BV8及其抗体与血管新生的关系
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摘要
BV8作为一种新发现的分泌蛋白,在内分泌腺、心血管、肾脏等器官血管新生中发挥重要作用,尤其与CD11b+Gr1+髓样细胞相关的肿瘤血管新生和发展密切相关。同时,动物模型研究证实,抗BV8抗体能明显抑制肿瘤中新生血管形成,从而起到显著的抗实体肿瘤作用。该综述对BV8的结构、功能、机制及其在疾病中的作用进行了系统回顾,以期为恶性肿瘤抗血管疗法新靶点的开发及后续BV8的研究提供新的思路和方向。
BV8, a lately defined secreted protein, is proved to play an important role in the angiogenesis process of endocrine, cardiovascular system, kidney and other organs. Moreover, it contributes to the CD11 b+Gr1+ myeloid cell-dependent tumor neo-vascularization. Meanwhile, anti-BV8 antibody therapy has been shown to be against solid tumors via inhibition of angiogenesis in animal models. This review systematically introduced the current knowledge on BV8 from structure to function, from mechanism to its role in diseases. Consequently, this review will probably provide new ideas and direction to the new target of the current anti-vascular therapy for cancer and to the future investigation.
BV8, a lately defined secreted protein, is proved to play an important role in the angiogenesis process of endocrine, cardiovascular system, kidney and other organs. Moreover, it contributes to the CD11 b+Gr1+ myeloid cell-dependent tumor neo-vascularization. Meanwhile, anti-BV8 antibody therapy has been shown to be against solid tumors via inhibition of angiogenesis in animal models. This review systematically introduced the current knowledge on BV8 from structure to function, from mechanism to its role in diseases. Consequently, this review will probably provide new ideas and direction to the new target of the current anti-vascular therapy for cancer and to the future investigation.
引文
[1]Carmeliet P.Mechanisms of angiogenesis and arteriogenesis[J].Nat Med,2000,6(4):389-395.
[2]Ferrara N,Alitalo K.Clinical applications of angiogenic growth factors and their inhibitors[J].Nat Med,1999,5(12):1359-1364.
[3]Mollay C,Wechselberger C,Mignogna G,et al.Bv8,a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats[J].Eur JPharmacol,1999,374(2):189-196.
[4]Le Couter J,Ferrara N.EG-VEGF and Bv8,a novel family of tissue-selective mediators of angiogenesis,endothelial phenotype,and function[J].Trends Cardiovasc Med,2003,13(7):276-282.
[5]Li M,Bullock CM,Knauer DJ,et al.Identification of two prokineticin c DNAs:recombinant proteins potently contract gastrointestinal smooth muscle[J].Mol Pharmacol,2001,59(4):692-698.
[6]Le Couter J,Lin R,Frantz G,et al.Mouse endocrine gland-derived vascular endothelial growth factor:a distinct expression pattern from its human ortholog suggests different roles as a regulator of organ-specific angiogenesis[J].Endocrinology,2003,144(6):2606-2616.
[7]Jilek A,Engel E,Beier D,et al.Murine Bv8 gene maps near a synteny breakpoint of mouse chromosome 6 and human 3p21[J].Gene,2000,256(1-2):189-195.
[8]Le Couter J,Lin R,Tejada M,et al.The endocrine-gland-derived VEGFhomologue Bv8 promotes angiogenesis in the testis:localization of Bv8 receptors to endothelial cells[J].Proc Natl Acad Sci U S A,2003,100(5):2685-2690.
[9]Kaser A,Winklmayr M,Lepperdinger G,et al.The AVIT protein family.secreted cysteine-rich vertebrate proteins with diverse functions[J].EMBO Rep,2003,4(5):469-473.
[10]Bullock CM,Li JD,Zhou QY.Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists[J].Mol Pharmacol,2004,65(3):582-588.
[11]Lin DC,Bullock CM,Ehlert FJ,et al.Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor[J].J Biol Chem,2002,277(22):19276-19280.
