神经菌毛素1在恶性肿瘤治疗中的相关研究进展
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摘要
作为一种跨膜糖蛋白,神经菌毛素1(NRP1)在轴突导向、血管生成和肿瘤免疫等多种反应过程中发挥重要作用。NRP1高表达于多种肿瘤细胞表面,尤其是上皮细胞肿瘤。阻断NRP1不仅能直接对肿瘤细胞的迁移及肿瘤的发生发展产生抑制作用,而且能够间接抑制肿瘤局部血管的生成与发展,继而影响肿瘤的生长发展。因此,NRP1有望成为抗肿瘤治疗的新突破点。简要探讨NRP1在肿瘤发生发展中的作用,以及以NRP1为靶点治疗恶性肿瘤的相关研究进展。
Neuropilin-1(NRP1), as a transmembrane glycoprotein, plays an important role in a variety of reactions such as axon guidance, angiogenesis and tumor immunity. The study found that NRP1 is highly expressed on the surface of a variety of tumor cells, especially epithelial tumors. Blocking NRP1 can not only directly inhibit the migration of tumor cells, and the occurrence and development of tumors, but also indirectly inhibit the formation and development of local blood vessels, which in turn affects the growth and development of tumors. Therefore, NRP1 is expected to become a new breakthrough in anti-tumor therapy. This article aimed to investigate the role of NRP1 in tumorigenesis and the development of NRP1 as a target for the treatment of malignant tumors.
Neuropilin-1(NRP1), as a transmembrane glycoprotein, plays an important role in a variety of reactions such as axon guidance, angiogenesis and tumor immunity. The study found that NRP1 is highly expressed on the surface of a variety of tumor cells, especially epithelial tumors. Blocking NRP1 can not only directly inhibit the migration of tumor cells, and the occurrence and development of tumors, but also indirectly inhibit the formation and development of local blood vessels, which in turn affects the growth and development of tumors. Therefore, NRP1 is expected to become a new breakthrough in anti-tumor therapy. This article aimed to investigate the role of NRP1 in tumorigenesis and the development of NRP1 as a target for the treatment of malignant tumors.
引文
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[26]Yoshida A,Shimizu A,Asano H,et al.VEGF-A/NRP1stimulates GIPC1 and Syx complex formation to promote RhoA activation andproliferation in skin cancer cells[J].Biol Open,2015,4:1063-1076.
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[28]Zhang L,Wang H,Li C,et al.VEGF-A/neuropilin 1pathway confers cancer stemness via activating Wnt/betacatenin axis in breast cancer cells[J].Cell Physiol Biochem,2017,44:1251-1262.
[29]Atzori M G,Tentori L,Ruffini F,et al.The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells[J].Exp Clin Cancer Res,2017,36:106.
[30]Cross M J,Dixelius J,Matsumoto T,et al.VEGF-receptor signal transduction[J].Method Enzymol,2008,443(9):261.
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[32]Liang W C,Dennis M S,Stawicki S,et al.Function blocking antibodies to neuropilin-1 generated from a designed human syntheticantibody phage library[J].Mol Biol,2007,366:815-829.
[33]Malinauskas T,Janssen B J C,Weir G A,et al.Neuropilins lock secreted Semaphorins onto plexins in a ternary signalling complex[J].Nat Struct Mol Biol,2013,104(2):613a-613a.
[34]Burke B,Giannoudis A,Corke K P,et al.Hypoxia-induced gene expression in human macrophages:implications for ischemic tissues and hypoxia-regulated gene therapy[J].Am J Pathol,2003,163(4):1233.
[35]Guthrie S.Axon guidance:starting and stopping with slit[J].Curr Biol,1999,9(12):R432.
[36]Biankin A V,Waddell N,Kassahn K S,et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes[J].Nature,2012,491(7424):399.
[37]Maione F,Molla F,Meda C,et al.Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models[J].J Clin Invest,2009,119(11):3356-3372.
[38]White G P,Watt P M,Holt B J,et al.Differential patterns of methylation of the IFN-gamma promoter at Cp G and non-CpG sites underlies differences in IFN-γgene expression between human neonatal and adult CD45RO-T cells[J].J Immunol,2002,168(6):2820.
[39]Bruniquel D,Schwartz R H.Selectivestable demethylation of the interleukin-2 gene enhances transcription by an active process[J].Nat Immunol,2003,4(3):235-240.
[40]Bird A.IL-2 transcription unleashed by active DNAdemethylation[J].Nat Immunol,2003,4(3):208-209.
