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Endothelium
Journal of Endothelial Cell Research
Volume 9, 2002 - Issue 3
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Research Article

Suppression of Tumor Angiogenesis Through the Inhibition of Integrin Function and Signaling in Endothelial Cells: Which Side to Target?

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Pages 151-160 | Published online: 13 Jul 2009

References

  • Akre K., Ekstrom A.M., Signorello L.B., Hansson L.E., and Nyren O. (2001) Aspirin and risk for gastric cancer: A population-based case-control study in Sweden. British Journal of Cancer, 84, 965–968.
  • Aoudjit F, and Vuori K. (2001) Matrix attachment regulates Fas-induced apoptosis in endothelial cells: A role for c-Flip and implications for anoikis. Journal of Cell Biology, 152, 633–643.
  • Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R., Li T, Witzenbichler B, Schatteman G, and Isner J.M.. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275, 964–967.
  • Attwell S, Roskelley C, and Dedhar S. (2000) The integrin-linked kinase (ILK) suppresses anoikis. Oncogene, 19, 3811–3815.
  • Bader B.L., Rayburn H, Crowley D, and Hynes R.O.. (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell, 95, 507–519.
  • Bello L, Francolini M, Marthyn P, Zhang J, Carroll R.S., Nikas D.C., Strasser J.F., Villani R, Cheresh D.A., and Black P.M.. (2001) Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery, 49, 380–389; discussion 390.
  • Boehm-Viswanathan T. (2000) Is angiogenesis inhibition the Holy Grail of cancer therapy? Current Opinion in Oncology, 12, 89–94.
  • Boger D.L., Goldberg J., Silletti S., Kessler T., and Cheresh D.A. (2001) Identi?cation of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin alpha(V)beta(3). Journal of the American Chemical Society, 123, 1280–1288.
  • Brooks P.C., Clark R.A., and Cheresh D.A. (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science, 264, 569–571.
  • Brooks P.C., Montgomery A.M., Rosenfeld M., Reisfeld R.A., Hu T., Klier G., and Cheresh D.A. (1994) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell, 79, 1157– 1164.
  • Brooks P.C., Stromblad S., Klemke R., Visscher D., Sarkar F.H., and Cheresh D.A. (1995) Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. Journal of Clinical Investigation, 96, 1815– 1822.
  • Brooks P.C., Stromblad S., Sanders L.C., von Schalscha T.L., Aimes R.T., Stetler-Stevenson W.G., Quigley J.P., and Cheresh D.A. (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell, 85, 683–693.
  • Burridge K., Chrzanowska-Wodnicka M., and Zhong C. (1997) Focal adhesion assembly. Trends in Cell Biology, 7, 342–347.
  • Byzova T.V., Goldman C.K., Pampori N., Thomas K.A., Bett A., Shattil S.J., and Plow E.F. (2000) A mechanism for modulation of cellular responses to VEGF: Activation of the integrins. Molecular Cell, 6, 851–860.
  • Cardone M.H., Salvesen G.S., Widmann C., Johnson G., and Frisch S.M. (1997) The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell, 90, 315–323.
  • Carmeliet P., and Jain R.K. (2000) Angiogenesis in cancer and other diseases. Nature, 407, 249–257.
  • Carswell E.A., Old L.J., Kassel R.L., Green S., Fiore N., and Williamson B. (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Science USA, 72, 3666–3670.
  • Cheresh D.A. (1987) Human endothelial cells synthesize and express an ArgGly-Asp-directed adhesion receptor involved in attachment to ?brinogen and von Willebrand factor. Proceedings of the National Academy of Science USA, 84, 6471–6475.
  • Cheresh D.A., and Stupack D.G. (2002) Integrin-mediated death: An explanation of the integrin-knockout phenotype? Nature Medicine, 8, 193–194.
  • Coleman R.A., Smith W.L., and Narumiya S. (1994) International Union of Pharmacology classi?cation of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes. Pharmacology Review, 46, 205–229.
