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Hamostaseologie 2012; 32(02): 105-114
DOI: 10.5482/ha-1163
Review
Schattauer GmbH

Angiogenesis in cancer[*]

Basic mechanisms and therapeutic advancesTumorangiogenese[*] Grundlagen und Therapieansätze
G. W. Prager
1   Comprehensive Cancer Center Vienna, Department of Medicine I, Medical University of Vienna, Austria
,
M. Poettler
1   Comprehensive Cancer Center Vienna, Department of Medicine I, Medical University of Vienna, Austria
› Author AffiliationsThis work was supported the Austrian Science Foundation project (FWF P21301) and the Initiative Krebsforschung project (UE71104018).
Further Information

Publication History

received: 07 June 2011

accepted in revised form: 18 July 2011

Publication Date:
28 December 2017 (online)

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Summary

Etiological concepts on cancer development, malignant growth and tumour propagation have undergone a revolutionary development during recent years: Among other aspects, the discovery of angiogenesis – the growth of new blood vessels from pre-existing vasculature – as a key element in the pathogenesis of malignancy has opened an abundance of biologic insights and subsequent therapeutic options, which have led to improved prognosis in many cancers including those originating from colon, lung, breast and kidney. Thereby, targeting the major pro-angiogenic stimulus vascular endothelial growth factor (VEGF) became the focus for therapeutic interventions. However, the use of VEGF-targeting drugs has been shown to be of limited efficacy, which might lie in the fact that tumor angiogenesis is mediated by a variety of different subcellular systems.

This review focuses on the basic mechanisms involved in angiogenesis, which potentially represent novel targets for pharmacological agents in the treatment of malignancies.

Zusammenfassung

Die fortlaufende Bestrebung der Krebsforschung nähere Einsichten in die Pathogenese maligner Erkrankungen zu gewinnen, hat unter anderem zur Entdeckung der Rolle der Angiogenese, dem Aussprossen neuer Blutgefäße aus dem bereits bestehenden Gefäßsystem, als tragenden Pfeiler in der Krebsentstehung, -wachstum, und -metastasierung geführt. Diese Erkenntnis konnte für neue Therapieansätze genutzt werden, die besonders bei Patienten mit Kolorektal-, Lungen-, Brustoder Nierenzellkarzinomen zu einer Verbesserungen der Prognose geführt hat. Dabei rückte insbesondere VEGF (vascular endothelial growth factor) als wichtigster Wachstumsfaktor in der Angiogenese ins Zentrum des therapeutischen Interesses. Trotzdem entsprachen die klinische Ergebnisse, die sich durch Hemmung des VEGF erzielen ließen, nicht immer den hohen Erwartungen, was sich durchaus durch die Tatsache erklären lässt, dass viele andere Systeme ebenfalls an der Regulation der Tumorangiogenese beteiligt sind.

Dieser Review soll daher einen Überblick über Grundlagen und mögliche neue Angriffspunkte der Tumorangiogenese geben.

Keywords

Angiogenesis - cancer - endothelial cells

Schlüsselwörter

Angiogenese - Tumorerkrankung - Endothelzellen

* This article is dedicated to the memory of Dr. Bernd R. Binder (1945–2010), an unique and caring teacher, physician, scientist and friend (see Hämostaseologie 2011; 31: 55).


* Dieser Artikel ist dem Gedenken an Prof. Dr. Bernd R. Binder (1945–2010), einem einzigartigen Lehrer, Arzt, Wissenschafter und Freund, ge - widmet (vgl. Hämostaseologie 2011; 31: 55).


 

