卵巢癌干细胞标志物及相关信号通路的研究进展和靶向治疗
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摘要
卵巢癌病死率高居妇科三大恶性肿瘤之首,目前标准的治疗方案是根治性手术联合铂类辅助化疗。虽然卵巢癌的治疗在生物技术方面取得了很大进展,但大部分患者仍会出现耐药及复发。近年来研究表明,肿瘤干细胞(CSC)是肿瘤耐药和复发的根源,因此从CSC出发可为临床治疗卵巢癌提供新的研究方向。目前,卵巢癌干细胞的鉴定及分离均取得了很大进步,在抗卵巢癌的治疗中,通过对卵巢癌干细胞相关分子标志物及信号转导通路的深入研究已经成功引进了新的治疗方法。
Ovarian cancer mortality is currently the top among three gynecological malignancies,and radical surgery combined with platinum-based adjuvant chemotherapy is the standard treatment now. Although there have been encouraging developments in biotechnology,most patients develop resistance and relapse. In recent years,studies have shown that cancer stem cells are the root of tumor resistance and relapse. Therefore,starting from cancer stem cells,may provide a new research direction for radical cure of ovarian cancer. Now the identification and isolation of ovarian cancer stem cells have made great progress. In the treatment of ovarian cancer,new treatments have been successfully introduced through in-depth study of ovarian cancer stem cell related molecular markers and signal transduction pathways.
Ovarian cancer mortality is currently the top among three gynecological malignancies,and radical surgery combined with platinum-based adjuvant chemotherapy is the standard treatment now. Although there have been encouraging developments in biotechnology,most patients develop resistance and relapse. In recent years,studies have shown that cancer stem cells are the root of tumor resistance and relapse. Therefore,starting from cancer stem cells,may provide a new research direction for radical cure of ovarian cancer. Now the identification and isolation of ovarian cancer stem cells have made great progress. In the treatment of ovarian cancer,new treatments have been successfully introduced through in-depth study of ovarian cancer stem cell related molecular markers and signal transduction pathways.
引文
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[20]Luo L,Zeng J,Liang B,et al.Ovarian cancer cells with the CD117phenotype are highly tumorigenic and are related to chemotherapy outcome[J].Exp Mol Pathol,2011,91(2):596-602
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[22]Kadivar A,Kamalidehghan B,Javar HA,et al.Antiproliferation effect of imatinib mesylate on MCF7,T-47D tumorigenic and MCF10A nontumorigenic breast cell lines via PDGFR-β,PDGF-BB,c-Kit and SCF genes[J].Drug Des Devel Ther,2017,11:469-481.
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[24]王爱春,王昀,顾依群,等.卵巢上皮性癌中CD24的表达及其临床病理意义[J].诊断病理学杂志,2013,20(7):387-389.
[25]Bretz NP,Salnikov AV,Perne C,et al.CD24controls Src/STAT3activity in human tumors[J].Cell Mol Life Sci,2012,69(22):3863-3879.
[26]Hsu SY,Liang SG,Hsueh AJ.Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled,seventransmembrane region[J].Mol Endocrinol,1998,12(12):1830-1845.
[27]Amsterdam A,Raanan C,Schreiber L,et al.Localization of the stem cell markers LGR5 and Nanog in the normal and the cancerous human ovary and their inter-relationship[J].Acta Histochem,2013,115(4):330-338.
[28]翟颖仙,张丽红,周莉,等.肿瘤干细胞标记物LGR5和CD133在卵巢癌中的表达和意义[J].中国实验诊断学,2013,17(9):1598-1601.
[29]Gong X,Azhdarinia A,Ghosh SC,et al.LGR5-targeted antibodydrug conjugate eradicates gastrointestinal tumors and prevents recurrence[J].Mol Cancer Ther,2016,15(7):1580-1590.
[30]李晓莹.细胞周期蛋白CDC50A参与维持卵巢癌干细胞特性及其相关作用机制的研究[D].北京:协和医学院,2016.
[31]卢余莉,谢程.γ分泌酶抑制剂阻断Notch信号通路对人卵巢癌SKOV3细胞增殖和凋亡的影响[J].四川大学学报(医学版),2014,45(4):578-581.
[32]Mohammed MK,Shao C,Wang J,et al.Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance[J].Genes Dis,2016,3(1):11-40.
[33]Madan B,Virshup DM.Targeting Wnts at the source—New mechanisms,new biomarkers,new drugs[J].Mol Cancer Ther,2015,14(5):1087-1094.
[34]Kühl SJ,Kühl M.On the role of Wnt/β-catenin signaling in stem cells[J].Biochim Biophys Acta,2013,1830(2):2297-2306.