  • Collo G., and Pepper M.S. (1999) Endothelial cell integrin alpha5beta1 expression is modulated by cytokines and during migration in vitro. Journal of Cellular Science, 112, 569–578.
  • Compagni A., and Christofori G. (2000) Recent advances in research on multistage tumorigenesis. British Journal of Cancer, 83, 1–5.
  • D’Angelo G., Lee H., and Weiner R.I. (1997) cAMP-Dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and ?broblast growth factor in capillary endothelial cells by blocking Raf activation. Journal of Cellular Biochemistry, 67, 353–366.
  • Datta S.R., Brunet A., and Greenberg M.E. (1999) Cellular survival: A play in three Akts. Genes and Development, 13, 2905–2927.
  • Day M.L., Foster R.G., Day K.C., Zhao X., Humphrey P., Swanson P., Postigo A.A., Zhang S.H., and Dean D.C. (1997) Cell anchorage regulates apoptosis through the retinoblastoma tumor suppressor/E2F pathway. Journal of Biological Chemistry, 272, 8125–8128.
  • Dechantsreiter M.A., Planker E., Matha B., Lohof E., Holzemann G., Jonczyk A., Goodman S.L., and Kessler H. (1999) <I>N</I>-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. Journal of Medicinal Chemistry, 42, 3033–3040.
  • Dignat-George F., Blann A., and Sampol J. (2000) Circulating endothelial cells in acute coronary syndromes. Blood, 95, 728.
  • Dormond O., Foletti A., Paroz C., and Ruegg C. (2001) NSAIDs inhibit alphaVbeta3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nature Medicine, 7, 1041–1047.
  • Dormond O., Lejeune F., and R¨uegg C. (2002) TNF and IFNgamma induced G1/S block in human endothelial cells is associated with expression of p16INK4a. Anticancer Research. In press.
  • Dormond O, and R¨uegg C. (2001) Inhibition of tumor angiogenesis by nonsteroidal anti-in?ammatory drugs: Emerging mechanisms and therapeutic perspectives. Drug Resistance Updates, 4, 314–321.
  • Eigenthaler M., Hofferer L., Shattil S.J., and Ginsberg M.H. (1997) A conserved sequence motif in the integrin beta3 cytoplasmic domain is required for its speci?c interaction with beta3-endonexin. Journal of Biological Chemistry, 272, 7693–7698.
  • Eliceiri B.P., and Cheresh D.A. (2000) Role of alpha V integrins during angiogenesis. Cancer Journal, 6, S245–S249.
  • Eliceiri B.P., Klemke R., Stromblad S., and Cheresh D.A. (1998) Integrin alphavbeta3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. Journal of Cell Biology, 140, 1255–1263.
  • Eliceiri B.P., Puente X.S., Hood J.D., Stupack D.G., Schlaepfer D.D., Huang X.Z., Sheppard D., and Cheresh D.A. (2002) Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling. Journal of Cell Biology, 157, 149–160.
  • Evers E.E., Zondag G.C., Malliri A., Price L.S., ten Klooster J.P., van der Kammen R.A., and Collard J.G. (2000) Rho family proteins in cell adhesion and cell migration. European Journal of Cancer, 36, 1269–1274.
  • Folkman J. (1971) Tumor angiogenesis: Therapeutical implications. New England Journal of Medicine, 285, 1182–1186.
  • Folkman J. (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine, 1, 27–31.
  • Folkman J., Watson K., Ingber D., and Hanahan D. (1989) Induction of angiogenesis during the transition for hyperplasia to neoplasia. Nature, 339, 58–61.
  • Friedlander M., Brooks P.C., Shaffer R.W., Kincaid C.M., Varner J.A., and Cheresh D.A. (1995) De?nition of two angiogenic pathways by distinct alpha v integrins. Science, 270, 1500–1502.
  • Frisch S.M., and Francis H. (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. Journal of Cell Biology, 124, 619–626.
  • Frisch S.M., and Ruoslahti E. (1997) Integrins and anoikis. Current Opinion in Cell Biology, 9, 701–706.