  • References

  • 1 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-257.
    CrossrefPubMedGoogle Scholar
  • 2 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353-364.
    CrossrefPubMedGoogle Scholar
  • 3 Dang DT, Chun SY, Burkitt K. et al. Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res 2008; 68: 1872-1880.
    CrossrefPubMedGoogle Scholar
  • 4 Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 02: 38-47.
    CrossrefPubMedGoogle Scholar
  • 5 Pepper MS, Ferrara N, Orci L, Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 1992; 189: 824-831.
    CrossrefPubMedGoogle Scholar
  • 6 Kendall RL, Wang G, DiSalvo J, Thomas KA. Specificity of vascular endothelial cell growth factor receptor ligand binding domains. Biochem Biophys Res Commun 1994; 201: 326-330.
    CrossrefPubMedGoogle Scholar
  • 7 Prager GW, Lackner EM, Krauth MT. et al. Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab. Mol Oncol 2010; 04: 150-160.
    CrossrefPubMedGoogle Scholar
  • 8 Hurwitz H, Fehrenbacher L, Novotny W. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335-2342.
    CrossrefPubMedGoogle Scholar
  • 9 Miller K, Wang M, Gralow J. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666-2676.
    CrossrefPubMedGoogle Scholar
  • 10 Abou-Alfa GK, Schwartz L, Ricci S. et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293-4300.
    CrossrefPubMedGoogle Scholar
  • 11 Rini BI, Wilding G, Hudes G. et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 4462-4468.
    CrossrefPubMedGoogle Scholar
  • 12 Cassidy J, Clarke S, Diaz-Rubio E. et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008; 26: 2006-2012.
    CrossrefPubMedGoogle Scholar
  • 13 Saltz LB, Clarke S, Diaz-Rubio E. et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26: 2013-2019.
    CrossrefPubMedGoogle Scholar
  • 14 Fischer C, Mazzone M, Jonckx B, Carmeliet P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?. Nat Rev Cancer 2008; 08: 942-956.
    CrossrefPubMedGoogle Scholar
  • 15 Ebos JM, Lee CR, Cruz-Munoz W. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009; 15: 232-239.
    CrossrefPubMedGoogle Scholar
  • 16 Paez-Ribes M, Allen E, Hudock J. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15: 220-231.
    CrossrefPubMedGoogle Scholar
  • 17 Grothey A, Sugrue MM, Purdie DM. et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 2008; 26: 5326-5334.
    CrossrefPubMedGoogle Scholar
  • 18 Marshall JL. Vascular endothelial growth factor plus epidermal growth factor receptor dual targeted therapy in metastatic colorectal cancer: Synergy or antagonism?. J Oncol 2009; 2009: 937305.
    PubMedGoogle Scholar
  • 19 Garmy-Susini B, Varner JA. Roles of integrins in tumor angiogenesis and lymphangiogenesis. Lymphat Res Biol 2008; 06: 155-163.
    CrossrefPubMedGoogle Scholar
  • 20 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11-25.
    CrossrefPubMedGoogle Scholar
  • 21 Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007; 08: 464-478.
    CrossrefPubMedGoogle Scholar
  • 22 Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110: 673-687.
    CrossrefPubMedGoogle Scholar
  • 23 Takagi J, Petre B, Walz T, Springer T. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110: 599.
    CrossrefPubMedGoogle Scholar
  • 24 Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 2010; 11: 288-300.
    CrossrefPubMedGoogle Scholar
  • 25 Arias-Salgado EG, Lizano S, Sarkar S. et al. Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proc Natl Acad Sci USA 2003; 100: 13298-13302.
    CrossrefPubMedGoogle Scholar
  • 26 Arregui CO, Balsamo J, Lilien J. Impaired integrin-mediated adhesion and signaling in fibroblasts expressing a dominant-negative mutant PTP1B. J Cell Biol 1998; 143: 861-873.
    CrossrefPubMedGoogle Scholar
  • 27 Hangan-Steinman D, Ho WC, Shenoy P. et al. Differences in phosphatase modulation of alpha4beta1 and alpha5beta1 integrin-mediated adhesion and migration of B16F1 cells. Biochem Cell Biol 1999; 77: 409-420.
    CrossrefPubMedGoogle Scholar
  • 28 Goel HL, Fornaro M, Moro L. et al. Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins. J Cell Biol 2004; 166: 407-418.
    CrossrefPubMedGoogle Scholar