[12]Soga T,Si M,Oda T,et al.Molecular cloning and characterization of prokineticin receptors[J].Biochim Biophys Acta,2002,1579(2-3):173-179.
[13]Masuda Y,Takatsu Y,Terao Y,et al.Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors[J].Biochem Biophys Res Commun,2002,293(1):396-402.
[14]Le Couter J,Zlot C,Tejada M,et al.Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[J].Proc Natl Acad Sci U S A,2004,101(48):16813-16818.
[15]Cheng MY,Bullock CM,Li C,et al.Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[J].Nature,2002,417(6887):405-410.
[16]Zhong C,Qu XM,Meng Y,et al.Characterization and regulation of Bv8 in human blood cells[J].Clin Cancer Res,2009,15(8):2675-2684.
[17]Kowanetz M,Ferrara N.Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+granulocytes[J].Proc Natl Acad Sci U S A,2010,107(50):21248.
[18]Monnier J,Quillien V,Piquet-Pellorce C,et al.Prokineticin 1 induces CCL4,CXCL1 and CXCL8 in human monocytes but not in macrophages and dendritic cells[J].Eur Cytokine Netw,2008,19(4):166-175.
[19]Cheng MY,Lee AG,Culbertson C,et al.Prokineticin 2 is an endangering mediator of cerebral ischemic injury[J].Proc Natl Acad Sci U S A,2012,109(14):5475-5480.
[20]Hoffmann P,Feige JJ,Alfaidy N.Expression and oxygen regulation of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 and its receptors in human placenta during early pregnancy[J].Endocrinology,2006,147(4):1675-1684.
[21]Kisliouk T,Podlovni H,Spanel-Borowski K,et al.Prokineticins(endocrine gland-derived vascular endothelial growth factor and BV8)in the bovine ovary:expression and role as mitogens and survival factors for corpus luteum-derived endothelial cells[J].Endocrinology,2005,146(9):3950-3958.
[22]Le Couter J,Kowalski J,Foster J,et al.Identification of an angiogenic mitogen selective for endocrine gland endothelium[J].Nature,2001,412(6850):877-884.
[23]Chen J,Kuei C,Sutton S,et al.Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[J].Mol Pharmacol,2005,67(6):2070-2076.
[24]Urayama K,Dedeoglu DB,Guilini C,et al.Transgenic myocardial overexpression of prokineticin receptor-2(GPR73b)induces hypertrophy and capillary vessel leakage[J].Cardiovasc Res,2009,81(1):28-37.
[25]Urayama K,Guilini C,Messaddeq N,et al.The prokineticin receptor-1(GPR73)promotes cardiomyocyte survival and angiogenesis[J].FASEB J,2007,21(11):2980-2993.
[26]Urayama K,Guilini C,Turkeri G,et al.Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation[J].Arterioscler Thromb Vasc Biol,2008,28(5):841-849.
[27]Evans J,Catalano RD,Morgan K,et al.Prokineticin 1 signaling and gene regulation in early human pregnancy[J].Endocrinology,2008,149(6):2877-2887.
[28]Qu X,Zhuang G,Yu L,et al.Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+cells:key role of Stat3 signaling[J].JBiol Chem,2012,287(23):19574-19584.
[29]Xin H,Lu R,Lee H,et al.G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells[J].J Biol Chem,2013,288(19):13842-13849.
[30]Urayama K,Guilini C,Messaddeq N,et al.The prokineticin receptor-1(GPR73)promotes cardiomyocyte survival and angiogenesis[J].FASEB J,2007,21(11):2980-2993.
[31]Urayama K,Guilini C,Turkeri G,et al.Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation[J].Arterioscler Thromb Vasc Biol,2008,28(5):841-849.
[32]Urayama K,Dedeoglu DB,Guilini C,et al.Transgenic myocardial overexpression of prokineticin receptor-2(GPR73b)induces hypertrophy and capillary vessel leakage[J].Cardiovasc Res,2009,81(1):28-37.
