肿瘤相关中性粒细胞蛋白酶在肿瘤增殖、侵袭及转移病机中的作用
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摘要
炎性微环境与肿瘤发生、发展关系十分密切。近年研究发现,肿瘤微环境中存在大量中性粒细胞浸润现象,即肿瘤相关中性粒细胞(TANs),深入研究证实TANs不仅参与肿瘤炎性微环境的形成和维持,而且广泛涉及肿瘤病理过程。TANs合成分泌大量蛋白酶,与肿瘤细胞增殖、侵袭、转移和新生血管形成密切相关;其中弹性蛋白酶主要参与肿瘤的增殖过程;组织蛋白酶与肿瘤的转移、侵袭和血管组织重塑密切相关基质金属蛋白酶调控肿瘤血管生成和转移。对TANs及其蛋白酶的深入研究可为肿瘤病理机制提供新的认识,而以蛋白酶为靶点来调控、抑制肿瘤细胞生长,可能成为干预肿瘤发生、发展的重要方法。
Inflammatory microenvironment is closely related to the occurrence and development of tumors.Recent studies have found that there is a phenomenon of neutrophil infiltration,i.e.tumor-associated neutrophils(TANs).Further studies have suggested that TANs is not only involved in the occurrence and sustainment of tumor inflammatory microenvironment,but is also extensively participating in tumor pathological process.Various kinds of proteases TANs synthesizes and secretes have been affirmed strongly related to tumor proliferation,invasion,metastasis and angiogenesis.Among different kinds of neutrophil-derived proteases,neutrophil elastase takes part in the process of proliferation; cathepsins are highly relevant to tumor invasion,metastasis and angiogenesis; matrix metalloproteinases regulate the metastasis and angiogenesis of tumor.Studies about the TANs and neutrophil-derived proteases have provided new insights into the pathological mechanisms of tumor.In addition,targeting the neutrophil-derived proteases to control and restrain the progress of tumor cells may play a key role in interfering with tumorigenesis and development.
Inflammatory microenvironment is closely related to the occurrence and development of tumors.Recent studies have found that there is a phenomenon of neutrophil infiltration,i.e.tumor-associated neutrophils(TANs).Further studies have suggested that TANs is not only involved in the occurrence and sustainment of tumor inflammatory microenvironment,but is also extensively participating in tumor pathological process.Various kinds of proteases TANs synthesizes and secretes have been affirmed strongly related to tumor proliferation,invasion,metastasis and angiogenesis.Among different kinds of neutrophil-derived proteases,neutrophil elastase takes part in the process of proliferation; cathepsins are highly relevant to tumor invasion,metastasis and angiogenesis; matrix metalloproteinases regulate the metastasis and angiogenesis of tumor.Studies about the TANs and neutrophil-derived proteases have provided new insights into the pathological mechanisms of tumor.In addition,targeting the neutrophil-derived proteases to control and restrain the progress of tumor cells may play a key role in interfering with tumorigenesis and development.
引文
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[31]Wilson TJ,Nannuru KC,Futakuchi M,et al.Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1[J].Cancer Lett,2010,288(2):162-169.
[32]Yui S,Osawa Y,Ichisugi T,et al.Neutrophil cathepsin G,but not elastase,induces aggregation of MCF-7 mammary carcinoma cells by a protease activity-dependent cell-oriented mechanism[J].Mediators Inflamm,2014,2014:971409.
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[34]Alatrash G,Garber HR,Zhang M,et al.Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target[J].Leukemia,2017,31(1):234-237.
[35]Grunwald B,Vandooren J,Locatelli E,et al.Matrix metalloproteinase-9(MMP-9)as an activator of nanosystems for targeted drug delivery in pancreatic cancer[J].J Control Release,2016,239:39-48.
[36]Gong L,Wu D,Zou J,et al.Prognostic impact of serum and tissue MMP-9 in non-small cell lung cancer:A systematic review and meta-analysis[J].Oncotarget,2016,7(14):18458-18468.
[37]Koo HK,Hong Y,Lim MN,et al.Relationship between plasma matrix metalloproteinase levels,pulmonary function,bronchodilator response,and emphysema severity[J].Int J Chron Obstruct Pulmon Dis,2016,11:1129-1137.
[38]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.
[39]Candido S,Abrams SL,Steelman LS,et al.Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy[J].Biochim Biophys Acta,2016,1863(3):438-448.