  • 29 ffrench-Constant C, Colognato H. Integrins: versatile integrators of extracellular signals. Trends Cell Biol 2004; 14: 678-686.
    CrossrefPubMedGoogle Scholar
  • 30 Walker JL, Fournier AK, Assoian RK. Regulation of growth factor signaling and cell cycle progression by cell adhesion and adhesion-dependent changes in cellular tension. Cytokine Growth Factor Rev 2005; 16: 395-405.
    CrossrefPubMedGoogle Scholar
  • 31 Feral CC, Nishiya N, Fenczik CA. et al. CD98hc (SLC3A2) mediates integrin signaling. Proc Natl Acad Sci USA 2005; 102: 355-360.
    CrossrefPubMedGoogle Scholar
  • 32 Prager GW, Feral CC, Kim C. et al. CD98hc (SLC3A2) Interaction with the Integrin beta Subunit Cytoplasmic Domain Mediates Adhesive Signaling. J Biol Chem 2007; 282: 24477-24484.
    CrossrefPubMedGoogle Scholar
  • 33 Feral CC, Zijlstra A, Tkachenko E. et al. CD98hc (SLC3A2) participates in fibronectin matrix assembly by mediating integrin signaling. J Cell Biol 2007; 178: 701-711.
    CrossrefPubMedGoogle Scholar
  • 34 Fenczik CA, Sethi T, Ramos JW. et al. Complementation of dominant suppression implicates CD98 in integrin activation. Nature 1997; 390: 81-85.
    CrossrefPubMedGoogle Scholar
  • 35 Rintoul RC, Buttery RC, Mackinnon AC. et al. Cross-linking CD98 promotes integrin-like signaling and anchorage-independent growth. Mol Biol Cell 2002; 13: 2841-2852.
    CrossrefPubMedGoogle Scholar
  • 36 Zent R, Fenczik CA, Calderwood DA. et al. Classand splice variant-specific association of CD98 with integrin beta cytoplasmic domains. J Biol Chem 2000; 275: 5059-5064.
    CrossrefPubMedGoogle Scholar
  • 37 Garmy-Susini B, Jin H, Zhu Y. et al. Integrin alpha4beta1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Invest 2005; 115: 1542-1551.
    CrossrefPubMedGoogle Scholar
  • 38 Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 2008; 358: 647-648.
    PubMedGoogle Scholar
  • 39 George EL, Georges-Labouesse EN, Patel-King RS. et al. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 1993; 119: 1079-1091.
    PubMedGoogle Scholar
  • 40 Fassler R, Pfaff M, Murphy J. et al. Lack of beta 1 integrin gene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts. J Cell Biol 1995; 128: 979-988.
    CrossrefPubMedGoogle Scholar
  • 41 Goh KL, Yang JT, Hynes RO. Mesodermal defects and cranial neural crest apoptosis in alpha5 integrin-null embryos. Development 1997; 124: 4309-4319.
    PubMedGoogle Scholar
  • 42 Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 2000; 156: 1345-1362.
    CrossrefPubMedGoogle Scholar
  • 43 Bell-McGuinn KM, Matthews CM, Ho SN. et al. A phase II, single-arm study of the anti-alpha5beta1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol Oncol 2011; 121: 273-279.
    CrossrefPubMedGoogle Scholar
  • 44 Senger DR, Claffey KP, Benes JE. et al. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci USA 1997; 94: 13612-13617.
    CrossrefPubMedGoogle Scholar
  • 45 Sweeney SM, DiLullo G, Slater SJ. et al. Angiogenesis in collagen I requires alpha2beta1 ligation of a GFP*GER sequence and possibly p38 MAPK activation and focal adhesion disassembly. J Biol Chem 2003; 278: 30516-30524.
    CrossrefPubMedGoogle Scholar
  • 46 Senger DR, Perruzzi CA, Streit M. et al. The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol 2002; 160: 195-204.
    CrossrefPubMedGoogle Scholar
  • 47 Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994; 264: 569-571.
    CrossrefPubMedGoogle Scholar
  • 48 Friedlander M, Brooks PC, Shaffer RW. et al. Definition of two angiogenic pathways by distinct alpha v integrins. Science 1995; 270: 1500-1502.
    CrossrefPubMedGoogle Scholar
  • 49 Drake CJ, Cheresh DA, Little CD. An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci 1995; 108: 2655-2661.
    PubMedGoogle Scholar
  • 50 Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics 2011; 01: 154-188.
    CrossrefPubMedGoogle Scholar
  • 51 Nabors LB, Mikkelsen T, Rosenfeld SS. et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 2007; 25: 1651-1657.
    CrossrefPubMedGoogle Scholar
  • 52 Weller M. Novel diagnostic and therapeutic approaches to malignant glioma. Swiss Med Wkly 2011; 141: w13210.
    PubMedGoogle Scholar
  • 53 Vermorken JB, Guigay J, Mesia R. et al. Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part. Br J Cancer 2011; 104: 1691-1696.