[41]Kersh E N,Fitzpatrick D R,Muralikrishna K,et al.Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells[J].J Immunol,2006,176(7):4083.
[42]Javierre B M,Fernandez A F,Richter J,et al.Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus[J].Genome Res,2010,20(2):170-179.
[43]Marr A K,Macisaac J L,Jiang R,et al.Leishmania donovani infection causes distinct epigenetic DNAmethylation changes in host macrophages[J].PLoSPathogens,2014,10(10):e1004419.
[44]Pacis A,Tailleux L,Morin A M,et al.Bacterial infection remodels the DNA methylation landscape of human dendritic cells[J].Genome Res,2015,25(12):1801.
[45]Tordjman R,Lepelletier Y,Lemarchandel V,et al.Aneuronal receptor,neuropilin-1 is essential for the initiation of the primary immune response[J].Nat Immunol,2002,3(5):477-482.
[46]Milka S,Andersen K G,Felix R,et al.Neuropilin-1expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition[J].Immunity,2008,28(3):402-413.
[47]Delgoffe G M,Woo S R,Turnis M E,et al.Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis[J].Nature,2013,501(7466):252-256.
[48]Chaudhry A,Rudensky A Y.Control of inflammation by integration of environmental cues by regulatory T cells[J].J Clin Invest,2013,123(3):939-944.
[49]Battaglia A,Buzzonetti A,Baranello C,et al.Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer[J].Cancer Immunol Immunother,2009,58(9):1363-1373.
[50]Chaudhary B,Khaled Y S,Ammori B J,et al.Neuropilin1:function and therapeutic potential in cancer[J].Cancer Immunol Immunother,2014,63(2):81-99.
[51]Gao Y L,Chai Y F,Qi A L,et al.Neuropilin-1high CD4+CD25+regulatory T cells exhibit primary negative immunoregulation in sepsis[J].Mediators Inflamm,2016,2016:7132158.
[52]Milpied P,Renand A,Bruneau J,et al.Neuropilin-1 is not a marker of human Foxp3+Treg[J].Eur J Immunol,2009,39(6):1466-1471.
[53]Piechnik A,Dmoszynska A,Omiotek M,et al.The VEGFreceptor,neuropilin-1,represents a promising novel target for chronic lymphocytic leukemia patients[J].Int Cancer,2013,133:1489-1496.
[54]Tatura R,Zeschnigk M,Hansen W,et al.Relevance of Foxp3+regulatory T cells for early and late phases of murine sepsis[J].Immunology,2015,146(1):144-156.
[55]Lee J,Elly C,Park Y,et al.E3 ubiquitin ligase VHLregulates hypoxia-inducible factor-1γto maintain regulatory T cell stability and suppressive capacity[J].Immunity,2015,42(6):1062-1074.
[56]Oldenhove G,Bouladoux N,Wohlfert E A,et al.Decrease of Foxp3+Treg cell number and acquisition of effector cell phenotype during lethal infection[J].Immunity,2009,31(5):772-786.
[57]Zhao J,Zhao J,Fett C,et al.IFN-γ-and IL-10-expressing virus epitope-specific Foxp3+T reg cells in the central nervous system during encephalomyelitis[J].J Exp Med,2011,208(8):1571-1577.
[2]Gagnon M L,Bielenberg D R,Gechtman Z,et al.Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor:in vivo expression and antitumor activity[J].Proc Natl Acad Sci USA,2000,97(6):2573-2578.
[3]Wang J,Lei Y,Xie C,et al.Targeted gene delivery to glioblastoma using a C-end rule RGERPPR peptidefunctionalised polyethylenemine complex[J].Int J Pharm,2013,458(1):48-56.
[4]Ball S G,Bayley C,Shuttleworth C A,et al.Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells[J].Biochem J,2010,427(1):29-40.
[5]Rossignol M,Gagnon M L,Klagsbrun M.Genomic organization of human neuropilin-1 and neuropilin-2genes:identification and distribution of splice variants and soluble isoforms[J].Genomics,2000,70(2):211-222.
[6]Lampropoulou A,Ruhrberg C.Neuropilin regulation of angiogenesis[J].Biochem Soc Trans,2014,42(6):1623-1628.
[7]Gu C,Limberg B J,Whitaker G B,et al.Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165[J].J Biol Chem,2002,277:18069-18076.
[8]Mamluk R,Gechtman Z,Kutcher M E,et al.Neuropilin-1 binds vascular endothelial growth factor 165,placenta growth factor-2,and heparin via its b domain[J].J Biol Chem,2002,277:24818-24825.