[33]Guilini C,Urayama K,Turkeri G,et al.Divergent roles of prokineticin receptors in the endothelial cells:angiogenesis and fenestration[J].Am Physiol Heart Circ Physiol,2010,298(3):H844-H852.
[34]Boulberdaa M,Turkeri G,Urayama K,et al.Genetic inactivation of prokineticin receptor-1 leads to heart and kidney disorders[J].Arterioscler Thromb Vasc Biol,2011,31(4):842-845.
[35]Boulberdaa M,Urayama K,Nebigil CG.Prokineticin receptor 1(PKR1)signalling in cardiovascular and kidney functions[J].Cardiovasc Res,2011,92(2):191-198.
[36]Wechselberger C,Puglisi R,Engel E,et al.The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes[J].FEBS Lett,1999,462(1-2):177-181.
[37]Ng KL,Li JD,Cheng MY,et al.Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling[J].Science,2005,308(5730):1923-1927.
[38]Collin O,Bergh A.Leydig cells secrete factors which increase vascular permeability and endothelial cell proliferation[J].Int J Androl,1996,19(4):221-228.
[39]Battersby S,Critchley HO,Morgan K,et al.Expression and regulation of the prokineticins(endocrine gland-derived vascular endothelial growth factor and Bv8)and their receptors in the human endometrium across the menstrual cycle[J].J Clin Endocrinol Metab,2004,89(5):2463-2469.
[40]Fraser HM,Bell J,Wilson H,et al.Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum[J].J Clin Endocrinol Metab,2005,90(1):427-434.
[41]Nozawa H,Chiu C,Hanahan D.Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis[J].Proc Natl Acad Sci U S A,2006,103(33):12493-12498[J].
[42]Fainaru O,Hantisteanu S,Hallak M.Immature myeloid cells accumulate in mouse placenta and promote angiogenesis[J].Am J Obstet Gynecol,2011,204(6):544.e18-544.e23.
[43]Kowanetz M,Wu X,Lee J,et al.Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+granulocytes[J].Proc Natl Acad Sci U S A,2010,107(50):21248-21255.
[44]Xin H,Lu R,Lee H,et al.G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells[J].J Biol Chem,2013,288(19):13842-13849.
[45]Shojaei F,Ferrara N.Refractoriness to antivascular endothelial growth factor treatment:role of myeloid cells[J].Cancer Res,2008,68(14):5501-5504.
[46]Jiang K,Kwak H,Tosato G.Granulocyte infiltration and expression of the pro-angiogenic BV8 protein in experimental EL4 and Lewis lung carcinoma tumors[J].Cureus,2013,5(1):82.
[47]Curtis VF,Wang H,Yang P,et al.A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer[J].PLo S One,2013,8(1):e54916.
[48]Shojaei F,Singh M,Thompson JD,et al.Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression[J].Proc Natl Acad Sci U S A,2008,105(7):2640-2645.
[49]Hasnis E,Alishekevitz D,Gingis-Veltski S,et al.Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy[J].Neoplasia,2014,16(6):501-510.
[2]Ferrara N,Alitalo K.Clinical applications of angiogenic growth factors and their inhibitors[J].Nat Med,1999,5(12):1359-1364.
[3]Mollay C,Wechselberger C,Mignogna G,et al.Bv8,a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats[J].Eur JPharmacol,1999,374(2):189-196.
[4]Le Couter J,Ferrara N.EG-VEGF and Bv8,a novel family of tissue-selective mediators of angiogenesis,endothelial phenotype,and function[J].Trends Cardiovasc Med,2003,13(7):276-282.
[5]Li M,Bullock CM,Knauer DJ,et al.Identification of two prokineticin c DNAs:recombinant proteins potently contract gastrointestinal smooth muscle[J].Mol Pharmacol,2001,59(4):692-698.
[6]Le Couter J,Lin R,Frantz G,et al.Mouse endocrine gland-derived vascular endothelial growth factor:a distinct expression pattern from its human ortholog suggests different roles as a regulator of organ-specific angiogenesis[J].Endocrinology,2003,144(6):2606-2616.
