Latent KSHV Infection of Endothelial Cells Induces Integrin Beta3 to Activate Angiogenic Phenotypes
Kaposi's Sarcoma (KS), the most common tumor of AIDS patients, is a highly vascularized tumor supporting large amounts of angiogenesis. The main cell type of KS tumors is the spindle cell, a cell of endothelial origin, the primary cell type involved in angiogenesis. Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of KS and is likely involved in both tumor formation and the induction of angiogenesis. Integrins, and specifically integrin αVβ3, have known roles in both tumor induction and angiogenesis. αVβ3 is also important for KSHV infection as it has been shown to be involved in KSHV entry into cells. We found that during latent infection of endothelial cells KSHV induces the expression of integrin β3 leading to increased surface levels of αVβ3. Signaling molecules downstream of integrins, including FAK and Src, are activated during viral latency. Integrin activation by KSHV is necessary for the KSHV-associated upregulation of a number of angiogenic phenotypes during latent infection including adhesion and motility. Additionally, KSHV-infected cells become more reliant on αVβ3 for capillary like formation in three dimensional culture. KSHV induction of integrin β3, leading to induction of angiogenic and cancer cell phenotypes during latency, is likely to be important for KS tumor formation and potentially provides a novel target for treating KS tumors.
Vyšlo v časopise:
Latent KSHV Infection of Endothelial Cells Induces Integrin Beta3 to Activate Angiogenic Phenotypes. PLoS Pathog 7(12): e32767. doi:10.1371/journal.ppat.1002424
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002424
Souhrn
Kaposi's Sarcoma (KS), the most common tumor of AIDS patients, is a highly vascularized tumor supporting large amounts of angiogenesis. The main cell type of KS tumors is the spindle cell, a cell of endothelial origin, the primary cell type involved in angiogenesis. Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of KS and is likely involved in both tumor formation and the induction of angiogenesis. Integrins, and specifically integrin αVβ3, have known roles in both tumor induction and angiogenesis. αVβ3 is also important for KSHV infection as it has been shown to be involved in KSHV entry into cells. We found that during latent infection of endothelial cells KSHV induces the expression of integrin β3 leading to increased surface levels of αVβ3. Signaling molecules downstream of integrins, including FAK and Src, are activated during viral latency. Integrin activation by KSHV is necessary for the KSHV-associated upregulation of a number of angiogenic phenotypes during latent infection including adhesion and motility. Additionally, KSHV-infected cells become more reliant on αVβ3 for capillary like formation in three dimensional culture. KSHV induction of integrin β3, leading to induction of angiogenic and cancer cell phenotypes during latency, is likely to be important for KS tumor formation and potentially provides a novel target for treating KS tumors.
Zdroje
1. WabingaHParkinDWabwire-MangenFMugerwaJ 1993 Cancer in Kampala, Uganda, in 1989-91: changes in incidence in the era of AIDS. Int J Cancer 54 26 36
2. ChokunongaELevyLBassettMMauchazaBThomasD 2000 Cancer incidence in the African population of Harare, Zimbabwe: second results from the cancer registry 1993-1995. Int J Cancer 85 54 59
3. StaskusKZhongWGebhardKHerndierBWangH 1997 Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71 715 719
4. LagunoffMBechtelJVenetsanakosERoyAAbbeyN 2002 De novo infection and serial transmission of Kaposi's sarcoma-associated herpesvirus in cultured endothelial cells. J Virol 76 2440 2448
5. BechtelJTLiangYHviddingJGanemD 2003 Host range of Kaposi's sarcoma-associated herpesvirus in cultured cells. J Virol 77 6474 6481
6. LagunoffMLukacDMGanemD 2001 Immunoreceptor tyrosine-based activation motif-dependent signaling by Kaposi's sarcoma-associated herpesvirus K1 protein: effects on lytic viral replication. J Virol 75 5891 5898
7. WangLDamaniaB 2008 Kaposi's sarcoma-associated herpesvirus confers a survival advantage to endothelial cells. Cancer Res 68 4640 4648
8. CoutyJLupu-MeiriMOronYGershengornM 2009 Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor-expressing endothelial cells exhibit reduced migration and stimulated chemotaxis by chemokine inverse agonists. J Pharmacol Exp Ther 329 1142 1147
9. QianLXieJYeFGaoS 2007 Kaposi's sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases. J Virol 81 7001 7010
10. SadagopanSSharma-WaliaNVeettilMBotteroVLevineR 2009 Kaposi's sarcoma-associated herpesvirus upregulates angiogenin during infection of human dermal microvascular endothelial cells, which induces 45S rRNA synthesis, antiapoptosis, cell proliferation, migration, and angiogenesis. J Virol 83 3342 3364
