摘要
卵巢癌为女性常见恶性肿瘤，死亡率居妇科恶性肿瘤首位，卵巢癌的侵袭性生长与转移是其预后不良的主要原因。研究已经发现卵巢癌组织中的脉管生成在肿瘤侵润生长与转移中扮演重要角色，但一直以来关于肿瘤脉管生成的研究主要集中在血管方面，对淋巴管的研究较少。临床观察发现高淋巴管密度与卵巢癌腹膜转移、远处转移及淋巴结转移显著相关，淋巴管生成在肿瘤淋巴转移起了重要作用。随着淋巴管特异性内皮细胞标记物的发现和淋巴管生成调控因子研究的深入，淋巴管生成对肿瘤侵袭转移的重要性逐渐得以认识，但其机制尚未明确。
近年来，肿瘤干细胞理论研究结果显示肿瘤组织内存在着极少数能自我更新、多向分化、高致瘤性的肿瘤干细胞是肿瘤发生、侵袭、转移和复发的根源。对卵巢癌的研究有类似发现，卵巢癌的发生、侵袭、转移与其体内存在的数量极少的肿瘤干细胞相关。而肿瘤的生长、侵袭和转移除肿瘤细胞自身的生物学行为以外，尚有血管、淋巴管生成以提供养料，同时肿瘤组织的脉管生成在肿瘤的转移中起重要作用。因此，研究肿瘤干细胞与淋巴管内皮细胞间的相互作用，以探索肿瘤干细胞在卵巢癌淋巴转移中的作用有重要意义。另外，肿瘤干细胞通过何种机制参与卵巢癌的淋巴转移？目前研究的热点集中在SDF-1/CXCR4信号轴，SDF-1/CXCR4信号轴参与体内多种生理、病理过程，与肿瘤的生长、侵袭和转移密切相关。新近的研究还发现SDF-1/CXCR4轴与肿瘤淋巴转移相关。卵巢癌患者腹水中检测到高水平SDF-1，卵巢癌组织高表达CXCR4，SDF-1在淋巴组织中高表达，高表达CXCR4的肿瘤细胞受SDF-1的趋化作用而发生淋巴转移。然而SDF-1在卵巢癌干细胞与淋巴管生成中的作用尚未见报道，需进一步研究。
卵巢癌的淋巴管生成和转移除了肿瘤干细胞的参与外，循环中淋巴管内皮祖细胞是否具有同样重要作用尚不清楚。实验已经发现外周血中骨髓来源的淋巴管内皮祖细胞参与了淋巴管新生，新近研究还发现肿瘤患者出现外周血淋巴管内皮祖细胞增多，淋巴管内皮祖细胞被动员参与肿瘤淋巴管生成。淋巴管内皮祖细胞参与淋巴管新生的机制极其复杂，涉及动员、趋化迁移、分化等多个环节，目前仅认为VEGF-C/VEGFR-3信号途径在其中起着重要的调控作用，具体机制尚不清。
在本研究中，首先，我们采用无血清悬浮培养法富集卵巢癌A2780细胞系中的细胞球，以CD133作为标记分子，用流式细胞仪从细胞球中分选出CD133~+细胞，通过对CD133~+自我更新、多向分化、致瘤性、干细胞标志基因等多种生物学特征进行检测，其生物学行为具备目前肿瘤干细胞的生物学特点，鉴定其为卵巢癌干细胞，为后续实验展开打下基础。然后，我们利用Transwell小室对CD133~+细胞和本课题组前期建株的人淋巴管内皮细胞共培养，观察共培养时两种细胞的相互作用。一方面观察共培养对淋巴管内皮细胞增殖的影响，用酶联免疫吸附实验检测上清液中细胞因子VEGF-C的浓度，同时观察共培养对淋巴管内皮细胞迁移的影响，用RayBio人细胞因子抗体芯片对淋巴管内皮细胞上清液进行细胞因子芯片筛查，对其中差异表达的趋化因子SDF-1用酶联免疫吸附实验进行验证，并进一步观察了上调和下调SDF-1对淋巴管内皮细胞迁移的影响。另一方面我们用WB检测了CD133~+细胞CXCR4蛋白的表达，观察了共培养对卵巢癌CD133~+细胞侵袭的影响，以及共培养后卵巢癌CD133~+细胞VEGF的表达。与此同时我们用流式细胞仪检测了卵巢癌患者外周血中淋巴管内皮祖细胞/CD34~+VEGFR3~+细胞的含量，酶联免疫吸附实验检测了患者外周血中VEGF-C、SDF-1的浓度，对淋巴管内皮祖细胞和患者临床资料进行相关性分析，并对淋巴管内皮祖细胞与外周血VEGF-C、SDF-1的浓度进行了相关性分析。主要的结果和结论如下：
1、卵巢癌A2780细胞系中存在极少量的CD133~+细胞，可通过悬浮条件培养法富集，流式细胞仪分选得到CD133~+细胞。悬浮培养方法简单，重复性强，CD133~+细胞比例稳定在0.2%左右。卵巢癌CD133~+细胞能自我更新、多向分化，致瘤性强，多种干细胞标志基因高表达，符合肿瘤干细胞的特征。CD133是其特异性表面标志，能用于后续卵巢癌干细胞研究中干细胞的分选和鉴定。
2、卵巢癌干细胞与淋巴管内皮细胞共培养对淋巴管内皮细胞和卵巢癌干细胞生长均产生作用。观察发现共培养时淋巴管内皮细胞增殖增加，ELISA检测共培养上清液VEGF-C含量明显升高。共培养时时淋巴管内皮细胞迁移增加，其共培养上清液中出现多种细胞因子差异表达，39种细胞因子上调，5种细胞因子下调，ELISA检测验证上清液中上清液SDF-1含量明显升高，在上调和下调了SDF-1的共培养体系中，SDF-1对淋巴管内皮细胞的迁移产生影响，100ng/ml SDF-1促进淋巴管内皮细胞迁移的作用明显，而拮抗剂AMD3100在75ug/ml则明显抑制淋巴管内皮细胞的迁移。观察还发现卵巢癌干细胞CXCR4高表达，卵巢癌干细胞与淋巴管内皮细胞共培养时卵巢癌CD133~+细胞侵袭能力增加，WB结果显示共培养后卵巢癌干细胞VEGF表达上调。
3、卵巢癌患者外周血中淋巴管内皮祖细胞含量升高，与患者肿瘤淋巴转移和临床分期相关。同时卵巢癌患者外周血中SDF-1和VEGF-C水平明显升高，淋巴管内皮祖细胞水平升高与SDF-1升高有相关性。
综上所述，CD133是卵巢癌A2780干细胞的特异标志因子，卵巢癌干细胞可用悬浮培养结合流式细胞仪分离。卵巢癌干细胞与淋巴管内皮细胞共培养时两细胞生长互相作用，共培养时淋巴管内皮细胞增殖迁移增加，卵巢癌干细胞侵袭能力加强。SDF-1/CXCR4信号轴参与了其中的调控。卵巢癌患者外周血淋巴管内皮祖细胞升高，淋巴管内皮祖细胞与肿瘤淋巴转移相关，并与外周血SDF-1升高有相关性。
Ovarian cancer is the fifth leading cause of cancer deaths and has the highest mortalityrate among gynecologic cancers. Whereas standard cytoreductive surgery andchemotherapy followed by taxane/platinum,70%of patients will relapse within two yearswith progressive disease. Novel therapeutic approaches are urgently needed to improveprognosis. Lymphangiogenesis, the formation of the lymphatic, play a crucial role in thespread of ovarian cancer. However, the role of lymphangiogenesis in the growth anddissemination of ovarian cancer has not been clearly established.