[7]Jilek A,Engel E,Beier D,et al.Murine Bv8 gene maps near a synteny breakpoint of mouse chromosome 6 and human 3p21[J].Gene,2000,256(1-2):189-195.
[8]Le Couter J,Lin R,Tejada M,et al.The endocrine-gland-derived VEGFhomologue Bv8 promotes angiogenesis in the testis:localization of Bv8 receptors to endothelial cells[J].Proc Natl Acad Sci U S A,2003,100(5):2685-2690.
[9]Kaser A,Winklmayr M,Lepperdinger G,et al.The AVIT protein family.secreted cysteine-rich vertebrate proteins with diverse functions[J].EMBO Rep,2003,4(5):469-473.
[10]Bullock CM,Li JD,Zhou QY.Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists[J].Mol Pharmacol,2004,65(3):582-588.
[11]Lin DC,Bullock CM,Ehlert FJ,et al.Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor[J].J Biol Chem,2002,277(22):19276-19280.
[12]Soga T,Si M,Oda T,et al.Molecular cloning and characterization of prokineticin receptors[J].Biochim Biophys Acta,2002,1579(2-3):173-179.
[13]Masuda Y,Takatsu Y,Terao Y,et al.Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors[J].Biochem Biophys Res Commun,2002,293(1):396-402.
[14]Le Couter J,Zlot C,Tejada M,et al.Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[J].Proc Natl Acad Sci U S A,2004,101(48):16813-16818.
[15]Cheng MY,Bullock CM,Li C,et al.Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[J].Nature,2002,417(6887):405-410.
[16]Zhong C,Qu XM,Meng Y,et al.Characterization and regulation of Bv8 in human blood cells[J].Clin Cancer Res,2009,15(8):2675-2684.
[17]Kowanetz M,Ferrara N.Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+granulocytes[J].Proc Natl Acad Sci U S A,2010,107(50):21248.
[18]Monnier J,Quillien V,Piquet-Pellorce C,et al.Prokineticin 1 induces CCL4,CXCL1 and CXCL8 in human monocytes but not in macrophages and dendritic cells[J].Eur Cytokine Netw,2008,19(4):166-175.
[19]Cheng MY,Lee AG,Culbertson C,et al.Prokineticin 2 is an endangering mediator of cerebral ischemic injury[J].Proc Natl Acad Sci U S A,2012,109(14):5475-5480.
[20]Hoffmann P,Feige JJ,Alfaidy N.Expression and oxygen regulation of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 and its receptors in human placenta during early pregnancy[J].Endocrinology,2006,147(4):1675-1684.
[21]Kisliouk T,Podlovni H,Spanel-Borowski K,et al.Prokineticins(endocrine gland-derived vascular endothelial growth factor and BV8)in the bovine ovary:expression and role as mitogens and survival factors for corpus luteum-derived endothelial cells[J].Endocrinology,2005,146(9):3950-3958.
[22]Le Couter J,Kowalski J,Foster J,et al.Identification of an angiogenic mitogen selective for endocrine gland endothelium[J].Nature,2001,412(6850):877-884.
[23]Chen J,Kuei C,Sutton S,et al.Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[J].Mol Pharmacol,2005,67(6):2070-2076.
[24]Urayama K,Dedeoglu DB,Guilini C,et al.Transgenic myocardial overexpression of prokineticin receptor-2(GPR73b)induces hypertrophy and capillary vessel leakage[J].Cardiovasc Res,2009,81(1):28-37.
[25]Urayama K,Guilini C,Messaddeq N,et al.The prokineticin receptor-1(GPR73)promotes cardiomyocyte survival and angiogenesis[J].FASEB J,2007,21(11):2980-2993.
[26]Urayama K,Guilini C,Turkeri G,et al.Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation[J].Arterioscler Thromb Vasc Biol,2008,28(5):841-849.
[27]Evans J,Catalano RD,Morgan K,et al.Prokineticin 1 signaling and gene regulation in early human pregnancy[J].Endocrinology,2008,149(6):2877-2887.