[35]Arend RC,Londo o Joshi AI,Straughn JM Jr,et al.The Wnt/β-catenin pathway in ovarian cancer:A review[J].Gynecol Oncol,2013,131(3):772-779.
[36]Duchartre Y,Kim YM,Kahn M.The Wnt signaling pathway in cancer[J].Crit Rev Oncol Hematol,2016,99:141-149.
[37]Pfankuchen DB,St9lting DP,Schlesinger M,et al.Low molecular weight heparin tinzaparin antagonizes cisplatin resistance of ovarian cancer cells[J].Biochem Pharmacol,2015,97(2):147-157.
[38]Pfankuchen DB,Baltes F,Batool T,et al.Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway[J].Oncotarget,2017,8(40):67553-67566.
[39]Arai MA,Utsumi T,Yanase N,et al.Efficient synthesis of heterocyclic flavonoids with hedgehog signal inhibitory activity[J].Chem Pharm Bull,2017,65(8):784-795.
[40]Fabregat I,Fernando J,Mainez J,et al.TGF-beta signaling in cancer treatment[J].Curr Pharm Des,2014,20(17):2934-2947.
[41]Lin W,Zhuang Q,Zheng L,et al.Pien Tze Huang inhibits Liver metastasis by targeting TGF-βsignaling in an orthotopic model of colorectal cancer[J].Oncol Rep,2015,33(4):1922-1928.
[42]Garson K,Vanderhyden B.Epithelial ovarian cancer stem cells:Underlying complexity of a simple paradigm[J].Reproduction,2015,149(2):R59-70.
[2]Clevers H.The cancer stem cell:Premises,promises and challenges[J].Nat Med,2011,17(3):313-319.
[3]Bapat SA,Mali AM,Koppikar CB,et al.Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer[J].Cancer Res,2005,65(8):3025-3029.
[4]Guo R,Wu Q,Liu F,et al.Description of the CD+133subpopulation of the human ovarian cancer cell Line OVCAR3[J].Oncol Rep,2011,25(1):141-146.
[5]Kwon MJ,Shin YK.Epigenetic regulation of cancer associated genes in ovarian cancer[J].Int J Mol Sci,2011,12(2):983-1008.
[6]Zhang J,Guo X,Chang DY,et al.CD133expression associated with poor prognosis in ovarian cancer[J].Mod Pathol,2012,25(3):456-464.
[7]Liang J,Yang B,Cao Q,et al.Association of Vasculogenic mimicry formation and CD133expression with poor prognosis in ovarian cancer[J].Gynecol Obstet Invest,2016,81(6):529-536.
[8]Long Q,Yang R,Lu W,et al.Adenovirus-mediated truncated Bid overexpression induced by the Cre/Lox P system promotes the cell apoptosis of CD+133ovarian cancer stem cells[J].Oncol Rep,2017,37(1):155-162.
[9]Ginestier C,Hur MH,Charafe-Jauffret E,et al.ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome[J].Cell Stem Cell,2007,1(5):555-567.
[10]Wang YC,Yo YT,Lee HY,et al.ALDH1-bright epithelial ovarian cancer cells are associated with CD44expression,drug resistance,and poor clinical outcome[J].Am J Pathol,2012,180(3):1159-1169.
[11]白雪,黄可欣,马洪喜,等.卵巢上皮性癌组织中ALDH1和CD55蛋白的表达及其临床意义[J].中国妇幼保健,2013,28(22):3658-3659.
[12]张坦.ALDH1 mRNA在卵巢癌组织中的表达特点及其临床意义[J].中国卫生检验杂志,2015(15):2564-2566.
[13]Landen CN Jr,Goodman B,Katre AA,et al.Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer[J].Mol Cancer Ther,2010,9(12):3186-3199.
[14]Meng E,Mitra A,Tripathi K,et al.ALDH1A1maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling[J].PLo S One,2014,9(9):e107142.
[15]Burgos-Ojeda D,Rueda BR,Buckanovich RJ.Ovarian cancer stem cell markers:Prognostic and therapeutic implications[J].Cancer Lett,2012,322(1):1-7.
[16]Kansu-Celik H,Gungor M,Ortac F,et al.Expression of CD44variant 6 and its prognostic value in benign and malignant endometrial tissue[J].Arch Gynecol Obstet,2017,296(2):313-318.
[17]Zhang S,Balch C,Chan MW,et al.Identification and characterization of ovarian cancer-initiating cells from primary human tumors[J].Cancer Res,2008,68(11):4311-4320.
[18]Gao Y,Foster R,Yang X,et al.Up-regulation of CD44in the development of metastasis,recurrence and drug resistance of ovarian cancer[J].Oncotarget,2015,6(11):9313-9326.