  • Frisch S.M., Vuori K., Kelaita D., and Sicks S. (1996) A role for Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA. Journal of Cell Biology, 135, 1377–1382.
  • Gabrilovich D.I., Ishida T., Nadaf S., Ohm J.E., and Carbone D.P. (1999) Antibodies to vascular endothelial growth factor enhance the ef?cacy of cancer immunotherapy by improving endogenous dendritic cell function. Clinical Cancer Research, 5, 2963–2970.
  • Galbraith S.M., Chaplin D.J., Lee F., Stratford M.R., Locke R.J., Vojnovic B., and Tozer G.M. (2001) Effects of combretastatin A4 phosphate on endothelial cell morphology in vitro and relationship to tumour vascular targeting activity in vivo. Anticancer Research, 21, 93–102.
  • Giancotti F.G., and Ruoslahti E. (1999) Transduction—Integrin signaling. Science, 285, 1028–1032.
  • Giardiello F.M., Hamilton S.R., Krush A.J., Piantadosi S., Hylind L.M., Celano P., Booker S.V., Robinson C.R., and Offerhaus G.J. (1993) Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. New England Journal of Medicine, 328, 1313–1316.
  • Gorski D.H., Mauceri H.J., Salloum R.M., Gately S., Hellman S., Beckett M.A., Sukhatme V.P., Soff G.A., Kufe D.W., and Weichselbaum R.R. (1998) Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Research, 58, 5686–5689.
  • Grif?oen A.W., and Molema G. (2000) Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic in?ammation. Pharmacological Reviews, 52, 237–268.
  • Gupta R.A., and DuBois R.N. (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Cancer Reviews, 1, 11–21.
  • Gutheil J.C., Campbell T.N., Pierce P.R., Watkins J.D., Huse W.D., Bodkin D.J., and Cheresh D.A. (2000) Targeted antiangiogenic therapy for cancer using Vitaxin: A humanized monoclonal antibody to the integrin alphavbeta3. Clinical Cancer Research, 6, 3056–3061.
  • Hammes H.P., Brownlee M., Jonczyk A., Sutter A., and Preissner K.T. (1996) Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nature Medicine, 2, 529–533.
  • Hanahan D, and Folkman J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86, 353–364.
  • Holash J., Maisonpierre P.C., Compton D., Boland P., Alexander C.R., Zagzag D., Yancopoulos G.D., and Wiegand S.J. (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science, 284, 1994–1998.
  • Holmgren L., O’Reilly M.S., and Folkman J. (1995) Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Medicine, 1, 149–153.
  • Huang X., Molema G., King S., Watkins L., Edgington T.S., and Thorpe P.E. (1997) Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science, 275, 547–550.
  • Hynes R.O. (1999) Cell adhesion: Old and new questions. Trends in Cell Biology, 9, M33–M37.
  • Ilic D., Furuta Y., Kanazawa S., Takeda N., Sobue K., Nakatsuji N., Nomura S., Fujimoto J., Okada M., and Yamamoto T. (1995) Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-de?cient mice. Nature, 377, 539–544.
  • Jones M.K., Wang H., Peskar B.M., Levin E., Itani R.M., Sarfeh I.J., and Tarnawski A.S. (1999) Inhibition of angiogenesis by nonsteroidal antiin?ammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing. Nature Medicine, 5, 1418–1423.
  • Kalka C., Masuda H., Takahashi T., Kalka-Moll W.M., Silver M., Kearney M., Li T., Isner J.M., and Asahara T. (2000) Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proceedings of the National Academy of Science USA, 97, 3422–3427.
  • Kerbel R.S. (2000) Tumor angiogenesis: Past, present and the near future. Carcinogenesis, 21, 505–515.
  • Kerbel R.S., Viloria-Petit A., Okada F, and Rak J. (1998) Establishing a link between oncogenes and tumor angiogenesis. Molecular Medicine, 4, 286–295.
  • Khwaja A., Rodriguez-Viciana P., Wennstrom S., Warne P.H., and Downward J. (1997) Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO Journal, 16, 2783–2793.
