Roles of integrin in tumor development and the target inhibitors
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摘要
Integrin is a large family of cell adhesion molecules(CAMs) which involves in the interaction of cells/cells and cells/extracellular matrix(ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.
Integrin is a large family of cell adhesion molecules(CAMs) which involves in the interaction of cells/cells and cells/extracellular matrix(ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.
Integrin is a large family of cell adhesion molecules(CAMs) which involves in the interaction of cells/cells and cells/extracellular matrix(ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.
引文
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[5]Desgrosellier JS,Cheresh DA.Integrins in cancer:biological implications and therapeutic opportunities[J].Nat Rev Cancer,2010,10(1):9-22.
[6]Hamidi H,Pietila M,Ivaska J,et al.The complexity of integrins in cancer and new scopes for therapeutic targeting[J].Br J Cancer,2016,115(9):1017-1023.
[7]Xia H,Nho RS,Kahm J,et al.Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway[J].JBiol Chem,2004,279(31):33024-33034.
[8]Ahmed N,Riley C,Rice GE,et al.Alpha(v)beta(6)integrin-Amarker for the malignant potential of epithelial ovarian cancer[J].J Histochem Cytochem,2002,50(10):1371-1380.
[9]Kim EJ,Kwon KA,Lee YE,et al.Korean Red Ginseng extract reduces hypoxia-induced epithelial-mesenchymal transition by repressing NF-kappaB and ERK1/2 pathways in colon cancer[J].J Ginseng Res,2018,42(3):288-297.
[10]Hamidi H,Ivaska J.Every step of the way:integrins in cancer progression and metastasis[J].Nat Rev Cancer,2018,18(9):533-548.
[11]Del Rosso M,Fibbi G,Pucci M,et al.Multiple pathways of cell invasion are regulated by multiple families of serine proteases[J].Clin Exp Metastasis,2002,19(3):193-207.
[12]Chen JC,Yang ST,Lin CY,et al.BMP-7 enhances cell migration and alphavbeta3 integrin expression via a c-Src-dependent pathway in human chondrosarcoma cells[J].PLoS One,2014,9(11):e112636.
[13]Ahmed N,Pansino F,Clyde R,et al.Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade[J].Carcinogenesis,2002,23(2):237-244.
[14]Guo X,Zhao B.Integration of mechanical and chemical signals by YAP and TAZ transcription coactivators[J].Cell Biosci,2013,3(1):33.
[15]Stupack DG,Puente XS,Boutsaboualoy S,et al.Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins[J].J Cell Biol,2001,155(3):459-470.
[16]Lotti R,Marconi A,Truzzi F,et al.A previously unreported function of beta(1)B integrin isoform in caspase-8-dependent integrin-mediated keratinocyte death[J].J Invest Dermatol,2010,130(11):2569-2577.
[17]Ata R,Antonescu CN.Integrins and cell metabolism:an intimate relationship impacting cancer[J].Int J Mol Sci,2017,18(1).
[18]Longmate W,DiPersio CM.Beyond adhesion:emerging roles for integrins in control of the tumor microenvironment[J].F1000Res,2017,6:1612.
[19]Silva R,D'Amico G,Hodivala-Dilke KM,et al.Integrins:the keys to unlocking angiogenesis[J].Arterioscler Thromb Vasc Biol,2008,28(10):1703-1713.
[20]Shattil SJ,Ginsberg MH.Integrin signaling in vascular biology[J].J Clin Invest,1997,100(11 Suppl):S91-95.
[21]Mahabeleshwar GH,Chen J,Feng W,et al.Integrin affinity modulation in angiogenesis[J].Cell Cycle,2008,7(3):335-347.
[22]Larsen AB,Stockhausen MT,Poulsen HS,et al.Cell adhesion and EGFR activation regulate EphA2 expression in cancer[J].Cell Signal,2010,22(4):636-644.
[23]Juan-Rivera MC,Martinez-Ferrer M.Integrin inhibitors in prostate cancer[J].Cancers(Basel),2018,10(2):44.
[24]Stupp R,Hegi ME,Neyns B,et al.Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma[J].J Clin Oncol,2010,28(16):2712-2718.
[25]Manegold C,Vansteenkiste J,Cardenal F,et al.Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer[J].Invest New Drugs,2013,31(1):175-182.
[26]Scaringi C,Minniti G,Caporello P,et al.Integrin inhibitor cilengitide for the treatment of glioblastoma:a brief overview of current clinical results[J].Anticancer Res,2012,32(10):4213-4223.
[27]Friess H,Langrehr JM,Oettle H,et al.A randomized multicenter phase II trial of the angiogenesis inhibitor Cilengitide(EMD 121974)and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer[J].BMCCancer,2006,6:285.
[28]Nabors LB,Mikkelsen T,Hegi ME,et al.A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma(NABTT 0306)[J].Cancer,2012,118(22):5601-5607.
[29]Mason WP.End of the road:confounding results of the COREtrial terminate the arduous journey of cilengitide for glioblastoma[J].Neurol Oncol,2015,17(5):634-635.
[30]Avraamides CJ,Garmy-Susini B,Varner JA,et al.Integrins in angiogenesis and lymphangiogenesis[J].Nat Rev Cancer,2008,8(8):604-617.
[31]van der Horst G,van den Hoogen C,Buijs JT,et al.Targeting of alpha(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer[J].Neoplasia,2011,13(6):516-525.
[32]Zhao Y,Bachelier R,Treilleux I,et al.Tumor alphavbeta3integrin is a therapeutic target for breast cancer bone metastases[J].Cancer Res,2007,67(12):5821-5830.
[33]Cirkel GA,Kerklaan BM,Vanhoutte F,et al.A dose escalating phase I study of GLPG0187,a broad spectrum integrin receptor antagonist,in adult patients with progressive high-grade glioma and other advanced solid malignancies[J].Invest New Drugs,2016,34(2):184-192.
[34]Rosenthal MA,Davidson P,Rolland F,et al.Evaluation of the safety,pharmacokinetics and treatment effects of an alpha(nu)beta(3)integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastases[J].Asia Pac J Clin Oncol,2010,6(1):42-48.
[35]Hutchinson JH,Halczenko W,Brashear KM,et al.Nonpeptide alphavbeta3 antagonists.8.In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis[J].J Med Chem,2003,46(22):4790-4798.
[36]Zhou X,Zhang J,Haimbach R,et al.An integrin antagonist(MK-0429)decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model[J].Pharmacol Res Perspect,2017,5(5):e00354.
[37]Pickarski M,Gleason A,Bednar B,et al.Orally active alphavbeta3 integrin inhibitor MK-0429 reduces melanoma metastasis[J].Oncol Rep,2015,33(6):2737-2745.
[38]Tucker GC.Integrins:molecular targets in cancer therapy[J].Curr Oncol Rep,2006,8(2):96-103.
[39]Chen Q,Manning CD,Millar H,et al.CNTO 95,a fully human anti alphav integrin antibody,inhibits cell signaling,migration,invasion,and spontaneous metastasis of human breast cancer cells[J].Clin Exp Metastasis,2008,25(2):139-148.
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