The theory of cancer stem cells (CSCs) has been developed during the last decade.CSCs have been the focal spot of the cancer research field, and have been considered as theorigin of tumorigenesis, metastasis and recurrence. CSCs, successfully isolated andidentified from ovarian cancer, are thought to have the ability to initiate tumour, a highcapacity of self-renewal, and the propensity to differentiate into actively proliferatingtumour cells. CSCs are often associated with elevated expression of the stem cell surfacemarker. In order to investigate the ovarian cancer lymphangiogenesis and lymph nodemetastasis, it is important that studing the interaction between CSCs and lymhaicendothelial cells. SDF-1/CXCR4has been known to have broad activities in different kindsof tumours. Previous studies on CXCR4have been shown that CXCR4are prognosticmarkers in ovarian cancer, and anti-CXCR4may have anti-tumour activity such asinhibition of invasion, migration, and angiogenic potential. Recent studies indicated that thesignaling of SDF-1/CXCR4was participated in lymphangiogenesis.
It is known that circulating CD34~+and VEGFR3~+lymphatic endothelial progenitorcells (LEPCs) involved in the lymangiogenesis. And recent studies found that LEPCs weresignificantly increased in patients with small cell lung cancer patients and LEPCs werecorrelated with tumor lymphangiogensis. However the role of LEPCs in thelymphangiogensis has not been clearly established.
In the current study, using flow cytometry, we isolated and characterized ovarian CSCs by expression antibody against CD133in anchorage-independent spheres from humanovarian cancer cell line A2780. We investigated proliferation and immigration oflymphatic endothelial cells while lymphatic endothelial cells cultured with ovarian cancerCD133~+cells by transwell chamber. The supernatants were detected by cytokines chips.VEGF-C and SDF-1production in the supernatants were measured with ELISA. Weobserved the effects of SDF-1down-regulation and up-regulation in the supernatantsolution of transwell chamber on immigration of lymph endothelial cells. Then weinvestigated the expression of CXCR4in CD133~+cells by WB, observed CD133~+cellsinvasion co-cultured with lymphatic endothelial cells by transwell assay, and studiedexpression of VEGF in CD133~+cells by WB. At the same time we studied levels ofcirculating LEPCs and lymph node metastasis in epithelial ovarian cancer patients, and alsotested plasma levels of VEGF-C and SDF-1to find out their possible relationships withLEPCs in patients with epithelial ovarian cancer.
The main results and conclusions are as follows:
1、The experiments demonstrate that only a minority of A2780cells were stainedpositive for CD133, a cell surface marker of CSCs. These CD133~+cells were capable ofself-renewal, multipotent differentiation and tumor initiation.
2、Lymphatic endothelial cells proliferation and immigration enhanced when lymphaticendothelial cells were cultured with ovarian CSCs. Cytokines chip and ELISA resultsshowed higher level of SDF-1in their cell supernatants. Up-regulation of SDF-1promotedmigration of lymphatic endothelial cells and down-regulation of SDF-1inhibited migrationof lymphatic endothelial cells. We found that higher level of CXCR4expression in ovarianCSCs. Invasion and VEGF expression of ovarian CSCs enhanced when ovarian CSCscultured with lymphatic endothelial cells.
3、We found that the level of circulating lymphatic endothelial progenitor cell wassignificantly correlated with lymph node metastasis and FIGO stage in patients with ovariancancer. There was also a statistically significant correlation between lymphatic endothelialprogenitor cells and SDF-1.
In summary, CD133positive cells may represent ovarian cancer stem cells in ovariancancer cell line A2780. Lymphatic endothelial cells proliferation and immigration enhanced,and ovarian CSCs invasion enhanced when ovarian CSCs were cultured with lymphatic endothelial cells. SDF-1/CXCR4axis may be one of the mechanisms responsible for thehigh migration of lymphatic endothelial cells and high invasive capacity of ovarian CSCs.High level of circulating lymphatic endothelial progenitor cells was significantly correlatedwith lymph node metastasis in patients with ovarian cancer.
引文
[1] Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparatemodel organisms[J]. Nat Rev Cancer.2005,5(5):355-366.
[2] Liu J, Huang J, Yao WY, et al. The origins of vascularization in tumors[J]. FrontBiosci,2012,1(17):2559-2565.
[3]邱敏,梁志清.微血管密度和淋巴管密度与卵巢癌临床病理参数的联系[J].华南国防医学杂志,2007,21(1):1-3.
[4] Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor,VEGF-C, is a ligand for the Flt4(VEGFR-3) and KDR(VEGFR-2) receptor tyrosinekinases[J]. EMBO J,1996,15(7):1751-1757.
[5] Schmid K, Birner P, Gravenhorst V, et al. Prognostic value of lymphatic and bloodvessel invasion in neuroendocrine tumors of the lung[J]. Am J Surg Pathol,2005,29(3):324-328.
[6] Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1in the induction ofthe lymphatic endothelial cell phenotype[J]. EMBO J,2002,21(7):1505-1513.
[7] Reya T，Morrison SJ，Clarke MF，et al. Stem cells，cancer，and cancer stem cells[J].Nature，2001,414(6859):105-111.
[8] Bapat SA, Mali AM, Koppikar CB, et al. Stem and progenitor-like cells contribute tothe aggressive behavior of human epithelial ovarian cancer[J]. Cancer Res,2005,65(8):3025-3029.
[9] Dagmar B, Peter H, Martin P, et al. CD133+and CD133-glioblastoma-derived cancerstem cells show differential growth characteristics and molecular profiles[J]. CancerRes,2007,67(9):4010-4015.
[10] Vander Griend DJ, Kathaus WL, Dalrymple S, et al. The role of CD133in normalhuman prostate stem cells and malignant cancer-initiating cells[J]. Cancer Res,2008,68(23):9703-9711.
[11] Eramo A, Lotti F, Sette G, et al. Identification and expansion of the tumorigenic lungcancer stem cell population[J]. Cell Death Differ,2008,15(3):504-514.