[40]Elewa MA,Al-Gayyar MM,Schaalan MF,et al.Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers[J].Clin Exp Metastasis,2015,32(5):479-493.
[41]Lee WT,Lee TH,Cheng CH,et al.Antroquinonol from Antrodia Camphorata suppresses breast tumor migration/invasion through inhibiting ERK-AP-1-and AKT-NF-kappa B-dependent MMP-9and epithelial-mesenchymal transition expressions[J].Food Chem Toxicol,2015,78:33-41.
[42]Shchors K,Nozawa H,Xu J,et al.Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis[J].Oncogene,2013,32(4):502-513.
[43]Choi SH,Lee HJ,Jin YB,et al.MMP9 processing of HSPB1 regulates tumor progression[J].PLo S One,2014,9(1):e85509.
[44]Arechavaleta-Velasco F,Cuevas-Antonio R,Dominguez-Lopez P,et al.Matrix metalloproteinase-8 promoter gene polymorphisms in Mexican women with ovarian cancer[J].Med Oncol,2014,31(8):132.
[2]Korniluk A,Koper O,Kemona H,et al.From inflammation to cancer[J].Ir J Med Sci,2017,186(1):57-62.
[3]Raposo TP,Beirao BC,Pang LY,et al.Inflammation and cancer:Till death tears them apart[J].Vet J,2015,205(2):161-174.
[4]Singel KL,Segal BH.Neutrophils in the tumor microenvironment:Trying to heal the wound that cannot heal[J].Immunol Rev,2016,273(1):329-343.
[5]Moses K,Brandau S.Human neutrophils:Their role in cancer and relation to myeloid-derived suppressor cells[J].Semin Immunol,2016,28(2):187-196.
[6]Bonavita O,Massara M,Bonecchi R.Chemokine regulation of neutrophil function in tumors[J].Cytokine Growth Factor Rev,2016,30:81-86.
[7]Kim J,Bae JS.Tumor-associated macrophages and neutrophils in tumor microenvironment[J].Mediators Inflamm,2016,2016:6058147.
[8]Powell DR,Huttenlocher A.Neutrophils in the tumor microenvironment[J].Trends Immunol,2016,37(1):41-52.
[9]Felix K,Gaida MM.Neutrophil-derived proteases in the microenvironment of pancreatic cancer—active players in tumor progression[J].Int J Biol Sci,2016,12(3):302-313.
[10]Zhou SL,Zhou ZJ,Hu ZQ,et al.Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib[J].Gastroenterology,2016,150(7):1646-1658.
[11]Rakaee M,Busund LT,Paulsen EE,et al.Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer[J].Oncotarget,2016.
[12]Zhang D,Zhou J,Tang D,et al.Neutrophil infiltration mediated by CXCL5 accumulation in the laryngeal squamous cell carcinoma microenvironment:A mechanism by which tumour cells escape immune surveillance[J].Clin Immunol,2017,175:34-40.
[13]Rhee I.Diverse macrophages polarization in tumor microenvironment[J].Arch Pharm Res,2016,39(11):1588-1596.
[14]Fridlender ZG,Sun J,Kim S,et al.Polarization of tumor-associated neutrophil phenotype by TGF-beta:"N1"versus"N2"TAN[J].Cancer Cell,2009,16(3):183-194.
[15]Mishalian I,Bayuh R,Levy L,et al.Tumor-associated neutrophils(TAN)develop pro-tumorigenic properties during tumor progression[J].Cancer Immunol Immunother,2013,62(11):1745-1756.
[16]Andzinski L,Wu CF,Lienenklaus S,et al.Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFNbeta[J].Int J Cancer,2015,136(3):572-583.
[17]Sevenich L,Joyce JA.Pericellular proteolysis in cancer[J].Genes Dev,2014,28(21):2331-2347.
[18]Pulz LH,Strefezzi RF.Proteases as prognostic markers in human and canine cancers[J].Vet Comp Oncol,2017,15(3):669-683.
[19]Mason SD,Joyce JA.Proteolytic networks in cancer[J].Trends Cell Biol,2011,21(4):228-237.
[20]Kristensen JH,Karsdal MA,Sand JM,et al.Serological assessment of neutrophil elastase activity on elastin during lung ECM remodeling[J].BMC Pulm Med,2015,15:53.
[21]Mayer C,Darb-Esfahani S,Meyer AS,et al.Neutrophil Granulocytes in Ovarian Cancer—Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration[J].J Cancer,2016,7(5):546-554.