  • Kim S., Bell K., Mousa S.A., and Varner J.A. (2000) Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of ?bronectin. American Journal of Pathology, 156, 1345–1362.
  • Kim S., Harris M., and Varner J.A. (2000) Regulation of integrin alpha vbeta 3mediated endothelial cell migration and angiogenesis by integrin alpha5beta1 and protein kinase A. Journal of Biological Chemistry, 275, 33920–33928.
  • Klinghoffer R.A., Sachsenmaier C., Cooper J.A., and Soriano P. (1999) Src family kinases are required for integrin but not PDGFR signal transduction. EMBO Journal, 18, 2459–2471.
  • Kolanus W., and Seed B. (1997) Integrins and inside-out signal transduction: Converging signals from PKC and PIP3. Current Opinion in Cell Biology, 9, 725–731.
  • LaFlamme S.E., Thomas L.A., Yamada S.S., and Yamada K.M. (1994) Single subunit chimeric integrins as mimics and inhibitors of endogenous integrin functions in receptor localization, cell spreading and migration, and matrix assembly. Journal of Cell Biology, 126, 1287–1298.
  • Leavesley D.I., Schwartz M.A., Rosenfeld M., and Cheresh D.A. (1993) Integrin beta 1-and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms. Journal of Cell Biology, 121, 163–170.
  • Lee J.W., and Juliano R.L. (2000) Alpha5beta1 integrin protects intestinal epithelial cells from apoptosis through a phosphatidylinositol 3-kinase and protein kinase B-dependent pathway. Molecular Biology of the Cell, 11, 1973–1987.
  • Lejeune F., R¨uegg C., and Li´enard D. (1998) Clinicalapplications of TNF-alpha in cancer. Current Opinion in Immunology, 10, 573–580.
  • Lienard D., Ewalenko P., Delmotte J.J., Renard N., and Lejeune F.J. (1992) High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. Journal of Clinical Oncology, 10, 52–60.
  • Liu K.Y., Timmons S., Lin Y.Z., and Hawiger J. (1996) Identi?cation of a functionally important sequence in the cytoplasmic tail of integrin beta 3 by using cell-permeable peptide analogs. Proceedings of the National Academy of Science USA, 93, 11819–11824.
  • Lode H.N., Moehler T., Xiang R., Jonczyk A., Gillies S.D., Cheresh D.A., and Reisfeld R.A. (1999) Synergy between an antiangiogenic integrin alphav antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. Proceedings of the National Academy of Science USA, 96, 1591–1596.
  • Lopez-Marure R., Ventura J.L., Sanchez L., Montano L.F., and Zentella A. (2000) Ceramide mimics tumour necrosis factor-alpha in the induction of cell cycle arrest in endothelial cells. Induction of the tumour suppressor p53 with decrease in retinoblastoma/protein levels. European Journal of Biochemistry, 267, 4325–4333.
  • Lukashev M.E., Sheppard D., and Pytela R. (1994) Disruption of integrin function and induction of tyrosine phosphorylation by the autonomously expressed beta 1 integrin cytoplasmic domain. Journal of Biological Chemistry, 269, 18311–18314.
  • Lund E.L., Bastholm L., and Kristjansen P.E. (2000) Therapeutic synergy of TNP-470 and ionizing radiation: Effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. Clinical Cancer Research, 6, 971–978.
  • Lyden D., Hattori K., Dias S., Costa C., Blaikie P., Butros L., Chadburn A., Heissig B., Marks W., Witte L., Wu Y., Hicklin D., Zhu Z., Hackett N.R., Crystal R.G., Moore M.A., Hajjar K.A., Manova K., Benezra R., and Ra?i S. (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Medicine, 7, 1194–1201.
  • Lyden D., Young A.Z., Zagzag D., Yan W., Gerald W., O’Reilly R., Bader B.L., Hynes R.O., Zhuang Y., Manova K., and Benezra R. (1999) Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature, 401, 670–677.