[12] O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable ofinitiating tumour growth in immunodeficient mice[J]. Nature,2007,445(4123):106-110.
[13] Knoepfler P. Journal club. A cell biologist looks at the risk and promise of a newinsight into stem cells and cancer[J]. Nature,2009,457(7228):361.
[14] Li CZ, Liu B, Wen ZO, et al. Inhibition of CD44expression by small interfering RNAto suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo[J].Folia Biol,2008,54(6):180-186.
[15] Domanska UM, Kruizinga RC，Nagengast WB, et al. A review on CXCR4/CXCL12axis in oncology: no place to hide[J]. Eur J Cancer,2013,49(1):219-230.
[16] Kato M, Kitayama J, Kazama S, et al. Expression pattern of CXC chemokinereceptor-4is correlated with lymph node metastasis in human invasive ductalcarcinoma. Breast Cancer Res,2003,5(5): R144-150.
[17] Kryczek I, Lange A, Mottram P, et al. CXCL12and vascular endothelial growth factorsynergistically induce neoangiogenesis in human ovarian cancers[J]. Cancer Res,2005,65(2):465-472.
[18] Popple A, Durrant LG, Spendlove I, et al. The chemokine, CXCL12, is an independentpredictor of poor survival in ovarian cancer[J]. Br J Cancer,2012,106(7):1306-1313.
[19] Barbieri F, Bajetto A, Florio T, et al. Role of chemokine network in the developmentand progression of ovarian cancer: a potential novel pharmacological target[J]. J Oncol,2010,2010:426956.
[20] Salven P, Mustjoki S, Alitalo R, et al. VEGFR3and CD133identify a population ofCD34+lymphatic/vascular endothelial precursor cells[J]. Blood,2003,101(1):168-172.
[21] Wang H, Tan Y, Zhang M, et al. Vascular endothelial growth factor-C-induceddifferentiation of CD34+CD133+VEGFR-3+EPCS towards lymphatic endothelialcells[J]. Jpn J Lymphol,2005,28(1):71-73.
[22] Kerjaschki D, Huttary N, Raab I, et al. Lymphatic endothelial progenitor cellscontribute to de novo lymphangiogenesis in human renal transplants[J]. Nat Med,2006,12(2):230-234.
[23] Religa P, Cao R, Bjorndahl M, et al. Presence of bone marrow-derived circulatingprogenitor endothelial cells in the newly formed lymphatic vessels[J]. Blood,2005,106(13):4186-4190.
[24] Bogos K, Renyi-Vamos F, Dobos J, et al. High VEGFR-3-positive circulatinglymphatic/vascular endothelial progenitor cell level is associated with poor prognosisin human small cell lung cancer[J]. Clin Cancer Res.2009,15(5):1741-1746.
[25] Miraglia S, Godfrey W, Yin AH, et al. A novel five-transmembrane hematopoietic stemcell antigen: isolation, characterization, and molecular cloning[J]. Blood,1997,90(12):5013-5021.
[26] Yin AH, Miraglia S, Zanjani ED, et al. AC133, a novel marker for humanhematopoietic stem and progenitor cells[J]. Blood,1997,90(12):5002-5012.
[27] Ferrandina G, Bonanno G, Pierelli L，et al. Expression of CD133-1and CD133-2inovarian cancer[J]. Int J Gynecol Cancer,2008,18(3):506-514.
[28] Baba T, Convery PA, Matsmura N, et al. Epigenetic regulation of CD133andtuorigenicity of CD133+ovarian cancer cells[J]. Oncogene,2009,28(2):209-218.
[29] Fong MY, Kakar SS. The role of cancer stem cells and the side population in epithelialovarian cancer[J]. Histol Histopathol,2010,25(1):113-120.
[30]谢伟.人卵巢癌细胞系A2780的肿瘤干细胞的分离培养和鉴定[D].2011.第三军医大学.
[31]赵颖.人上皮性卵巢癌细胞中CD133和CD44的表达状况及其功能研究[D].2008.山东大学.
[32] Zhang S, Curt Balch, Michael W，et al. Identification and characterization of ovariancancer-initiating cells from primary human tumors[J]. Cancer Res,2008,68(11):4311-4320.
[33] Alvero AB, Chen R, Fu HH, et al. Molecular phenotyping of human ovarian cancerstem cells unravels the mechanisms for repair and chemoresistance[J]. Cell Cycle,2009,8(1):158-166.
[34] Shi MF, Jiao J, Lu WG, et al. Identification of cancer stem sell-like cells from humanepithelial ovarian carcinoma cell line[J]. Cell Mol Life Sci,2010,67(22):3915-3925.
[35] Garcia GI, Elvira G, Zapata, AG, et al. Mesenchymal stem cells: biological propertiesand clinical applications[J]. Expert Opin Biol Ther,2010,10(10):1453-1468.
[36] Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of theadult mammalian central nervous system[J]. Science,1992,255(5052):1707-1710.
[37] Han M, Jeon TY, Hwang SH, et al. Cancer spheres from gastric cancer patients providean ideal model system for cancer stem cell research[J]. Cell Mol Life Sci,2011,68(21):3589-3605.
[38] Meissner A. Epigenetic modifications in pluripotent and differentiated cells[J]. NatBiotechnol,2010,28(10):1079-1088.
[39] Nozaki K, Ogawa M, Williams J, et al. A molecular signature og gastric metaplasiaarising in response to acute parietal cell loss[J]. Gastroenterology,2008,134(2):511-522.
[40] Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in huambrain tumor[J]. Cancer Res,2003,63(18):5821-5828.
[41] Tang DG, Patrawala L, Calhoun T, et al. Prostate cancer stem/progenitor cells:identification, characterization, and implications [J]. Mol Carcinog,2007,46(1):1-14.
[42] Singh SK, Hawkins C, Clarke I D, et al. Identification of human brain tumourinitiating cells [J]. Nature,2004,432(7015):396-401.
[43] Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required formaintenance of pluripotency in mouse epiblast and ES cells [J]. Cell,2003,113(5):631-642.
[44] Charmbers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, apluripotency factor in embryonic stem cells [J]. Cell,2003,113(5):643-655.
[45] Fasano CA, Dimos JT, Ivanova NB, et al. shRNA knockdown of Bmi-1reveals acritical role for p21-Rb pathway in NSC self-renewal during development[J]. CellStem Cell,2007,1(1):87-99.
[46] Wiese C, Rolletschek A, Kania G, et al. Nestin expression-a property of multi-lineageprogenitor cells[J]? Cell Mol Life Sci,2004,61(19-20):2510-2522.
[47] Morrison SJ, Perez SE, Qiao Z, et al. Transient notch activation initiates an irreversibleswitch from neurogenesis to gliogenesis by neural crest stem cells[J]. Cell,2000,101(5):499-510.