[28]Qu X,Zhuang G,Yu L,et al.Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+cells:key role of Stat3 signaling[J].JBiol Chem,2012,287(23):19574-19584.
[29]Xin H,Lu R,Lee H,et al.G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells[J].J Biol Chem,2013,288(19):13842-13849.
[30]Urayama K,Guilini C,Messaddeq N,et al.The prokineticin receptor-1(GPR73)promotes cardiomyocyte survival and angiogenesis[J].FASEB J,2007,21(11):2980-2993.
[31]Urayama K,Guilini C,Turkeri G,et al.Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation[J].Arterioscler Thromb Vasc Biol,2008,28(5):841-849.
[32]Urayama K,Dedeoglu DB,Guilini C,et al.Transgenic myocardial overexpression of prokineticin receptor-2(GPR73b)induces hypertrophy and capillary vessel leakage[J].Cardiovasc Res,2009,81(1):28-37.
[33]Guilini C,Urayama K,Turkeri G,et al.Divergent roles of prokineticin receptors in the endothelial cells:angiogenesis and fenestration[J].Am Physiol Heart Circ Physiol,2010,298(3):H844-H852.
[34]Boulberdaa M,Turkeri G,Urayama K,et al.Genetic inactivation of prokineticin receptor-1 leads to heart and kidney disorders[J].Arterioscler Thromb Vasc Biol,2011,31(4):842-845.
[35]Boulberdaa M,Urayama K,Nebigil CG.Prokineticin receptor 1(PKR1)signalling in cardiovascular and kidney functions[J].Cardiovasc Res,2011,92(2):191-198.
[36]Wechselberger C,Puglisi R,Engel E,et al.The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes[J].FEBS Lett,1999,462(1-2):177-181.
[37]Ng KL,Li JD,Cheng MY,et al.Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling[J].Science,2005,308(5730):1923-1927.
[38]Collin O,Bergh A.Leydig cells secrete factors which increase vascular permeability and endothelial cell proliferation[J].Int J Androl,1996,19(4):221-228.
[39]Battersby S,Critchley HO,Morgan K,et al.Expression and regulation of the prokineticins(endocrine gland-derived vascular endothelial growth factor and Bv8)and their receptors in the human endometrium across the menstrual cycle[J].J Clin Endocrinol Metab,2004,89(5):2463-2469.
[40]Fraser HM,Bell J,Wilson H,et al.Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum[J].J Clin Endocrinol Metab,2005,90(1):427-434.
[41]Nozawa H,Chiu C,Hanahan D.Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis[J].Proc Natl Acad Sci U S A,2006,103(33):12493-12498[J].
[42]Fainaru O,Hantisteanu S,Hallak M.Immature myeloid cells accumulate in mouse placenta and promote angiogenesis[J].Am J Obstet Gynecol,2011,204(6):544.e18-544.e23.
[43]Kowanetz M,Wu X,Lee J,et al.Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+granulocytes[J].Proc Natl Acad Sci U S A,2010,107(50):21248-21255.
[44]Xin H,Lu R,Lee H,et al.G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells[J].J Biol Chem,2013,288(19):13842-13849.
[45]Shojaei F,Ferrara N.Refractoriness to antivascular endothelial growth factor treatment:role of myeloid cells[J].Cancer Res,2008,68(14):5501-5504.
[46]Jiang K,Kwak H,Tosato G.Granulocyte infiltration and expression of the pro-angiogenic BV8 protein in experimental EL4 and Lewis lung carcinoma tumors[J].Cureus,2013,5(1):82.
[47]Curtis VF,Wang H,Yang P,et al.A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer[J].PLo S One,2013,8(1):e54916.
[48]Shojaei F,Singh M,Thompson JD,et al.Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression[J].Proc Natl Acad Sci U S A,2008,105(7):2640-2645.
[49]Hasnis E,Alishekevitz D,Gingis-Veltski S,et al.Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy[J].Neoplasia,2014,16(6):501-510.