Endothelial-Rac1 Is Not Required for Tumor Angiogenesis unless αvβ3-Integrin Is Absent

PLoS ONE

Volumn 5, Issue 3, 2010, Pages

  D'Amico, Gabriela ^a,e   Robinson, Stephen D ^a   Germain, Mitchel ^a   Reynolds, Louise E ^a   Thomas, Gareth J ^a   Elia, George ^a   Saunders, Garry ^a   Fruttiger, Marcus ^b   Tybulewicz, Victor ^c   Mavria, Georgia ^d   Hodivala Dilke, Kairbaan M ^a  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

^d INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^e UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

NEUROPEPTIDE; RAC PROTEIN; RAC1 PROTEIN; RAC1 PROTEIN, HUMAN; RAC1 PROTEIN, MOUSE; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR 2; VITRONECTIN RECEPTOR;

ANIMAL; ARTICLE; C57BL MOUSE; CELL MOTION; CHEMOTAXIS; CYTOLOGY; ENDOTHELIUM; ENDOTHELIUM CELL; HUMAN; METABOLISM; MOUSE; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY; RETINA BLOOD VESSEL; VASCULAR ENDOTHELIUM;

ANIMALS; CELL MOVEMENT; CHEMOTAXIS; ENDOTHELIAL CELLS; ENDOTHELIUM; ENDOTHELIUM, VASCULAR; HUMANS; INTEGRIN ALPHAVBETA3; MICE; MICE, INBRED C57BL; NEOVASCULARIZATION, PATHOLOGIC; NEUROPEPTIDES; RAC GTP-BINDING PROTEINS; RAC1 GTP-BINDING PROTEIN; RETINAL VESSELS; RHO GTP-BINDING PROTEINS; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 79551644747     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0009766     Document Type: Article

References (68)

1. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438: 932-936.
2. Silva R, D'Amico G, Hodivala-Dilke KM, Reynolds LE (2008) Integrins: the keys to unlocking angiogenesis. Arterioscler Thromb Vasc Biol 28: 1703-1713.
3. Eskens FA, Dumez H, Hoekstra R, Perschl A, Brindley C, et al. (2003) Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours. Eur J Cancer 39: 917-926.
4. Friess H, Langrehr JM, Oettle H, Raedle J, Niedergethmann M, et al. (2006) A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer 6: 285.
5. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, et al. (2000) Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 6: 3056-3061.
6. Hariharan S, Gustafson D, Holden S, McConkey D, Davis D, et al. (2007) Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. Ann Oncol 18: 1400-1407.
7. Nabors LB, Mikkelsen T, Rosenfeld SS, Hochberg F, Akella NS, et al. (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25: 1651-1657.
8. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2: 727-739.
9. Stupp R, Ruegg C (2007) Integrin inhibitors reaching the clinic. J Clin Oncol 25: 1637-1638.
10. Tucker GC (2006) Integrins: molecular targets in cancer therapy. Curr Oncol Rep 8: 96-103.
11. Ellis LM, Hicklin DJ (2008) Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res 14: 6371-6375.
12. Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, et al. (2002) Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8: 27-34.
13. Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV (2006) Integrin signaling is critical for pathological angiogenesis. J Exp Med 203: 2495-2507.
14. Le Gat L, Gogat K, Van Den Berghe L, Brizard M, Kobetz A, et al. (2003) The beta3 integrin gene is expressed at high levels in the major haematopoietic and lymphoid organs, vascular system, and skeleton during mouse embryo development. Cell Commun Adhes 10: 129-140.
15. Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, et al. (2003) Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell 3: 589-601.
16. Mechtersheimer G, Barth T, Quentmeier A, Moller P (1994) Differential expression of beta 1, beta 3, and beta 4 integrin subunits in nonneoplastic neural cells of the peripheral and autonomic nervous system and in tumors derived from these cells. Lab Invest 70: 740-752.
17. Sato T, Konishi K, Kimura H, Maeda K, Yabushita K, et al. (2001) Vascular integrin beta 3 and its relation to pulmonary metastasis of colorectal carcinoma. Anticancer Res 21: 643-647.
18. Sato T, Miwa A (2002) Ets-1 and integrin beta3 for lung metastasis from colorectal cancer. APMIS 110: 347-353.
19. Oxboel J, Binderup T, Knigge U, Kjaer A (2009) Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors. Oncol Rep 21: 769-775.
20. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21: 247-269.
21. Bryan BA, D'Amore PA (2007) What tangled webs they weave: Rho-GTPase control of angiogenesis. Cell Mol Life Sci 64: 2053-2065.
22. Merajver SD, Usmani SZ (2005) Multifaceted role of Rho proteins in angiogenesis. J Mammary Gland Biol Neoplasia 10: 291-298.
23. Tzima E (2006) Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. Circ Res 98: 176-185.
24. Sawada N, Salomone S, Kim HH, Kwiatkowski DJ, Liao JK (2008) Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1. Circ Res 103: 360-368.
25. Tan W, Palmby TR, Gavard J, Amornphimoltham P, Zheng Y, et al. (2008) An essential role for Rac1 in endothelial cell function and vascular development. FASEB J 22: 1829-1838.
26. Lamalice L, Le Boeuf F, Huot J (2007) Endothelial cell migration during angiogenesis. Circ Res 100: 782-794.
27. Reynolds AR, Reynolds LE, Nagel TE, Lively JC, Robinson SD, et al. (2004) Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res 64: 8643-8650.
28. Walmsley MJ, Ooi SK, Reynolds LF, Smith SH, Ruf S, et al. (2003) Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 302: 459-462.
29. Claxton S, Kostourou V, Jadeja S, Chambon P, Hodivala-Dilke K, et al. (2008) Efficient, inducible Cre-recombinase activation in vascular endothelium. Genesis 46: 74-80.
30. Sahai E, Garcia-Medina R, Pouyssegur J, Vial E (2007) Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility. J Cell Biol 176: 35-42.
31. Sahai E, Marshall CJ (2003) Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 5: 711-719.
32. Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, et al. (2008) Rac activation and inactivation control plasticity of tumor cell movement. Cell 135: 510-523.
33. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9: 653-660.
34. Constien R, Forde A, Liliensiek B, Grone HJ, Nawroth P, et al. (2001) Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis 30: 36-44.
35. Griffin CT, Brennan J, Magnuson T (2008) The chromatin-remodeling enzyme BRG1 plays an essential role in primitive erythropoiesis and vascular development. Development 135: 493-500.
36. Mettouchi A, Klein S, Guo W, Lopez-Lago M, Lemichez E, et al. (2001) Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. Mol Cell 8: 115-127.
37. Wells CM, Walmsley M, Ooi S, Tybulewicz V, Ridley AJ (2004) Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci 117: 1259-1268.