[48] Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts[J]. Annu RevMed,2007,58:267-284.
[49] Yao XH, Ping YF, Chen JH, et al. Glioblastoma stem cells produce vascularendothelial growth factor by activation of a G-protein coupled formylpeptide receptorFPR[J]. J Pathol,2008,215(4):369-376.
[50] Furusato B, Mohamed A, Uhlén M, et al. CXCR4and cancer[J]. Pathology Int,2010,60(7):497-505.
[51] Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breastcancer metastasis[J]. Nature,2001,410(6824):50-56.
[52] Hall JM, Korach KS. Stromal cell-derived factor1, a novel target of estrogen receptoraction, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells[J].Mol Endocrinol,2003,17(5):792-803.
[53] Kaifi JT, Yekebas EF, Schurr P, et al. Tumor-cell homing to lymph nodes and bonemarrow and CXCR4expression in esophageal cancer[J]. J Natl Cancer Inst,2005,97(24):1840-1847.
[54] Taichman RS, Cooper C, Keller ET, et al. Use of the stromal cell-derivedfactor-1/CXCR4pathway in prostate cancer metastasis to bone[J]. Cancer Res,2002,62(6):1832-1837
[55] Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparatemodel organisms[J]. Nat Rev Cancer.2005,5(5):355-366.
[56] Chen JC, Chang YW, Hong CC, et al. The role of the VEGF-C/VEGFRs axis in tumorprogression and therapy[J]. Int J Mol Sci,2012,14(1):88-107.
[57] Stacker SA, Achen MG. The VEGF signaling pathway in cancer: the road ahead[J].Chin J Cancer,2013,5(6):297-302.
[58]Cheng D, Liang B,Li Y. Serum vascular endothelial growth factor(VEGF-C)as adiagnostic and prognosic marker in patients with ovarian cancer[J]. PLoS One,2013,8(2): e55309.
[59] Ochi N, Matsuo Y, Sawai H, et al. Vascular endothelial growth factor-C secreted bypancreatic cancer cell line promotes lymphatic endothelial cell migration in an in vitromodel of tumor lymphangiogenesis[J]. Pancreas,2007,34(4):444-451.
[60] Yang H, Kim C, Kim MJ, et al. Soluble vascular endothelial growth factor receptor-3suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer[J]. MolCancer,2011,11(10):36-48.
[61] Shi Y, Tong M, Wu Y, et al. VEGF-C ShRNA inhibits pancreatic cancer growth andlymphangiogenesis in an orthotopic fluorescent nude mouse model[J]. Anticancer Res,2013,33(2):409-417.
[62]刘锐,谭玉珍,王海杰等.细胞因子对淋巴管内皮祖细胞的趋化和动员作用[J].解剖学报，2008，39(1):45-49.
[63] Archibald KM, Kulbe H, Kwong J, et al. Sequential genetic change at the TP53andchemokine receptor CXCR4locus during transformation of human ovarian surfaceepithelium[J]. Oncogene,2012,31(48):4987-4995.
[64] Scotton CJ, Wilson JL, Scott K, et al. Multiple actions of the chemokine CXCL12onepithelial tumor cells in human ovarian cancer[J]. Cancer Res,2002,62(20):5930-5938.
[65] Barbieri F, Bajetto A, Florio T, et al. Role of chemokine network in the developmentand progression of ovarian cancer: a potential novel pharmacological target[J]. J Oncol,2010,2010:426956.
[66] Obermajer N, Muthuswamy R, Odunsi K, et al. PGE(2)-induced CXCL12productionand CXCR4expression controls the accumulation of human MDSCs in ovarian cancerenvironment[J]. Cancer Res,2011,71(24):7463-7470.
[67] Hassan S, Buchanan M, Jahan K, et al. CXCR4peptide antagonist inhibits primarybreast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment ordocetaxel in a transgenic mouse model[J]. Int J Cancer,2011,129(1):225-232.
[68] Righi E, Kashiwagi S, Yuan J, et al. CXCL12/CXCR4blockade induces multimodalantitumor effects that prolong survival in an immunocompetent mouse model ofovarian cancer[J]. Cancer Res,2011,71(16):5522-5534.
[69] Ray P, Lewin SA, Mihalko LA, et al. Noninvasive imaging reveals inhibition ofovarian cancer by targeting CXCL12-CXCR4[J]. Neoplasia,2011,13(12):1152-1161.
[70] Cui K, Zhao W, Wang C, et al. The CXCR4-CXCL12pathway facilitates theprogression of pancreatic cancer via induction of angiogenesis and lymphangiogenesis[J]. J Surg Res,2011,171(1):143-150.
[71] Tanabe S, Nakadai T, Furuoka H, et al. Expression of mRNA of chemokine receptorCXCR4in feline mammary adenocarcinoma[J]. Vet Rec,2002,151(24):729-733.
[72] Retz MM, Sidhu SS, Blaveri E, et al. CXCR4expression reflects tumor progressionand regulates motility of bladder cancer cells[J]. Int J Cancer,2005,114(2):182-189.
[73] Liu S, Ginestier C, Ou SJ, et al. Breast cancer stem cells are regulated bymesenchymal stem cells through cytokine networks[J]. Cancer Res,2011,71(2):614-624.
[74] Desteli GA, Gultekin M, Usubutun A, et al. Lymph node metastasis in grosslyapparent clinical stage Ia epithelial ovarian cancer: Hacettepe experience and reviewof literature[J]. World J Surg Oncol.2010,30(8):106-111.
[75] Canino F,Fuda G,Ciccone G, et al.Significance of lymph node sampling in epithelialcarcinoma of the ovary[J]. Gynecol Oncol,1997,65(3):467-472.
[76]吴小华,张志毅,唐美琴等.卵巢恶性肿瘤腹膜后淋巴结转移率及危险因素的临床研究[J].中华妇产科杂志,1996,31(9):543-546.
[77]曹泽毅.妇科肿瘤学[M].北京：北京人民出版社，2001：832-837.
[78]沈铿.卵巢上皮性癌淋巴转移的诊治[J].实用妇产科杂志,2010,26(10):732-733.
[79] Maggioni A, Benedetti Panici P, Dell’Anna T, et al. Randomised study of systematiclymphadenectomy in patients with epithelial ovarian cancer macroscopically confinedto the pelvis[J]. Br J Cancer,2006,95(6):699-704.
[80]王莹,李文媛,贾桦,等.喉癌组织中VEGF-D表达与淋巴管生成及预后的关系[J].解剖科学进展,2011,17(2):116-120.
[81] Tang H, Wang J, Bai F, et al. Positive correlation of osteopontin, cyclooxygenase-2and vascular endothelial growth factor in gastric cancer[J]. Cancer Invest,2008,26(1):60-67.