    CrossrefPubMedGoogle Scholar
  • 54 Cheng C, Komljenovic D, Pan L. et al. Evaluation of treatment response of cilengitide in an experimental model of breast cancer bone metastasis using dynamic PET with 18F-FDG. Hell J Nucl Med 2011; 14: 15-20.
    PubMedGoogle Scholar
  • 55 Reardon DA, Neyns B, Weller M. et al. Cilengitide: an RGD pentapeptide alphanubeta3 and alphanubeta5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol 2011; 07: 339-354.
    CrossrefPubMedGoogle Scholar
  • 56 Oliveira-Ferrer L, Hauschild J, Fiedler W. et al. Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway. J Exp Clin Cancer Res 2008; 27: 86.
    CrossrefPubMedGoogle Scholar
  • 57 Nisato RE, Tille JC, Jonczyk A. et al. Alphav beta 3 and alphav beta 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 2003; 06: 105-119.
    CrossrefPubMedGoogle Scholar
  • 58 Zhang D, Pier T, McNeel DG. et al. Effects of a monoclonal anti-alphavbeta3 integrin antibody on blood vessels – a pharmacodynamic study. Invest New Drugs 2007; 25: 49-55.
    PubMedGoogle Scholar
  • 59 Cai W, Wu Y, Chen K. et al. In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3. Cancer Res 2006; 66: 9673-9681.
    CrossrefPubMedGoogle Scholar
  • 60 Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010; 10: 9-22.
    CrossrefPubMedGoogle Scholar
  • 61 Kuwada SK. Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 2007; 09: 92-98.
    PubMedGoogle Scholar
  • 62 Ricart AD, Tolcher AW, Liu G. et al. Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study. Clin Cancer Res 2008; 14: 7924-7929.
    CrossrefPubMedGoogle Scholar
  • 63 Trikha M, Zhou Z, Nemeth JA. et al. CNTO 95, a fully human monoclonal antibody that inhibits alphav integrins, has antitumor and antiangiogenic activity in vivo. Int J Cancer 2004; 110: 326-335.
    CrossrefPubMedGoogle Scholar
  • 64 O’Day SJ, Pavlick AC, Albertini MR. et al. Clinical and pharmacologic evaluation of two dose levels of intetumumab (CNTO 95) in patients with melanoma or angiosarcoma. Invest New Drugs. 2011 doi10.1007/s10637–011–9639-z.
    PubMedGoogle Scholar
  • 65 Mullamitha SA, Ton NC, Parker GJ. et al. Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res 2007; 13: 2128-2135.
    CrossrefPubMedGoogle Scholar
  • 66 Brooks PC, Silletti S, von Schalscha TL. et al. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998; 92: 391-400.
    CrossrefPubMedGoogle Scholar
  • 67 Crocker M, Ashley S, Giddings I. et al. Serum angiogenic profile of patients with glioblastoma identifies distinct tumor subtypes and shows that TIMP-1 is a prognostic factor. Neuro Oncol 2011; 13: 99-108.
    CrossrefPubMedGoogle Scholar
  • 68 Holten-Andersen MN, Stephens RW, Nielsen HJ. et al. High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer. Clin Cancer Res 2000; 06: 4292-4299.
    PubMedGoogle Scholar
  • 69 Gouyer V, Conti M, Devos P. et al. Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer 2005; 103: 1676-1684.
    CrossrefPubMedGoogle Scholar
  • 70 Chun TH, Sabeh F, Ota I. et al. MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix. J Cell Biol 2004; 167: 757-767.
    CrossrefPubMedGoogle Scholar
  • 71 Blasi F, Carmeliet P. UPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 03: 932-943.
    CrossrefPubMedGoogle Scholar
  • 72 Montuori N, Carriero MV, Salzano S. et al. The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 2002; 277: 46932-46939.
    CrossrefPubMedGoogle Scholar
  • 73 Resnati M, Pallavicini I, Wang JM. et al. The fibrinolytic receptor for urokinase activates the G proteincoupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 2002; 99: 1359-1364.
    CrossrefPubMedGoogle Scholar
  • 74 Nykjaer A, Petersen CM, Moller B. et al. Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem 1992; 267: 14543-14546.
    PubMedGoogle Scholar
  • 75 Nykjaer A, Conese M, Christensen EI. et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 1997; 16: 2610-2620.
    CrossrefPubMedGoogle Scholar
  • 76 Leksa V, Loewe R, Binder B. et al. Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation. Circ Res 2011; 108: 676-685.
    CrossrefPubMedGoogle Scholar