38. Garrett TA, Van Buul JD, Burridge K (2007) VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp Cell Res 313: 3285-3297.
39. Soga N, Connolly JO, Chellaiah M, Kawamura J, Hruska KA (2001) Rac regulates vascular endothelial growth factor stimulated motility. Cell Commun Adhes 8: 1-13.
40. Zeng H, Zhao D, Mukhopadhyay D (2002) KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA. J Biol Chem 277: 46791-46798.
41. Bayless KJ, Davis GE (2002) The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. J Cell Sci 115: 1123-1136.
42. Cascone I, Giraudo E, Caccavari F, Napione L, Bertotti E, et al. (2003) Temporal and spatial modulation of Rho GTPases during in vitro formation of capillary vascular network. Adherens junctions and myosin light chain as targets of Rac1 and RhoA. J Biol Chem 278: 50702-50713.
43. Connolly JO, Simpson N, Hewlett L, Hall A (2002) Rac regulates endothelial morphogenesis and capillary assembly. Mol Biol Cell 13: 2474-2485.
44. Davis GE, Bayless KJ (2003) An integrin and Rho GTPase-dependent pinocytic vacuole mechanism controls capillary lumen formation in collagen and fibrin matrices. Microcirculation 10: 27-44.
45. Davis GE, Bayless KJ, Mavila A (2002) Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat Rec 268: 252-275.
46. Hoang MV, Whelan MC, Senger DR (2004) Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc Natl Acad Sci U S A 101: 1874-1879.
47. Koh W, Mahan RD, Davis GE (2008) Cdc42-and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. J Cell Sci 121: 989-1001.
48. Liu ZJ, Snyder R, Soma A, Shirakawa T, Ziober BL, et al. (2003) VEGF-A and alphaVbeta3 integrin synergistically rescue angiogenesis via N-Ras and PI3-K signaling in human microvascular endothelial cells. FASEB J 17: 1931-1933.
49. Dormond O, Foletti A, Paroz C, Ruegg C (2001) NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med 7: 1041-1047.
50. Ruegg C, Dormond O, Mariotti A (2004) Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis. Biochim Biophys Acta 1654: 51-67.
51. Elfenbein A, Rhodes JM, Meller J, Schwartz MA, Matsuda M, et al. (2009) Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway. J Cell Biol 186: 75-83.
52. Bass MD, Roach KA, Morgan MR, Mostafavi-Pour Z, Schoen T, et al. (2007) Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix. J Cell Biol 177: 527-538.
53. Robinson SD, Reynolds LE, Wyder L, Hicklin DJ, Hodivala-Dilke KM (2004) Beta3-integrin regulates vascular endothelial growth factor-A-dependent permeability. Arterioscler Thromb Vasc Biol 24: 2108-2114.
54. Engl T, Relja B, Marian D, Blumenberg C, Muller I, et al. (2006) CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 8: 290-301.
55. Laferriere J, Houle F, Huot J (2002) Regulation of the metastatic process by Eselectin and stress-activated protein kinase-2/p38. Ann N Y Acad Sci 973: 562-572.
56. Rousseau S, Houle F, Huot J (2000) Integrating the VEGF signals leading to actin-based motility in vascular endothelial cells. Trends Cardiovasc Med 10: 321-327.
57. Hodivala-Dilke K (2008) alphavbeta3 integrin and angiogenesis: a moody integrin in a changing environment. Curr Opin Cell Biol 20: 514-519.
58. Pampori N, Hato T, Stupack DG, Aidoudi S, Cheresh DA, et al. (1999) Mechanisms and consequences of affinity modulation of integrin alpha(V)beta(3) detected with a novel patch-engineered monovalent ligand. J Biol Chem 274: 21609-21616.
59. Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA (2001) Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol 155: 459-470.
60. Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, et al. (2009) Stimulation of tumor growth and angiogenesis by low concentrations of RGDmimetic integrin inhibitors. Nat Med 15: 392-400.
61. Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, et al. (1999) Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103: 229-238.
62. Gustafsson E, Brakebusch C, Hietanen K, Fassler R (2001) Tie-1-directed expression of Cre recombinase in endothelial cells of embryoid bodies and transgenic mice. J Cell Sci 114: 671-676.
63. Reynolds LE, Hodivala-Dilke KM (2006) Primary mouse endothelial cell culture for assays of angiogenesis. Methods Mol Med 120: 503-509.
64. Ventura A, Meissner A, Dillon CP, McManus M, Sharp PA, et al. (2004) Crelox-regulated conditional RNA interference from transgenes. Proc Natl Acad Sci U S A 101: 10380-10385.
65. Robinson SD, Reynolds LE, Kostourou V, Reynolds AR, Graca da Silva R, et al. (2009) Alphavbeta3-integrin limits the contribution of neuropilin-1 to VEGF-induced angiogenesis. J Biol Chem.
66. Nystrom ML, McCulloch D, Weinreb PH, Violette SM, Speight PM, et al. (2006) Cyclooxygenase-2 inhibition suppresses alphavbeta6 integrin-dependent oral squamous carcinoma invasion. Cancer Res 66: 10833-10842.
67. Andrade SP, Machado RD, Teixeira AS, Belo AV, Tarso AM, et al. (1997) Sponge-induced angiogenesis in mice and the pharmacological reactivity of the neovasculature quantitated by a fluorimetric method. Microvasc Res 54: 253-261.
68. Abraham S, Yeo M, Montero-Balaguer M, Paterson H, Dejana E, et al. (2009) VE-Cadherin-mediated cell-cell interaction suppresses sprouting via signaling to MLC2 phosphorylation. Curr Biol 19: 668-674.