[82] Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growthfactor-C-mediated lymphangiogenesis promotes tumor metastasis[J]. EMBO J,2001,20(4):672-682.
[83] Asahara T, Murobara T, Sullivan A, et al. Isolation of putative progenitor endothelialcells for angiogenesis[J]. Science,1997,275(5302):964-967.
[84] Karpanen T, Egeblad M, Karkkainen M, et al. Vascularendothelial growth factor Cpromotes tumor lymangiogenesis and intralymphatic tumor growth[J]. Cancer Res,2001,61(5):1786-1790.
[85] Stacker SA, Baldwin ME, Achen MG, et al. The role of tumor lymphangiogenesis inmetastatic spread[J]. FASEB J,2002,16(9):922-934.
[86]刘慧冬,赵玲辉,李玉兰,等.人胃癌淋巴管的超微结构[J].解剖学报,2004,35(5):513-516.
[87] Chen W, Chen M, Liao Z, et al. Lymphatic vessel density as predictive marker for thelocal recurrence of rectal cancer[J]. Dis Colon Rectum,2009,52(3):513-519.
[88] Jones A, Fujiyama C, Turner K, et al. Angiogenesis and lymphangiogenesis in stage1germ cell tumours of the testis[J]. BJU Int,2000,86(1):80-86.
[89] Mu oz-Guerra MF, Marazuela EG, Martín-Villar E, et al. Prognostic significance ofintratumoral lymphangiogenesis in squamous cell carcinoma of the oral cavity[J].Cancer,2004,100(3):553-560.
[90] Saad RS, Kordunsky L, Liu YL, et al. Lymphatic microvessel density as prognosticmarker in colorectal cancer[J]. Mod Pathol,2006,19(10):1317-1323.
[91] Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread oftumor cells via the lymphatics[J]. Nat Med,2001,7(2):186-191.
[92] Lui Z, Ma Q, Wang X, et al. Inhibiting tumor growth of colorectal cancer by blockingthe expression of vascular endothelial growth factor receptor3using interferencevector-based RNA interference[J]. Int J Mol Med,2010,25(1):59-64.
[93] Yang H, Kim C, Kim MJ, et al. Soluble vascular endothelial growth factor receptor-3suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer[J]. MolCancer,2011,10(36):36-48.
[94] Chen JC, Chang YW, Hong CC, et al. The role of the VEGF-C/VEGFRs axis in tumorprogression and therapy[J]. Int J Mol Sci,2012,14(1):88-107.
[95] Thiele W, Sleeman JP. Tumor-induced lymphangiogenesis: a target for cancertherapy[J]? J Biotechnol,2006,124(1):224-241.
[96] Takahashi S, Shinya T, Sugiyama A. Angiostatin inhibition of vascular endothelialgrowth factor-stimulated nitric oxide production in endothelial cells[J]. J PharmacolSci,2010,112(4):432-437.
[97] Kozlowski M, Naumnik W, Niklinski J, et al. Vascular endothelial growth factor C andD expression correlates with lymph node metastasis and poor prognosis in patientswith resected esophageal cancer[J]. Neoplasma,2011,58(4):311-319.
[98] Ochi N, Matsuo Y, Sawai H, et al. Vascular endothelial growth factor-C secreted bypancreatic cancer cell line promotes lymphatic endothelial cell migration in an in vitromodel of tumor lymphangiogenesis[J]. Pancreas,2007,34(4):444-451.
[99] Hirakawa S, Brown LF, Kodama S, et al. VEGF-C-induced lymphangiogenesis insentinel lymph nodes promotes tumor metastasis to distant sites[J]. Blood,2007,109(3):1010-1017.
[100] Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1in the inductionof the lymphatic endothelial cell phenotype[J]. EMBO J,2002,21(7):1505-1513.
[101] Witmer AN, van Blijswijk BC, Dai J, et al. VEGFR-3in adult angiogenesis[J]. JPathol,2001,195(4):490-497.
[102] Ny A, Koch M, Schneider M, et al. A genetic xenopus laevis tadpole model tostudy lymphangiogenesis[J]. Nat Med,2005,11(9):998-1004.
[103] Liersch R, Nay F, Lu L, et al. Induction of lymphatic endothelial celldifferentiation in embryoid bodies[J]. Blood,2006,107(3):1214-1216.
[104] Lyden D, Hattori K, Dias S. Impaired recruitment of bone marrow-derivedendothelial and hematopoietic precursor cells blocks tumor angiogenesis andgrowth[J]. Nat Med,2001,7(11):1194-1201.
[105] Nikitenko L, Boshoff C. Endothelial cells and cancer[J]. Handb Exp Pharmacol,2006,176(2):307-334.
[106] Laschke MW, Giebels C, Nickels RM, et al. Endothelial progenitor cells contributeto the vascularization of endometriotic lesions[J]. Am J Pathol,2011,178(1):442-450.
[107] Gao D, Nolan DJ, Mellick AS, et al. Endothelial progenitor cells control theangiogenic switch in mouse lung metastasis[J]. Science,2008,319(5860):195-198.
[108] Tamura M, Unno K, Yonezawa S, et al. In vivo trafficking of endothelial progenitorcells their possible involvement in the tumor neovascularization[J]. Life Sci,2004,75(5):575-584.
[109] Shaked Y, Bertolini F, Man S, et al. Genetic heterogeneity of the vasculogenicphenotype parallels angiogenesis; implications for cellular surrogate marker analysisof antiangiogenesis[J]. Cancer Cell,2005,7(1):101-111.
[110]郭子姮.骨髓来源的内皮祖细胞参与肿瘤新生淋巴管形成的研究[D].2006.第二军医大学.
[111]刘锐,谭玉珍,王海杰等.细胞因子对淋巴管内皮祖细胞的趋化和动员作用[J].解剖学报,2008,39(1):45-49.
[112]刘锐,谭玉珍,王海杰等.犬外周血淋巴管内皮祖细胞的分选及其向内皮细胞的诱导分化研究[J].中华血液学杂志,2007,28(3):169-173.
[113]Bock F, Onderka J, Dietrich T, et al. Blockade of VEGFR3-signalling specificallyinhibits lymphangiogenesis in inflammatory corneal neovascularisation[J]. GraefesArch Clin Exp Ophthalmol,2008,246(1):115-119.
[114]Cao Y. Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphaticmetastasis[J]. Nat Rev Cancer,2005,5(9):735-743.
[115]Kuil J, Buckle T, van Leeuwen FW.Imaging agents for the chemokine receptor4(CXCR4)[J].Chem Soc Rev,2012,41(15):5239-5261.
[116]M hle R, Bautz F, Rafii S, et al. The chemokine receptor CXCR-4is expressed onCD34+hematopoietic progenitors and leukemic cells and mediates transendothelialmigration induced by stromal cell-derived factor-1[J]. Blood,1998,91(12):4523-4530.
