999,155(3):675-9.
15. Vartanian AA, Burova OS, Stepanova EV, et al. Melanoma vasculogenic mimicry is strongly related to reactive oxygen species level[J]. Melanoma Res, 2007,17(6):370-9.
16. van der Schaft DW, Seftor RE, Seftor EA, et al. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells[J]. J Natl Cancer Inst, 2004,96(19):1473-7.
17. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy[J]. Nat Rev Cancer, 2004,4(6):423-36.
18. Folkins C, Man S, Xu P, et al. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors[J]. Cancer Res, 2007,67(8):3560-4.
19. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer[J]. J Clin Oncol, 2001,19(3):843-50.
20. Nakamura R, Kataoka H, Sato N, et al. EPHA2/EFNA1 expression in human gastric cancer[J]. Cancer Sci, 2005,96(1):42-7.
21. Hendrix MJ, Seftor EA, Hess AR, et al. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma[J]. Nat Rev Cancer, 2003,3(6):411-21.
22. Vihanto MM, Plock J, Erni D, et al. Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin[J]. FASEB J, 2005,19(12):1689-91.
1 Hanahan D, Bergers G,Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice[J]. J Clin Invest, 2000,105(8):1045-7.
2 Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer[J]. Cancer Res, 2000,60(7):1878-86.
3 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy[J]. Nat Rev Cancer, 2004,4(6):423-36.
4 Vacca A, Iurlaro M, Ribatti D, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine[J]. Blood, 1999,94(12):4143-55.
5 Wang J, Lou P, Lesniewski R, et al. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly[J]. Anticancer Drugs, 2003,14(1):13-9.
6 Bocci G, Nicolaou KC,Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs[J]. Cancer Res, 2002,62(23):6938-43.
7 Bocci G, Francia G, Man S, et al. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy[J]. Proc Natl Acad Sci U S A, 2003,100(22):12917-22.
8 Hamano Y, Sugimoto H, Soubasakos MA, et al. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression[J]. Cancer Res, 2004,64(5): 1570-4.
9 Dawson DW, Pearce SF, Zhong R, et al. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells[J]. J Cell Biol, 1997,138(3):707-17.
10 Jimenez B, Volpert OV, Crawford SE, et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1[J]. Nat Med, 2000,6(1):41-8.
11 Gupta K, Gupta P, Wild R, et al. Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis[J]. Angiogenesis, 1999,3(2):147-58.
12 Lam T, Hetherington JW, Greenman J, et al. From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials[J]. Anticancer Drugs, 2006,17(2): 113-21.
13 Shaked Y, Bertolini F, Man S, et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis[J]. Cancer Cell, 2005,7(1):101-11.
14 Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water[J]. Cancer Res, 2002,62(10):2731-5.
15 Klement G, Huang P, Mayer B, et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts[J]. Clin Cancer Res, 2002,8(1):221-32.
16 Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity [J]. J Clin Invest, 2000,105(8):R15-24.
17 Kim ES, Soffer SZ, Huang J, et al. Distinct response of experimental neuroblastoma to combination antiangiogenic strategies [J]. J Pediatr Surg, 2002,37(3):518-22.
18 Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer[J]. J Clin Oncol, 2005,23(5):939-52.
19 Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels[J]. Ann Oncol, 2002,13(1):73-80.
20 Tuettenberg J, Grobholz R, Korn T, et al. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme[J]. J Cancer Res Clin Oncol, 2005,131(1):31-40.
1 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases[J]. Nature, 2000,407(6801):249-57.
2 Martin A, Komada MR,Sane DC. Abnormal angiogenesis in diabetes mellitus[J]. Med Res Rev, 2003,23(2): 117-45.
3 Koch AE. Angiogenesis as a target in rheumatoid arthritis[J]. Ann Rheum Dis, 2003,62 Suppl 2:ii60-7.
4 Carmeliet P. Angiogenesis in life, disease and medicine[J]. Nature, 2005,438(7070):932-6.
5 Hanahan D, Weinberg RA. The hallmarks of cancer[J]. Cell, 2000,100(1):57-70.
6 Ferrara N, Gerber HP,LeCouter J. The biology of VEGF and its receptors[J]. Nat Med, 2003,9(6):669-76.
7 Hurwitz H, Kabbinavar F. Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer[J]. Oncology, 2005,69 Suppl 3:17-24.
8 Burri PH, Hlushchuk R,Djonov V. Intussusceptive angiogenesis: its emergence, its characteristics, and its significance[J]. Dev Dyn, 2004,231(3):474-88.
9 Patan S, Munn LL,Jain RK. Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis[J]. Microvasc Res, 1996,51(2):260-72.
10 Asahara T, Kawamoto A. Endothelial progenitor cells for postnatal vasculogenesis[J]. Am J Physiol Cell Physiol, 2004,287(3):C572-9.
11 Garmy-Susini B, Varner JA. Circulating endothelial progenitor cells[J]. Br J Cancer, 2005,93(8):855-8.
12 Urbich C, Aicher A, Heeschen C, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells[J]. J Mol Cell Cardiol, 2005,39(5):733-42.
13 Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth[J]. Nat Med, 2001,7(11):1194-201.
14 Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche[J]. Nature, 2005,438(7069):820-7.
15 Leenders WP, Kusters B,de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis[J]. Endothelium, 2002,9(2):83-7.
16 Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF[J]. Science, 1999,284(5422):1994-8.
17 Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis[J]. Science, 1997,277(5322):55-60.
18 Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry[J]. Am J Pathol, 1999,155(3):739-52.
19 Hendrix MJ, Seftor EA, Hess AR, et al. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma[J]. Nat Rev Cancer, 2003,3(6):411-21.
20 Seftor EA, Brown KM, Chin L, et al. Epigenetic transdifferentiation of normal melanocytes by a metastatic melanoma microenvironment[J]. Cancer Res, 2005,65(22): 10164-9.
21 Postovit LM, Seftor EA, Seftor RE, et al. Influence of the microenvironment on melanoma cell fate determination and phenotype[J]. Cancer Res, 2006,66(16):7833-6,
22 Sun B, Zhang D, Zhang S, et al. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma[J]. Cancer Lett, 2007,249(2): 188-97.
23 Clarijs R, Otte-Holler I, Ruiter DJ, et al. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2002,43(4):912-8.
24 Shirakawa K, Kobayashi H, Heike Y, et al. Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft[J]. Cancer Res, 2002,62(2):560-6.
25 Frenkel S, Barzel I, Levy J, et al. Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography[J], Eye, 2007.
26 Folberg R, Maniotis AJ. Vasculogenic mimicry[J]. APMIS, 2004,112(7-8):508-25.
27 Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy[J], Science, 2005,307(5706):58-62.
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