[9]Jubb A M,Strickland L A,Liu S D,et al.Neuropilin-1 expression in cancer and development[J].J Pathol,2012,226(1):50-60.
[10]Rizzolio S,Rabinowicz N,Rainero E,et al.Neuropilin-1-dependent regulation of EGF-receptor signaling[J].Cancer Res,2012,72(22):5801.
[11]Wild J R L,Staton C A,ChappleàK,et al.Neuropilins:expression and roles in the epithelium[J].Int J Exp Pathol,2012,93(2):81-103.
[12]Teesalu T,Sugahara K N,Kotamraju V R,et al.C-end rule peptides mediate neuropilin-1-dependent cell,vascular,and tissue penetration[J].Proc Natl Acad Sci USA,2009,106:16157-16162.
[13]Yuan L,Moyon D,Pardanaud L,et al.Abnormal lymphatic vessel development in neuropilin 2 mutant mice[J].Development,2002,129:4797-4806.
[14]Stalmans I,Ng Y S,Rohan R,et al.Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms[J].Clin Investig,2002,109,327-336.
[15]Gu C,Rodriguez E R,Reimert D V,et al.Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development[J].Dev Cell,2003,5:45-57.
[16]Soker S,Takashima S,Miao H Q,et al.Neuropilin-1 is expressed by endothelialand tumor cells as an isoformspecific receptor for vascular endothelial growth factor[J].Cell,1998,92:735-745.
[17]Kitsukawa T,Shimono A,Kawakami A,et al.Over expression of a membrane protein neuropilinin chimeric mice causes anomalies in the cardiovascular system,nervous system and limbs[J].Development,1995,121:4309-4318.
[18]Kawasaki T,Kitsukawa T,Bekku Y,et al.A requirement for neuropilin-1 in embryonic vessel formation[J].Development,1999,126:4895-4902.
[19]Takashima S,Kitakaze M,Asakura M,et al.Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis[J].Proc Natl Acad Sci USA,2002,99:3657-3662.
[20]Mazzone M,Comoglio P M.The Met pathway:master switch and drug target in cancer progression[J].FASEBJ,2006,20:1611-1621.
[21]Birchmeier C,Birchmeier W,Gherardi E.Met,metastasis,motility and more[J].Nat Rev Mol Cell Biol,2003,4:915-925.
[22]Hu B,Guo P,Bar-Joseph I,et al.Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway[J].Oncogene,2007,26:5577-5586.
[23]Matsushita A,Gotze T,Korc M.Hepatocyte growth factormediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1[J].Cancer Res,2007,67:10309-10316.
[24]Herzog Y,Kalcheim C,Kahane N,et al.Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins[J].Mech Dev,2001,109(1):115-119.
[25]Takahashi T,Fournier A,Nakamura F,et al.Plexinneuropilin-1 complexes form functional semaphorin-3Areceptors[J].Cell,1999,99(1):59-69.
[26]Yoshida A,Shimizu A,Asano H,et al.VEGF-A/NRP1stimulates GIPC1 and Syx complex formation to promote RhoA activation andproliferation in skin cancer cells[J].Biol Open,2015,4:1063-1076.
[27]Smith N R,Baker D,James N H,et al.Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarilyto the vasculature in human primary solid cancers[J].Clin Cancer Res,2010,16:3548-3561.
[28]Zhang L,Wang H,Li C,et al.VEGF-A/neuropilin 1pathway confers cancer stemness via activating Wnt/betacatenin axis in breast cancer cells[J].Cell Physiol Biochem,2017,44:1251-1262.
[29]Atzori M G,Tentori L,Ruffini F,et al.The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells[J].Exp Clin Cancer Res,2017,36:106.
[30]Cross M J,Dixelius J,Matsumoto T,et al.VEGF-receptor signal transduction[J].Method Enzymol,2008,443(9):261.
[31]Inai T,Mancuso M,Hashizume H,et al.Inhibition of vascular endothelial growth factor(VEGF)signaling in cancer causes loss of endothelial fenestrations,regression of tumor vessels,and appearance of basement membrane ghosts[J].Am J Pathol,2004,165(1):35-52.
[32]Liang W C,Dennis M S,Stawicki S,et al.Function blocking antibodies to neuropilin-1 generated from a designed human syntheticantibody phage library[J].Mol Biol,2007,366:815-829.
[33]Malinauskas T,Janssen B J C,Weir G A,et al.Neuropilins lock secreted Semaphorins onto plexins in a ternary signalling complex[J].Nat Struct Mol Biol,2013,104(2):613a-613a.