[117]Hiasa K, Ishibashi M, Ohtani K, et al. Gene transfer of stromal cell-derivedfactor-1alpha enhances vasculogenesis and angiogenesis via vascular endothelialgrowth factor/endothelial nitric oxide synthase-related pathway: next-generationchemokine therapy for therapeutic neovascularization[J]. Circulation,2004,109(20):2454-2461.
[118]Aghi M, Cohen KS, Klein RJ, et al. Tumor stromal-derived factor-1recruits vascularprogenitors to mitotic neovasculature, where microenvironment influences theirdifferentiated phenotypes[J]. Cancer Res,2006,66(18):9056-9064.
[119]Eguchi M, Masude H, Asahara T, et al. Endothelial progenitor cells for postnatalvasculogenesis[J]. Clin Exp Nephrol,2007,11(1):18-25.
[120] D me B, Hendrix MJ, Paku S, et al. Alternative vascularization mechanisms incancer: Pathology and therapeutic implications[J]. Am J Pathol,2007,170(1):1-15.
[121] Taylor M, R ssler J, Geoerger B, et al. High levels of circulating VEGFR2+bonemarrow-derived progenitor cells correlate with metastatic disease in patients withpediatric solid malignancies[J]. Clin Cancer Res,2009,15(14):4561-4571.
[122] Lin J, Lalani AS, Harding TC, et al. Inhibition of lymphogenous metastasis usingadeno-associated virus-mediated gene transfer of a soluble VEGFR-3decoyreceptor[J]. Cancer Res,2005,65(15):6901-6909.
[1] Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparatemodel organisms[J]. Nat Rev Cancer.2005,5(5):355-366.
[2] Reya T，Morrison SJ，Clarke MF，et al. Stem cells，cancer，and cancer stem cells[J].Nature，2001,414(6859):105-111.
[3] Bapat SA, Mali AM, Koppikar CB, et al. Stem and progenitor-like cells contribute tothe aggressive behavior of human epithelial ovarian cancer[J]. Cancer Res,2005,65(8):3025-3029.
[4] Miraglia S, Godfrey W, Yin AH, et al. A novel five-transmembrane hematopoietic stemcell antigen: isolation, characterization, and molecular cloning[J]. Blood,1997,90(12):5013-5021.
[5] Yin AH, Miraglia S, Zanjani ED, et al. AC133, a novel marker for humanhematopoietic stem and progenitor cells[J]. Blood,1997,90(12):5002-5012.
[6] Beier D, Hau P, Proescholdt M, et al. CD133+and CD133-glioblastoma-derivedcancer stem cells show differential growth characteristics and molecular profiles[J].Cancer Res,2007,67(9):4010-4015.
[7] Vander Griend DJ, Kathaus WL, Dalrymple S, et al. The role of CD133in normalhuman prostate stem cells and malignant cancer-initiating cells[J]. Cancer Res,2008,68(23):9703-9711.
[8] Eramo A, Lotti F, Sette G, et al. Identification and expansion of the tumorigenic lungcancer stem cell population[J]. Cell Death Differ,2008,15(3):504-514.
[9] O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable ofinitiating tumour growth in immunodeficient mice[J]. Nature,2007,445(7123):106-110.
[10] Ferrandina G, Bonanno G, Pierelli L，et al. Expression of CD133-1and CD133-2inovarian cancer[J]. Int J Gynecol Cancer,2008,18(3):506-514.
[11] Baba T, Convery PA, Matsumura N，et al. Epigenetic regulation of CD133andtumorigenicity of CD133+ovarian cancer cells[J]. Oncogene,2009,28(2):209-218.
[12] Zhang S, Curt Balch, Michael W，et al. Identification and characterization of ovariancancer-initiating cells from primary human tumors[J]. Cancer Res,2008,68(11):4311-4320.
[13] Fathalla MF. Incessant ovulation:A factor in ovarian neoplasia[J]? Lancet,1971,11(7716):163.
[14] Scully RE, Young RH, Clement PB, et al. Tumors of the ovary, maldeveloped gonads,fallopian tube, and broad ligament[A]. In:Atlas of tumor pathology, fascicle233rdseries[C]. Washington, DC: Armed Forces Institute of Pathology,1998:1-168.
[15] Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells-perspectives on current statusand future directions: AACR workshop on cancer stem cells[J]. Cancer Res,2006,66(19):9339-9344.
[16] Knoepfler P. Journal club. A cell biologist looks at the risk and promise of a newinsight into stem cells and cancer[J]. Nature,2009,457(7728):361.
[17] Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification oftumorigenic breast cancer cell[J]. Proc Natl Acad Sci USA,2003,100(11):3983-3988.
[18] Levina V, Marrangoni AM, DeMarco R, et al. Drug-selected human lung cancer stemcells cytokine network, tumorigenic and metastatic prosperties[J]. PLoS One,2008,3(8): e3077.
[19] Yi L, Zhou ZH, Ping YF, et al. Isolation and characterization of stem cell-likeprecursor cells from primary human anaplastic oligoastrocytoma[J]. Mod Pathol,2007,20(10):1061-1068.
[20] Yang ZF, Nagai P, Ho DW et al. Identification of local and circulating cancer stem cellin human liver cancer[J]. Hepatology,2008,47(3):919-928.
[21] Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostatecancer stem cells [J]. Cancer Res,2005,65(23):10946-10951.
[22] Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer side populationdefines cells with stem cell-like characteristics and Mullerian Inhibiting Substanceresponsiveness[J]. Proc Natl Acad Sci USA,2006,103(30):11154-11159.
[23] Singh SK, Hawkins C, Clarke I D, et al. Identification of human brain tumourinitiating cells[J]. Nature,2004,432(7015):396-401.
[24] Bata T, Convery PA, Matsmura N, et al. Epigenetic regulation of CD133andtuorigenicity of CD133+ovarian cancer cells[J]. Oncogene,2009,28(2):209-218.
[25] Li CZ, Liu B, Wen ZQ, et al. Inhibition of CD44expression by small interfering RNAto suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo[J].Folia Biol,2008,54(6):180-186.
[26] Fong MY, Kakar SS. The role of cancer stem cells and the side population in epithelialovarian cancer[J]. Histol Histopathol,2010,25(1):113-120.
[27] Gao MQ，Choi YP, Kang S, et al. CD24+cells from hierarchically organized ovariancancer are enriched in cancer stem cells[J]. Oncogene,2010,29(18):2672-2680.
[28] Auersperg N, Wong AS, Choi KC, et al. Ovarian surface epithelium: biologyendocrinology, and pathology[J]. Endocr Rev,2001,22(2):255-288.