  • MacDonald T.J., Taga T., Shimada H., Tabrizi P., Zlokovic B.V., Cheresh D.A., and Laug W.E. (2001) Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery, 48, 151–157.
  • Makimoto H., Koizumi K., Tsunoda S., Wakai Y., Matsui J., Tsutsumi Y., Nakagawa S., Ohizumi I., Taniguchi K., Saito H., Utoguchi N., Ohsugi Y., and Mayumi T. (1999) Tumor vascular targeting using a tumor-tissue endothelium-speci?c monoclonal antibody as an effective strategy for cancer chemotherapy. Biochemical Biophysical Research Communications, 260, 346–350.
  • Mancuso P., Burlini A., Pruneri G., Goldhirsch A., Martinelli G., and Bertolini F. (2001) Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood, 97, 3658–3661.
  • Max R., Gerritsen R.R., Nooijen P.T., Goodman S.L., Sutter A., Keilholz U., Ruiter D.J., and De Waal R.M. (1997) Immunohistochemical analysis of integrin alpha vbeta3 expression on tumor-associated vessels of human carcinomas. International Journal of Cancer, 71, 320–324.
  • Meredith J., Jr., Fazeli B., and Schwartz M.A. (1993) The extracellular matrix as a cell survival factor. Molecular Biology of the Cell, 4, 953–961.
  • Miranti C.K., and Brugge J.S. (2002) Sensing the environment: A historical perspective on integrin signal transduction. Nature Cell Biology, 4, 83–90.
  • Murohara T., Horowitz J.R., Silver M., Tsurumi Y., Chen D., Sullivan A., and Isner J.M. (1998) Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation, 97, 99–107.
  • Murohara T., Ikeda H., Duan J., Shintani S., Sasaki K., Eguchi H., Onitsuka I., Matsui K., and Imaizumi T. (2000) Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. Journal of Clinical Investigation, 105, 1527–1536.
  • Nilsson F., Kosmehl H., Zardi L., and Neri D. (2001) Targeted delivery of tissue factor to the ED-B domain of ?bronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Research, 61, 711–716.
  • Oguey D., George P.W., and R¨uegg C. (2000) Disruption of integrin-dependent adhesion and survival of endothelial cells by recombinant adenovirus expressing isolated beta integrin cytoplasmic domains. Gene Therapy, 7, 1292–1303.
  • O’Reilly M.S., Holmgren L., Chen C., and Folkman J. (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nature Medicine, 2, 689–692.
  • O’Reilly M.S., Holmgren L., Shing Y., Chen C., Rosenthal R.A., Moses M., Lane W.S., Cao Y., Sage E.H., and Folkman J. (1994) Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma [see comments]. Cell, 79, 315–328.
  • Pasqualini R., Koivunen E., and Ruoslahti E. (1997) Alpha v integrins as receptors for tumor targeting by circulating ligands. Nature Biotechnology, 15, 542–546.
  • Paul R., Zhang Z.G., Eliceiri B.P., Jiang Q., Boccia A.D., Zhang R.L., Chopp M., and Cheresh D.A. (2001) Src de?ciency or blockade of Src activity in mice provides cerebral protection following stroke. Nature Medicine, 7, 222–227.
  • Posey J.A., Khazaeli M.B., DelGrosso A., Saleh M.N., Lin C.Y., Huse W., and LoBuglio A.F. (2001) A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer. Cancer Biotherapy Radiopharmaceutics, 16, 125–132.
  • Re F., Zanetti A., Sironi M., Polentarutti N., Lanfrancone L., Dejana E., and Colotta F. (1994) Inhibition of anchorage-dependent cell spreading triggers apoptosis in cultured human endothelial cells. Journal of Cell Biology, 127, 537–546.
  • Reynolds L.E., Wyder L., Lively J.C., Taverna D., Robinson S.D., Huang X., Sheppard D., Hynes R.O., and Hodivala-Dilke K.M. (2002) Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nature Medicine, 8, 27–34.
  • Risau W. (1997) Mechanisms of angiogenesis. Nature, 386, 671–674.