11. SadagopanSSharma-WaliaNVeettilMRaghuHSivakumarR 2007 Kaposi's sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression. J Virol 81 3949 3968
12. SivakumarRSharma-WaliaNRaghuHVeettilMSadagopanS 2008 Kaposi's sarcoma-associated herpesvirus induces sustained levels of vascular endothelial growth factors A and C early during in vitro infection of human microvascular dermal endothelial cells: biological implications. J Virol 82 1759 1776
13. MasoodRCesarmanESmithDLGillPSFloreO 2002 Human herpesvirus-8-transformed endothelial cells have functionally activated vascular endothelial growth factor/vascular endothelial growth factor receptor. Am J Pathol 160 23 29
14. CarrollPBrazeauELagunoffM 2004 Kaposi's sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology 328 7 18
15. CarrollPKenersonHYeungRLagunoffM 2006 Latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J Virol 80 10802 10812
16. WangHWTrotterMWLagosDBourbouliaDHendersonS 2004 Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36 687 693
17. HongYKForemanKShinJWHirakawaSCurryCL 2004 Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36 683 685
18. Sharma-WaliaNPaulAGBotteroVSadagopanSVeettilMV 2010 Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion. PLoS Pathog 6 e1000777
19. VartRNikitenkoLLagosDTrotterMCannonM 2007 Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res 67 4042 4051
20. YeFBlackbournDMengelMXieJQianL 2007 Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1. J Virol 81 3980 3991
21. MaTJhamBCHuJFriedmanERBasileJR 2010 Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma. Proc Natl Acad Sci U S A 107 14363 14368
22. MansouriMRosePMosesAFrühK 2008 Remodeling of endothelial adherens junctions by Kaposi's sarcoma-associated herpesvirus. J Virol 82 9615 9628
23. GuilluyCZhangZBhendePMSharekLWangL 2011 Latent KSHV infection increases the vascular permeability of human endothelial cells. Blood 118 5344 5354
24. QianLGreeneWYeFGaoS 2008 Kaposi's sarcoma-associated herpesvirus disrupts adherens junctions and increases endothelial permeability by inducing degradation of VE-cadherin. J Virol 82 11902 11912
25. DwyerJLe GuelteAGalan MoyaEMSumbalMCarlottiA 2011 Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor. Oncogene 30 190 200
26. QinZDaiLSlomianyMGTooleBPParsonsC 2010 Direct activation of emmprin and associated pathogenesis by an oncogenic herpesvirus. Cancer Res 70 3884 3889
27. DaiLBratoevaMTooleBPQinZParsonsC 2011 KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction. Int J Cancer. E-pub ahead of print doi:10.1002/ijc.26428
28. AokiYJaffeEChangYJonesKTeruya-FeldsteinJ 1999 Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93 4034 4043
29. BakkenTHeMCannonML 2010 The phosphatase Shp2 is required for signaling by the Kaposi's sarcoma-associated herpesvirus viral GPCR in primary endothelial cells. Virology 397 379 388
30. MasoodRXiaGSmithDLScaliaPStillJG 2005 Ephrin B2 expression in Kaposi sarcoma is induced by human herpesvirus type 8: phenotype switch from venous to arterial endothelium. Blood 105 1310 1318
31. XieJPanHYooSGaoS 2005 Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol 79 15027 15037
32. McAllisterSCHansenSGRuhlRARaggoCMDeFilippisVR 2004 Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood 103 3465 3473
33. FonsatoVButtiglieriSDeregibusMCBussolatiBCaselliE 2008 PAX2 expression by HHV-8-infected endothelial cells induced a proangiogenic and proinvasive phenotype. Blood 111 2806 2815
34. CaiQMurakamiMSiHRobertsonE 2007 A potential alpha-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1alpha in normoxia. J Virol 81 10413 10423
35. ShinYJooCGackMLeeHJungJ 2008 Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1 alpha to induce vascular endothelial growth factor expression. Cancer Res 68 1751 1759
36. WangLDittmerDTomlinsonCFakhariFDamaniaB 2006 Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus. Cancer Res 66 3658 3666
37. BoshoffCEndoYCollinsPTakeuchiYReevesJ 1997 Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278 290 294
38. StineJWoodCHillMEppARaportC 2000 KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood 95 1151 1157
39. ArvanitakisLGeras-RaakaEVarmaAGershengornMCesarmanE 1997 Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385 347 350
40. MontanerSSodhiAPeceSMesriEGutkindJ 2001 The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B. Cancer Res 61 2641 2648
41. SodhiAMontanerSPatelVZoharMBaisC 2000 The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res 60 4873 4880
42. BaisCSantomassoBCosoOArvanitakisLRaakaE 1998 G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391 86 89