  • 77 Schiller HB, Szekeres A, Binder BR. et al. Mannose 6-phosphate/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. Mol Biol Cell 2009; 20: 745-756.
    CrossrefPubMedGoogle Scholar
  • 78 Brunner PM, Heier PC, Mihaly-Bison J. et al. Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells. Blood 2011; 117: 4154-4161.
    CrossrefPubMedGoogle Scholar
  • 79 Prager GW, Breuss JM, Steurer S. et al. Vascular endothelial growth factor (VEGF) induces rapid prourokinase (pro-uPA) activation on the surface of endothelial cells. Blood 2004; 103: 955-962.
    PubMedGoogle Scholar
  • 80 Prager GW, Breuss JM, Steurer S. et al. Vascular endothelial growth factor receptor-2-induced initial endothelial cell migration depends on the presence of the urokinase receptor. Circ Res 2004; 94: 1562-1570.
    CrossrefPubMedGoogle Scholar
  • 81 Bajou K, Noel A, Gerard RD. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 04: 923-928.
    CrossrefPubMedGoogle Scholar
  • 82 Gerber HP, McMurtrey A, Kowalski J. et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998; 273: 30336-30343.
    PubMedGoogle Scholar
  • 83 Fujio Y, Walsh K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 1999; 274: 16349-16354.
    CrossrefPubMedGoogle Scholar
  • 84 Prager GW, Mihaly J, Brunner PM. et al. Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein. Blood 2009; 113: 1383-1390.
    CrossrefPubMedGoogle Scholar
  • 85 Kim J, Park J, Choi S. et al. X-linked inhibitor of apoptosis protein is an important regulator of vascular endothelial growth factor-dependent bovine aortic endothelial cell survival. Circ Res 2008; 102: 896-904.
    CrossrefPubMedGoogle Scholar
  • 86 Guerrero J, Santibanez JF, Gonzalez A, Martinez J. EGF receptor transactivation by urokinase receptor stimulus through a mechanism involving Src and matrix metalloproteinases. Exp Cell Res 2004; 292: 201-208.
    CrossrefPubMedGoogle Scholar
  • 87 Sidenius N, Andolfo A, Fesce R, Blasi F. Urokinase regulates vitronectin binding by controlling urokinase receptor oligomerization. J Biol Chem 2002; 277: 27982-27990.
    CrossrefPubMedGoogle Scholar
  • 88 Chaurasia P, Aquirre-Ghiso JA, Liang OD. et al. A region in urokinase plasminogen receptor domain III controlling a functional association with alpha5beta1 integrin and tumor growth. J Biol Chem 2006; 281: 14852-14863.
    CrossrefPubMedGoogle Scholar
  • 89 Carriero MV, Del VS, Capozzoli M. et al. Urokinase receptor interacts with alpha(v)beta5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer. Cancer Res 1999; 59: 5307-5314.
    PubMedGoogle Scholar
  • 90 Wei Y, Czekay RP, Robillard L. et al. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. J Cell Biol 2005; 168: 501-511.
    CrossrefPubMedGoogle Scholar
  • 91 Czekay RP, Aertgeerts K, Curriden SA, Loskutoff DJ. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 2003; 160: 781-791.
    CrossrefPubMedGoogle Scholar
  • 92 Novotny r, Unseld M, Poettler M. et al. Urokinase receptor (uPAR)-dependent integrin redistribution represents a central mechanism for growth factor induced endothelial cell migration. ASH Annual Meeting. 2010 Abstr. 2119.
    PubMedGoogle Scholar
  • 93 Bais C, Wu X, Yao J. et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 2010; 141: 166-177.
    CrossrefPubMedGoogle Scholar
  • 94 Sandler A, Gray R, Perry MC. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-smallcell lung cancer. N Engl J Med 2006; 355: 2542-2550.
    CrossrefPubMedGoogle Scholar
  • 95 Jubb AM, Hurwitz HI, Bai W. et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 2006; 24: 217-227.
    CrossrefPubMedGoogle Scholar
  • 96 Kopetz S, Hoff PM, Morris JS. et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010; 28: 453-459.
    CrossrefPubMedGoogle Scholar
  • 97 Schneider BP, Wang M, Radovich M. et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008; 26: 4672-4678.
    CrossrefPubMedGoogle Scholar
  • 98 Hasselbalch B, Eriksen JG, Broholm H. et al. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS 2010; 118: 585-594.
    PubMedGoogle Scholar
  • 99 Rini BI. et al. Axitinib versus sorafenib as secondline therapy for metastatic renal cell carcinoma (mRCC): Results of phase III AXIS trial. J Clin Oncol 2011; 29 (suppl): 4503.
    CrossrefPubMedGoogle Scholar