  • R¨uegg C., Yilmaz A., Bieler G., Bamat J., Chaubert P., and Lejeune F.J. (1998) Evidence for the involvement of endothelial cell integrin alpha-v-beta-3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nature Medicine, 4, 408–414.
  • Scatena M., Almeida M., Chaisson M.L., Fausto N., Nicosia R.F., and Giachelli C.M. (1998) NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. Journal of Cell Biology, 141, 1083–1093.
  • Schiller J.H., and Bittner G. (1999) Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: Effects on tumor neovascularization. Clinical Cancer Research, 5, 4287– 4294.
  • Schnitzer J.E. (1998) Vascular targeting as a strategy for cancer therapy. New England Journal of Medicine, 339, 472–474.
  • Schwartz M.A., Schaller M.D., and Ginsberg M.H. (1995) Integrins: Emerging paradigms of signal transduction. Annual Review of Cell and Developmental Biology, 11, 549–599.
  • Shalinsky D.R., Brekken J., Zou H., Bloom L.A., McDermott C.D., Zook S., Varki N.M., and Appelt K. (1999) Marked antiangiogenic and antitumor ef?cacy of AG3340 in chemoresistant human non-small cell lung cancer tumors: Single agent and combination chemotherapy studies. Clinical Cancer Research, 5, 1905–1917.
  • Shi Q., Rafii S., Wu M.H., Wijelath E.S., Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage L.R., Moore M.A., Storb R.F., and Hammond W.P.. (1998) Evidence for circulating bone marrow-derived endothelial cells. Blood, 92, 362–367.
  • Shiff S.J., and Rigas B. (1999) The role of cyclooxygenase inhibition in the antineoplastic effects of nonsteroidal antiin?ammatory drugs (NSAIDs). Journal of Experimental Medicine, 190, 445–450.
  • Sieg D.J., Hauck C.R., and Schlaepfer D.D. (1999) Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. Journal of Cellular Science, 112, 2677–2691.
  • Sipkins D.A., Cheresh D.A., Kazemi M.R., Nevin L.M., Bednarski M.D., and Li K. (1998) Detection of tumor angiogenesis in vivo by alpha V beta 3-targeted magnetic resonance imaging. Nature Medicine, 4, 623–626.
  • Skobe M., Hawighorst T., Jackson D.G., Prevo R., Janes L., Velasco P., Riccardi L., Alitalo K., Claffey K., and Detmar M. (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Medicine, 7, 192–198.
  • Soldi R., Mitola S., Strasly M., Deflippi P., Tarone G, and Bussolino F. (1999) Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO Journal, 18, 882–892.
  • Solovey A., Lin Y., Browne P., Choong S., Wayner E., and Hebbel R.P. (1997) Circulating activated endothelial cells in sickle cell anemia. New England Journal of Medicine, 337, 1584–1590.
  • Stacker S.A., Caesar C., Baldwin M.E., Thornton G.E., Williams R.A., Prevo R., Jackson D.G., Nishikawa S., Kubo H., and Achen M.G. (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nature Medicine, 7, 186–191.
  • Stromblad S., Becker J.C., Yebra M., Brooks P.C., and Cheresh D.A. (1996) Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis. Journal of Clinical Investigation, 98, 426–433.
  • Stromblad S., Fotedar A., Brickner H., Theesfeld C., Aguilar de Diaz E., Friedlander M, and Cheresh D.A.. (2002) Loss of p53 compensates for alpha v-integrin function in retinal neovascularization. Journal of Biological Chemistry, 277, 13371–13374.
  • Stupack D.G., Puente X.S., Boutsaboualoy S., Storgard C.M., and Cheresh D.A. (2001) Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. Journal of Cell Biology, 155, 459–470.
  • Takahashi Y., Bucana C.D., Cleary K.R., and Ellis L.M. (1998) P53, vessel count, and vascular endothelial growth factor expression in human colon cancer. International Journal of Cancer, 79, 34–38.
  • Taverna D., and Hynes R.O. (2001) Reduced blood vessel formation and tumor growth in alpha5-integrin-negative teratocarcinomas and embryoid bodies. Cancer Research, 61, 5255–5261.