43. BaisCVan GeelenAErolesPMutluAChiozziniC 2003 Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/KDR. Cancer Cell 3 131 143
44. ShanBMorrisCAZhuoYShelbyBDLevyDR 2007 Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J Mol Cell Cardiol 42 517 525
45. DourmishevLDourmishevAPalmeriDSchwartzRLukacD 2003 Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiol Mol Biol Rev 67 175 212 table of contents
46. MurakamiYYamagoeSNoguchiKTakebeYTakahashiN 2006 Ets-1-dependent expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus through interaction with Daxx. J Biol Chem 281 28113 28121
47. MitraSSchlaepferD 2006 Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18 516 523
48. AvraamidesCJGarmy-SusiniBVarnerJA 2008 Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8 604 617
49. HehlgansSHaaseMCordesN 2007 Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta 1775 163 180
50. GaspariniGBrooksPCBiganzoliEVermeulenPBBonoldiE 1998 Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. Clin Cancer Res 4 2625 2634
51. BelloLZhangJNikasDCStrasserJFVillaniRM 2000 Alpha(v)beta3 and alpha(v)beta5 integrin expression in meningiomas. Neurosurgery 47 1185 1195
52. BrooksPCClarkRAChereshDA 1994 Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264 569 571
53. BrooksPCMontgomeryAMRosenfeldMReisfeldRAHuT 1994 Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79 1157 1164
54. BrooksPCStrömbladSKlemkeRVisscherDSarkarFH 1995 Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96 1815 1822
55. SheuJRYenMHKanYCHungWCChangPT 1997 Inhibition of angiogenesis in vitro and in vivo: comparison of the relative activities of triflavin, an Arg-Gly-Asp-containing peptide and anti-alpha(v)beta3 integrin monoclonal antibody. Biochim Biophys Acta 1336 445 454
56. GarriguesHJRubinchikovaYEDipersioCMRoseTM 2008 Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of Kaposi's sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor. J Virol 82 1570 1580
57. DesgrosellierJSBarnesLAShieldsDJHuangMLauSK 2009 An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 15 1163 1169
58. DysonOFOxendineTLHamdenKEFordPWAkulaSM 2008 Differential regulation of the attachment of Kaposi's sarcoma-associated herpesvirus (KSHV)-infected human B cells to extracellular matrix by KSHV-encoded gB and cellular alphaV integrins. Cell Microbiol 10 1546 1558
59. DysonOBryanBLambertPFordPAkulaS 2007 Beta1 integrins mediate tubule formation induced by supernatants derived from KSHV-infected cells. Intervirology 50 245 253
60. DesgrosellierJSChereshDA 2010 Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10 9 22
61. MahabeleshwarGHFengWReddyKPlowEFByzovaTV 2007 Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis. Circ Res 101 570 580
62. ReynoldsLEWyderLLivelyJCTavernaDRobinsonSD 2002 Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8 27 34
63. ReynoldsARReynoldsLENagelTELivelyJCRobinsonSD 2004 Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res 64 8643 8650
64. MahabeleshwarGHFengWPhillipsDRByzovaTV 2006 Integrin signaling is critical for pathological angiogenesis. J Exp Med 203 2495 2507
65. DeSRazorenovaOMcCabeNPO'TooleTQinJ 2005 VEGF-integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci U S A 102 7589 7594
66. NemerowGChereshD 2002 Herpesvirus hijacks an integrin. Nat Cell Biol 4 E69 71
67. VeettilMSadagopanSSharma-WaliaNWangFRaghuH 2008 Kaposi's sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection. J Virol 82 12126 12144
68. KrishnanHSharma-WaliaNStreblowDNaranattPChandranB 2006 Focal adhesion kinase is critical for entry of Kaposi's sarcoma-associated herpesvirus into target cells. J Virol 80 1167 1180
69. Sharma-WaliaNNaranattPKrishnanHZengLChandranB 2004 Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein gB induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements. J Virol 78 4207 4223
70. WangFAkulaSSharma-WaliaNZengLChandranB 2003 Human herpesvirus 8 envelope glycoprotein B mediates cell adhesion via its RGD sequence. J Virol 77 3131 3147
71. VenetsanakosEMirzaAFantonCRomanovSRTlstyT 2002 Induction of tubulogenesis in telomerase-immortalized human microvascular endothelial cells by glioblastoma cells. Exp Cell Res 273 21 33
72. RenneRZhongWHerndierBMcGrathMAbbeyN 1996 Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 2 342 346
73. ChenLLagunoffM 2005 Establishment and maintenance of Kaposi's sarcoma-associated herpesvirus latency in B cells. J Virol 79 14383 14391
74. RothermelTEngelhardtBSheibaniN 2005 Polyoma virus middle-T-transformed PECAM-1 deficient mouse brain endothelial cells proliferate rapidly in culture and form hemangiomas in mice. J Cell Physiol 202 230 239
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