[22]Caruso JA,Akli S,Pageon L,et al.The serine protease inhibitor elafin maintains normal growth control by opposing the mitogenic effects of neutrophil elastase[J].Oncogene,2015,34(27):3556-3567.
[23]Houghton AM,Rzymkiewicz DM,Ji H,et al.Neutrophil elastasemediated degradation of IRS-1 accelerates lung tumor growth[J].Nat Med,2010,16(2):219-223.
[24]Mittendorf EA,Alatrash G,Qiao N,et al.Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response[J].Cancer Res,2012,72(13):3153-3162.
[25]Bian B,Mongrain S,Cagnol S,et al.Cathepsin B promotes colorectal tumorigenesis,cell invasion,and metastasis[J].Mol Carcinog,2016,55(5):671-687.
[26]Akkari L,Gocheva V,Quick ML,et al.Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer[J].Genes Dev,2016,30(2):220-232.
[27]Tan G,Liu Q,Tang X,et al.Diagnostic values of serum cathepsin B and D in patients with nasopharyngeal carcinoma[J].BMC Cancer,2016,16:241.
[28]Sun T,Jiang D,Zhang L,et al.Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients[J].Oncol Lett,2016,11(1):575-583.
[29]Guszcz T,Swieczkowska M,Milewska E,et al.Cathepsin D and B activity in the serum of patients with urothelial bladder cancer[J].Pol Merkur Lekarski,2014,36(216):386-388.
[30]Gocheva V,Chen X,Peters C,et al.Deletion of cathepsin H perturbs angiogenic switching,vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer[J].Biol Chem,2010,391(8):937-945.
[31]Wilson TJ,Nannuru KC,Futakuchi M,et al.Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1[J].Cancer Lett,2010,288(2):162-169.
[32]Yui S,Osawa Y,Ichisugi T,et al.Neutrophil cathepsin G,but not elastase,induces aggregation of MCF-7 mammary carcinoma cells by a protease activity-dependent cell-oriented mechanism[J].Mediators Inflamm,2014,2014:971409.
[33]Morimoto-Kamata R,Mizoguchi S,Ichisugi T,et al.Cathepsin G induces cell aggregation of human breast cancer MCF-7 cells via a2-step mechanism:Catalytic site-independent binding to the cell surface and enzymatic activity-dependent induction of the cell aggregation[J].Mediators Inflamm,2012,2012:456462.
[34]Alatrash G,Garber HR,Zhang M,et al.Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target[J].Leukemia,2017,31(1):234-237.
[35]Grunwald B,Vandooren J,Locatelli E,et al.Matrix metalloproteinase-9(MMP-9)as an activator of nanosystems for targeted drug delivery in pancreatic cancer[J].J Control Release,2016,239:39-48.
[36]Gong L,Wu D,Zou J,et al.Prognostic impact of serum and tissue MMP-9 in non-small cell lung cancer:A systematic review and meta-analysis[J].Oncotarget,2016,7(14):18458-18468.
[37]Koo HK,Hong Y,Lim MN,et al.Relationship between plasma matrix metalloproteinase levels,pulmonary function,bronchodilator response,and emphysema severity[J].Int J Chron Obstruct Pulmon Dis,2016,11:1129-1137.
[38]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.
[39]Candido S,Abrams SL,Steelman LS,et al.Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy[J].Biochim Biophys Acta,2016,1863(3):438-448.
[40]Elewa MA,Al-Gayyar MM,Schaalan MF,et al.Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers[J].Clin Exp Metastasis,2015,32(5):479-493.
[41]Lee WT,Lee TH,Cheng CH,et al.Antroquinonol from Antrodia Camphorata suppresses breast tumor migration/invasion through inhibiting ERK-AP-1-and AKT-NF-kappa B-dependent MMP-9and epithelial-mesenchymal transition expressions[J].Food Chem Toxicol,2015,78:33-41.
[42]Shchors K,Nozawa H,Xu J,et al.Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis[J].Oncogene,2013,32(4):502-513.
[43]Choi SH,Lee HJ,Jin YB,et al.MMP9 processing of HSPB1 regulates tumor progression[J].PLo S One,2014,9(1):e85509.
[44]Arechavaleta-Velasco F,Cuevas-Antonio R,Dominguez-Lopez P,et al.Matrix metalloproteinase-8 promoter gene polymorphisms in Mexican women with ovarian cancer[J].Med Oncol,2014,31(8):132.