[29] Santisteban M, Reiman JM, Asiedu MK, et al. Immune-induced epithelial tomesenchymal transition in vivo generates breast cancer stem cells[J]. Cancer Res,2009,69(7):2887-2895.
[30] Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer:role of phosphatidylinositol3' kinase/AKT pathways [J]. Oncogeng,2005,24(50):7443-7454.
[31] Alvero AB, Chen R, Fu HH, et al. Molecular phenotyping of human ovarian cancerstem cells unravels the mechanisms for repair and chemoresistance[J]. Cell Cycle,2009,8(1):158-166.
[32] Shi MF, Jiao J, Lu WG, et al. Identification of cancer stem sell-like cells from humanepithelial ovarian caicinoma cell line[J]. Cell Mol Life Sci,2010,67(22):3915-3925.
[33]许健,王水,许立生,等.乳腺癌细胞系中肿瘤干细胞相关亚群初步研究[J].南京医科大学学报,2007,27(4):350-355.
[34] Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells[J].Cancer Res,2007,67(3):1030-1037.
[35] Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched intumorigenic, stem-like cancer stem cells, whereas ABCG2+and ABCG2-cancer cellsare similarly tumorigenic[J]. Cancer Res,2005,65(14):6207-6219.
[36] Cariati M, Naderi A, Brown JP, et al. Alpha-6integrin is necessary for thetumorigenicity of a stem cell-like subpopulation with in the MCF7breast cancer cellline[J]. Int J Cancer,2008,122(2):298-304.
[37] Zhong Y, Zhou C, Ma W, et al. Most MCF7and SKOV3cells were deprived of theirstem nature by Hoechst33342[J]. Biochem Biophys Res Commun,2007,364(2):338-343.
[38] Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of theadult mammalian central nervous system[J]. Science,1992,255(5052):1707-1710.
[39] Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expression of humancolon-cancer-initiating cells[J]. Nature,2007,445(7123):111-115.
[40] Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in huambrain tumor[J]. Cancer Res,2003,63(18):5821-5828.
[41] Garcia GI, Elvira G, Zapata, AG, et al. Mesenchymal stem cells: biological propertiesand clinical applications[J]. Expert Opin Biol Ther,2010,10(10):1453-1468.
[42] Lee J, Kotliarova S, Kotliarov Y, et al. Tumor stem cells derived from glioblastomascultured in bFGF and EGF more closely mirror the phenotype and genotype ofprimary tumors than do serum-cultured cell lines[J]. Cancer Cell,2006,9(5):391-403.
[43] Han M, Jeon TY, Hwang SH, et al. Cancer spheres from gastric cancer patientsprovide an ideal model system for cancer stem cell research[J]. Cell Mol Life Sci,2011,68(21):3589-3605.
[44] Meissner A. Epigenetic modifications in pluripotent and differentiated cells[J]. NatBiotechnol,2010,28(10):1079-1088.
[45] Nozaki K, Ogawa M, Williams J, et al. A molecular signature og gastric metaplasiaarising in response to acute parietal cell loss[J]. Gastroenterology,2008,134(2):511-522.
[46] Burrows RC, Wancio D, Levitt P, et al. Response diversity and the timing ofprogenitor cell maturation are regulated by developmental changes in EGFRexpression in the cortex[J]. Neuron,1997,19(2):251-267.
[47] Tang DG, Patrawala L, Calhoun T, et al. Prostate cancer stem/progenitor cells:identification, characterization, and implications[J]. Mol Careinog,2007,46(1):1-14.
[48] Pardo M, Lang B, Yu L, et al. An expanded Oct4interaction network: implications forstem cell biology, development, and disease[J]. Cell Stem Cell,2010,6(4):382-395.
[49] Hu T, Liu S, Breiter DR, et al. Oct-4small interfering RNA results in cancer stemcell-like cell apoptosis[J]. Cancer Res,2008,68(16):6533-6540.
[50]周秀怀.靶向抑制Oct-4表达增加食管癌化疗敏感性的研究[J].实用医学杂志,2012,28(7):1052-1054.
[51] Mitsui K, Tokuzawa Y, Itoh H, et al. The humeopmteln Nanog is required formaintenance of pludpotency in mouse epiblast and ES cells[J]. Cell,2003,113(5):631-642.
[52] Charmbers I, Colby D, Robertson M, et al. Functioncal expression cloning of Nanog, apluripotency factor in embryonic stem cells[J]. Cell,2003,113(5):643-655.
[53] Li SD, Howell SB. CD44-targeted microparticles for delivery of cisplatin to peritonealmetastases[J]. Mol Pharm,2010,7(1):280-290.
[54]赵林涛,卞修武,姜建勇,等.下调CXCR4表达对胶质瘤干细胞侵袭能力和VEGF分泌量的影响[J].第三军医大学学报,2009,31(11):1049-1052.
[55] Hambardzumyan D, Squatrito M, Holland EC. Radiation resistance and stem-like cellsin brain tumors[J]. Cancer Cell,2006,10(6):454-456.
[56] Robey RW, Polgar O, Deeken J, et al. ABCG2: determining its relevance in clinicaldrug resistance[J]. Cancer Metastasis Rev,2007,26(1):39-57.
[57] Zielske SP, Spalding AC, Lawrence TS. Loss of tumor-initiating cell activity incyclophosphamide-treated breast xenografts[J]. Transl Oncol,2010,3(3):149-152.
[1] Furusato B, Mohamed A, Uhlén M, et al. CXCR4and cancer[J]. Pathol Int,2010,60(7):497-505.
[2] Tachibana K, Hirota S, lizasa H, et al. The chemokine receptor CXCR4is essential forvascularization of the gastrointestinal tract[J]. Nature,1998,393(6685):591-594.
[3] Caruz A, Samsom M, Alonso JM, et al. Geneomic organization and promotercharacterization of human CXCR4gene[J]. FEBS Lett,1998,426(2):271-278.
[4] Hamm HE. The many faces of G protein signaling[J]. J Biol Chem,1998,273(2):669-672.
[5] Wojcechowskyj JA, Lee JY, Seeholzer SH, et al. Quantitative phosphoproteomics ofCXCL12(SDF-1) signaling[J]. PLoS One,2011,6(9): e24918.
[6] Nagasawa T, Hirota S, Tachibana K. et al. Defects of B-cell lymphopoiesis andbone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1[J].Nature,1996,382(6592):635-638.
[7] Domanska UM, Kruizinga RC, Nagengast WB, et al. A review on CXCR4/CXCL12axis in oncology: no place to hide[J]. Eur J Cancer,2013,49(1):219-230.
[8] Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breastcancer metastasis[J]. Nature,2001,410(6824):50-56.
[9] Hall JM, Korach KS. Stromal cell-derived factor1, a novel target of estrogen receptoraction, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells[J].Mol Endocrinol,2003,17(5):792-803.