[34]Burke B,Giannoudis A,Corke K P,et al.Hypoxia-induced gene expression in human macrophages:implications for ischemic tissues and hypoxia-regulated gene therapy[J].Am J Pathol,2003,163(4):1233.
[35]Guthrie S.Axon guidance:starting and stopping with slit[J].Curr Biol,1999,9(12):R432.
[36]Biankin A V,Waddell N,Kassahn K S,et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes[J].Nature,2012,491(7424):399.
[37]Maione F,Molla F,Meda C,et al.Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models[J].J Clin Invest,2009,119(11):3356-3372.
[38]White G P,Watt P M,Holt B J,et al.Differential patterns of methylation of the IFN-gamma promoter at Cp G and non-CpG sites underlies differences in IFN-γgene expression between human neonatal and adult CD45RO-T cells[J].J Immunol,2002,168(6):2820.
[39]Bruniquel D,Schwartz R H.Selectivestable demethylation of the interleukin-2 gene enhances transcription by an active process[J].Nat Immunol,2003,4(3):235-240.
[40]Bird A.IL-2 transcription unleashed by active DNAdemethylation[J].Nat Immunol,2003,4(3):208-209.
[41]Kersh E N,Fitzpatrick D R,Muralikrishna K,et al.Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells[J].J Immunol,2006,176(7):4083.
[42]Javierre B M,Fernandez A F,Richter J,et al.Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus[J].Genome Res,2010,20(2):170-179.
[43]Marr A K,Macisaac J L,Jiang R,et al.Leishmania donovani infection causes distinct epigenetic DNAmethylation changes in host macrophages[J].PLoSPathogens,2014,10(10):e1004419.
[44]Pacis A,Tailleux L,Morin A M,et al.Bacterial infection remodels the DNA methylation landscape of human dendritic cells[J].Genome Res,2015,25(12):1801.
[45]Tordjman R,Lepelletier Y,Lemarchandel V,et al.Aneuronal receptor,neuropilin-1 is essential for the initiation of the primary immune response[J].Nat Immunol,2002,3(5):477-482.
[46]Milka S,Andersen K G,Felix R,et al.Neuropilin-1expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition[J].Immunity,2008,28(3):402-413.
[47]Delgoffe G M,Woo S R,Turnis M E,et al.Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis[J].Nature,2013,501(7466):252-256.
[48]Chaudhry A,Rudensky A Y.Control of inflammation by integration of environmental cues by regulatory T cells[J].J Clin Invest,2013,123(3):939-944.
[49]Battaglia A,Buzzonetti A,Baranello C,et al.Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer[J].Cancer Immunol Immunother,2009,58(9):1363-1373.
[50]Chaudhary B,Khaled Y S,Ammori B J,et al.Neuropilin1:function and therapeutic potential in cancer[J].Cancer Immunol Immunother,2014,63(2):81-99.
[51]Gao Y L,Chai Y F,Qi A L,et al.Neuropilin-1high CD4+CD25+regulatory T cells exhibit primary negative immunoregulation in sepsis[J].Mediators Inflamm,2016,2016:7132158.
[52]Milpied P,Renand A,Bruneau J,et al.Neuropilin-1 is not a marker of human Foxp3+Treg[J].Eur J Immunol,2009,39(6):1466-1471.
[53]Piechnik A,Dmoszynska A,Omiotek M,et al.The VEGFreceptor,neuropilin-1,represents a promising novel target for chronic lymphocytic leukemia patients[J].Int Cancer,2013,133:1489-1496.
[54]Tatura R,Zeschnigk M,Hansen W,et al.Relevance of Foxp3+regulatory T cells for early and late phases of murine sepsis[J].Immunology,2015,146(1):144-156.
[55]Lee J,Elly C,Park Y,et al.E3 ubiquitin ligase VHLregulates hypoxia-inducible factor-1γto maintain regulatory T cell stability and suppressive capacity[J].Immunity,2015,42(6):1062-1074.
[56]Oldenhove G,Bouladoux N,Wohlfert E A,et al.Decrease of Foxp3+Treg cell number and acquisition of effector cell phenotype during lethal infection[J].Immunity,2009,31(5):772-786.
[57]Zhao J,Zhao J,Fett C,et al.IFN-γ-and IL-10-expressing virus epitope-specific Foxp3+T reg cells in the central nervous system during encephalomyelitis[J].J Exp Med,2011,208(8):1571-1577.