[19]Lu X,Huang X.Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding[J].Glycoconj J,2015,32(7):549-556.
[20]Luo L,Zeng J,Liang B,et al.Ovarian cancer cells with the CD117phenotype are highly tumorigenic and are related to chemotherapy outcome[J].Exp Mol Pathol,2011,91(2):596-602
[21]Yang B,Yan X,Liu L,et al.Overexpression of the cancer stem cell marker CD117predicts poor prognosis in epithelial ovarian cancer patients:Evidence from meta-analysis[J].Onco Targets Ther,2017,10:2951-2961.
[22]Kadivar A,Kamalidehghan B,Javar HA,et al.Antiproliferation effect of imatinib mesylate on MCF7,T-47D tumorigenic and MCF10A nontumorigenic breast cell lines via PDGFR-β,PDGF-BB,c-Kit and SCF genes[J].Drug Des Devel Ther,2017,11:469-481.
[23]Lee JH,Kim SH,Lee ES,et al.CD24overexpression in cancer development and progression:A meta-analysis[J].Oncol Repo,2009,22(5):1149-1156.
[24]王爱春,王昀,顾依群,等.卵巢上皮性癌中CD24的表达及其临床病理意义[J].诊断病理学杂志,2013,20(7):387-389.
[25]Bretz NP,Salnikov AV,Perne C,et al.CD24controls Src/STAT3activity in human tumors[J].Cell Mol Life Sci,2012,69(22):3863-3879.
[26]Hsu SY,Liang SG,Hsueh AJ.Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled,seventransmembrane region[J].Mol Endocrinol,1998,12(12):1830-1845.
[27]Amsterdam A,Raanan C,Schreiber L,et al.Localization of the stem cell markers LGR5 and Nanog in the normal and the cancerous human ovary and their inter-relationship[J].Acta Histochem,2013,115(4):330-338.
[28]翟颖仙,张丽红,周莉,等.肿瘤干细胞标记物LGR5和CD133在卵巢癌中的表达和意义[J].中国实验诊断学,2013,17(9):1598-1601.
[29]Gong X,Azhdarinia A,Ghosh SC,et al.LGR5-targeted antibodydrug conjugate eradicates gastrointestinal tumors and prevents recurrence[J].Mol Cancer Ther,2016,15(7):1580-1590.
[30]李晓莹.细胞周期蛋白CDC50A参与维持卵巢癌干细胞特性及其相关作用机制的研究[D].北京:协和医学院,2016.
[31]卢余莉,谢程.γ分泌酶抑制剂阻断Notch信号通路对人卵巢癌SKOV3细胞增殖和凋亡的影响[J].四川大学学报(医学版),2014,45(4):578-581.
[32]Mohammed MK,Shao C,Wang J,et al.Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance[J].Genes Dis,2016,3(1):11-40.
[33]Madan B,Virshup DM.Targeting Wnts at the source—New mechanisms,new biomarkers,new drugs[J].Mol Cancer Ther,2015,14(5):1087-1094.
[34]Kühl SJ,Kühl M.On the role of Wnt/β-catenin signaling in stem cells[J].Biochim Biophys Acta,2013,1830(2):2297-2306.
[35]Arend RC,Londo o Joshi AI,Straughn JM Jr,et al.The Wnt/β-catenin pathway in ovarian cancer:A review[J].Gynecol Oncol,2013,131(3):772-779.
[36]Duchartre Y,Kim YM,Kahn M.The Wnt signaling pathway in cancer[J].Crit Rev Oncol Hematol,2016,99:141-149.
[37]Pfankuchen DB,St9lting DP,Schlesinger M,et al.Low molecular weight heparin tinzaparin antagonizes cisplatin resistance of ovarian cancer cells[J].Biochem Pharmacol,2015,97(2):147-157.
[38]Pfankuchen DB,Baltes F,Batool T,et al.Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway[J].Oncotarget,2017,8(40):67553-67566.
[39]Arai MA,Utsumi T,Yanase N,et al.Efficient synthesis of heterocyclic flavonoids with hedgehog signal inhibitory activity[J].Chem Pharm Bull,2017,65(8):784-795.
[40]Fabregat I,Fernando J,Mainez J,et al.TGF-beta signaling in cancer treatment[J].Curr Pharm Des,2014,20(17):2934-2947.
[41]Lin W,Zhuang Q,Zheng L,et al.Pien Tze Huang inhibits Liver metastasis by targeting TGF-βsignaling in an orthotopic model of colorectal cancer[J].Oncol Rep,2015,33(4):1922-1928.
[42]Garson K,Vanderhyden B.Epithelial ovarian cancer stem cells:Underlying complexity of a simple paradigm[J].Reproduction,2015,149(2):R59-70.