[10] Kaifi JT, Yekebas EF, Schurr P, et al. Tumor-cell homing to lymph nodes and bonemarrow and CXCR4expression in esophageal cancer[J]. J Nat Cancer Inst,2005,97(24):1840-1847.
[11] Taichman RS, Cooper C, Keller ET, et al. Use of the stromal cell-derivedfactor-1/CXCR4pathway in prostate cancer metastasis to bone[J]. Cancer Res,2002,62(6):1832-1837
[12] Barbieri E, Bajetto A, Florio T, et al. Role of chemokine network in the developmentand progression of ovarian cancer: a potential novel pharmacological target[J]. J Oncol,2010,2010:426956.
[13] Scotton CJ, Wilson JL, Milliken D, et al. Epithelial cancer cell migration: a role forchemokine receptors[J]? Cancer Res,2001,61(13):4961-4965.
[14] Popple A, Durrant LG, Spendlove I, et al. The chemokine, CXCL12, is an independentpredictor of poor survival in ovarian cancer[J]. Br J Cancer,2012,106(7):1306-1313.
[15] Archibald KM, Kulbe H, Kwong J, et al. Sequential genetic change at the TP53andchemokine receptor CXCR4locus during transformation of human ovarian surfaceepithelium[J]. Oncogene,2012,31(48):4987-4995.
[16] Jiang YP, Wu XH, Shi B, et al. Expression of chemokine CXCL12and its receptorCXCR4in human epithelial ovarian cancer: an independent prognostic factor fortumor pregression[J]. Gynecol Oncol,2006,103(1):226-233.
[17] Obermajer N, Muthuswamy R, Odunsi K, et al. PGE(2)-induced CXCL12productionand CXCR4expression controls the accumulation of human MDSCs in ovarian cancerenvironment[J]. Cancer Res,2011,71(24):7463-7470.
[18] Hassan S, Buchanan M, Jahan K, et al. CXCR4peptide antagonist inhibits primarybreast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment ordocetaxel in a transgenic mouse model[J]. Int J Cancer,2011,129(1):225-232.
[19] Righi E, Kashiwagi S, Yuan J, et al. CXCL12/CXCR4blockade induces multimodalantitumor effects that prolong survival in an immunocompetent mouse model ofovarian cancer[J]. Cancer Res,2011,71(16):5522-5534.
[20] Ray P, Lewin SA, Mihalko LA, et al. Noninvasive imaging reveals inhibition ofovarian cancer by targeting CXCL12-CXCR4[J]. Neoplasia,2011,13(12):1152-1161.
[21] Spano JP, Andre F, Morat L, et al. Chemokine receptor CXCR4and early-stagenon-small cell lung cancer: pattern of expression and correlation with outcome[J]. AnnOncol,2004,15(4):613-617.
[22] Huang EH, Singh B, Cristofanilli M, et al. A CXCR4antagonist CTCE-9908inhibitsprimary tumor growth and metastasis of breast cancer[J]. J Surg Res,2009,155(2):231-236.
[23] Liang Z, Brooks J, Willard M, et al. CXCR4/CXCL12axis promotes VEGF-mediatedtumor angiogenesis through Akt signaling pathway[J]. Biochem Biophys Res Commun,2007,359(3):716-722.
[24] Du R, Lu KV, Petritsch C, et al. HIFαlpha induces the recruitment of bonemarrow-derived vascular modulatory cells to regulate tumor angiogenesis andinvasion[J]. Cancer Cell,2008,13(3):206-220.
[25] Jin DK, Shido K, Kopp HG, et al. Cytokine-mediated deployment of SDF-1inducesrevascularization through recruitment of CXCR4+hemangiocytes[J]. Nat Med,2006,12(5):557-567.
[26] Jodele S, Chantrain CF, Blavier L, et al. The contribution of bone marrow-derived cellsto the tymor vasculature in neuroblastoma is matrix metalloproteinase-9dependent[J].Cancer Res,2005,65(8):3200-3208.
[27] Cui K, Zhao W, Wang C, et al. The CXCR4-CXCL12pathway facilitates theprogression of pancreatic cancer via induction of angiogenesis andlymphangiogenesis[J]. J Surg Res,2011,171(1):143-150.
[28] Kato M, Kitayama J, Kazama S, et al. Expression pattern of CXC chemokinereceptor-4is correlated with lymph node metastasis in human invasive ductalcarcinoma[J]. Breast Cancer Res,2003,55(5): R144-150.
[29] Tanabe S, Nakadai T, Furuoka H, et al. Expression of mRNA of chemokine receptorCXCR4in feline mammary adenocarcinoma[J]. Vet Rec,2002,151(24):729-733.
[30] Kryczek I, Lange A, Mottram P, et al. CXCL12and vascular endothelial growth factorsynergistically induce neoangiogenesis in human ovarian cancers[J]. Cancer Res,2005,65(2):465-472.
[31] Retz MM, Sidhu SS, Blaveri E, et al. CXCR4expression reflects tumor progressionand regulates motility of bladder cancer cells[J]. Int J Cancer,2005,114(2):182-189.
[32] Xu L, Duda DG, di Tomaso E, et al. Direct evidence that bevacizumab, an anti-VEGFantibody, up-regulations SDFlalpha, CXCR4, CXCL6, and neuropilin1in tumors frompatients with rectal cancer[J]. Cancer Res,2009,69(20):7905-7910.
[33] Kioi M, Vogel H, Schultz G, et al. Inhibition of vasculogenesis, but not angiogenesis,prevents the recurrence of glioblastoma after irradiation in mice[J]. J Clin Invest,2010,120(3):694-705.
[34] Kim DH, Rossi JJ. Strategies for silencing human disease using RNA interference[J].Nat Rev Genet,2007,8(3):173-184.
[35] Kajiyama H, Shibata K, Terauchi M, et al. Involvement of SDF-1alpha/CXCR4axis inthe enhanced peritoneal metastasis of epithelial ovarian carcinoma[J]. Int J Cancer,2008,122(1):91-99.
[36] Dipersio JF, Uy GL, Yasothan U, et al. Plerixafor[J]. Nat Rev Drug Discov,2009,8(2):105-106.
[37] Burger JA, Stewart DJ. CXCR4chemokine receptor antagonists: perspectives inSCLC[J]. Expert Opin Investig Drugs,2009,18(4):481-490.
[38] Kim M, Koh YJ, Kim KE, et al. CXCR4signaling regulates metastasis ofchemoresistant melanoma cells by a lymphatic metastatic niche[J]. Cancer Res,2010,70(24):10411-10421.
[39] Shaked Y, Henke E, Roodhart JM, et al. Rapid chemotherapy-induced acuteendothelial progenitor cell mobilization: implications for antiangiogenic drugs aschemosensitizing agents[J]. Cancer Cell,2008,14(3):263-273.