  • Thun M.J., Namboodiri M.M., and Heath C.W., Jr. (1991) Aspirin use and reduced risk of fatal colon cancer. New England Journal of Medicine, 325, 1593–1596.
  • Troussard A.A., Costello P., Yoganathan T.N., Kumagai S., Roskelley C.D., and Dedhar S. (2000) The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene, 19, 5444–5452.
  • Tsujii M., Kawano S., Tsuji S., Sawaoka H., Hori M., and DuBois R.N. (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell, 93, 705–716.
  • Vane J.R., Bakhle Y.S., and Botting R.M. (1998) Cyclooxygenases 1 and 2. Annual Review of Pharmacology and Toxicology, 38, 97–120.
  • Varner J.A., and Cheresh D.A. (1996) Tumor angiogenesis and the role of vascular cell integrin alphavbeta3. Important Advances in Oncology, 2, 69–87.
  • Vassalli G., Oguey D., Bamat J., Paroz C., and R¨uegg C. (2001) Induction of endothelial cells detachment and apoptosis by intravascular delivery of recombinant adenovirus expressing isolated b1 integrin cytoplasmic domain. Submitted.
  • Weidner N, Semple J.P., Welch W.R., and Folkman J. (1991) Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. New England Journal of Medicine, 324, 1–8.
  • Welsh C.F., and Assoian R.K. (2000) A growing role for Rho family GTPases as intermediaries in growth factor-and adhesion-dependent cell cycle progression. Biochimica Biophysica Acta, 1471, M21–M29.
  • Williams C.S., Mann M., and DuBois R.N. (1999) The role of cyclooxygenases in in?ammation, cancer, and development. Oncogene, 18, 7908–7916.
  • Williams C.S., Tsujii M., Reese J., Dey S.K., and DuBois R.N. (2000) Host cyclooxygenase-2 modulates carcinoma growth. Journal of Clinical Investigation, 105, 1589–1594.
  • Xia Z., Dickens M., Raingeaud J., Davis R., and Greenberg M. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science, 270, 1326– 1331.
  • Xiong J.P., Stehle T., Diefenbach B., Zhang R., Dunker R., Scott D.L., Joachimiak A., Goodman S.L., and Arnaout M.A. (2001) Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science, 294, 339–345.
  • Xiong J.P., Stehle T., Zhang R., Joachimiak A., Frech M., Goodman S.L., and Arnaout M.A. (2002) Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science, 296, 151–155.
  • Yancopoulos G.D., Davis S., Gale N.W., Rudge J.S., Wiegand S.J., and Holash J. (2000) Vascular-speci?c growth factors and blood vessel formation. Nature, 407, 242–248.
  • Yilmaz A., Bieler G., Spertini O., Lejeune F.J., and R¨uegg C. (1998) Pulse treatment of human vascular endothelial cells with high doses of tumor necrosis factor and interferon-gamma results in simultaneous synergistic and reversible effects on proliferation and morphology. International Journal of Cancer, 77, 592–599.
  • Yoganathan T.N., Costello P., Chen X., Jabali M., Yan J., Leung D., Zhang Z., Yee A., Dedhar S., and Sanghera J. (2000) Integrin-linked kinase (ILK): A “hot” therapeutic target. Biochemical Pharmacology, 60, 1115–1119.
  • Yokoyama Y., Dhanabal M., Griffoen A.W., Sukhatme V.P., and Ramakrishnan S. (2000) Synergy between angiostatin and endostatin: Inhibition of ovarian cancer growth. Cancer Research, 60, 2190–2196.
  • Zetter B.R.. (1998) Angiogenesis and tumor metastasis. Annual Review of Medicine, 49, 407–424.
  • Zhang Z., Vuori K., Reed J.C., and Ruoslahti E. (1995) The alpha 5 beta 1 integrin supports survival of cells on ?bronectin and up-regulates Bcl-2 expression. Proceedings of the National Academy of Science USA, 92, 6161–6165.

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