Integrins: Players in cancer progression and targets in cancer therapy

Anti-Cancer Drugs

Volumn 25, Issue 10, 2014, Pages 1107-1121

  Sun, Cui Cui ^a   Qu, Xian Jun ^a,b   Gao, Zu Hua ^b,c,d  

^a SHANDONG UNIVERSITY   (China)

^b School of Pharmaceutical Sciences   (China)

^c CAPITAL MEDICAL UNIVERSITY   (China)

^d MCGILL UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTEGRIN; VASCULAR CELL ADHESION MOLECULE 1; ANTINEOPLASTIC AGENT;

ANGIOGENESIS; APOPTOSIS; CANCER CELL; CANCER GROWTH; CANCER THERAPY; CARTILAGE CELL; CELL ADHESION; CELL DIFFERENTIATION; CELL FUNCTION; CELL INTERACTION; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL PRACTICE; DRUG TARGETING; EMBRYO DEVELOPMENT; ENDOTHELIUM CELL; EXTRACELLULAR MATRIX; HUMAN; INTRACELLULAR SIGNALING; LEUKOCYTE ADHERENCE; LIGAND BINDING; OSTEOPOROSIS; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; THROMBOCYTE AGGREGATION; VASCULAR SMOOTH MUSCLE; ANIMAL; CELL MOTION; CHEMISTRY; DISEASE COURSE; DRUG RESISTANCE; METABOLISM; NEOPLASMS; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY; PROGNOSIS; SIGNAL TRANSDUCTION; TUMOR INVASION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL MOVEMENT; DISEASE PROGRESSION; DRUG RESISTANCE, NEOPLASM; HUMANS; INTEGRINS; NEOPLASM INVASIVENESS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROGNOSIS; SIGNAL TRANSDUCTION;

EID: 84916885426     PISSN: 09594973     EISSN: 14735741     Source Type: Journal    
DOI: 10.1097/CAD.0000000000000145     Document Type: Review

References (188)

1. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110:673-687.
2. Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res 2010; 339:269-280.
3. Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J Biol Chem 2000; 275:21785-21788.
4. Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, et al. α(V)β(3) Integrin crystal structures and their functional implications. Biochemistry 2012; 51:8814-8828.
5. Zhu JQ, Zhu JH, Springer TA. Complete integrin headpiece opening in eight steps. J Cell Biol 2013; 201:1053-1068.
6. Arnaout MA, Mahalingam B, Xiong JP. Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 2005; 21:381-410.
7. Schlaepfer DD, Hunter T. Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 1997; 272:13189-13195.
8. Campbell ID, Humphries MJ. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 2011; 3:a004994.
9. Guo W, Giancotti FG. Integrin signaling during tumor progression. Nat Rev Mol Cell Biol 2004; 5:816-826.
10. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010; 10:9-22.
11. Wehrle-Haller B, Imhof BA. Integrin-dependent pathologies. J Pathol 2003; 200:481-487.
12. Etzioni A. Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol 2010; 38:54-60.
13. Zhou HF, Chan HW, Wickline SA, Lanza GM, Pham CT. Alphavbeta3-targeted nanotherapy suppresses inflammatory arthritis in mice. FASEB J 2009; 23:2978-2985.
14. Worthingtion JJ, Fenton TM, Czajkowska BI, Klementowicz JE, Travis MA. Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells. Immunobiology 2012; 217:1259-1265.
15. Chen X, Song CH, Feng BS, Li TL, Li P, Zheng PY, et al. Intestinal epithelial cell-derived integrin αβ6 plays an important role in the induction of regulatory T cells and inhibits an antigen-specific Th2 response. J Leukoc Biol 2011; 90:751-759.
16. Schumann H, Kiritsi D, Pigors M, Hausser I, Kohlhase J, Peters J, et al. Phenotypic spectrum of epidermolysis bullosa associated with α6β4 integrin mutations. Br J Dermatol 2013; 169:115-124.
17. Bao F, Omana V, Brown A, Weaver LC. The systemic inflammatory response after spinal cord injury in the rat is decreased by α4β1 integrin blockade. J Neurotrauma 2012; 29:1626-1637.
18. Suchard SJ, Stetsko DK, Davis PM, Skala S, Potin D, Launay M, et al. An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis. J Immunol 2010; 184:3917-3926.
19. Kuijpers TW, RAW vanLier, Hamann D, de Boer M, Thung LY, Weening RS, et al. Leukocyte adhesion deficiency type 1 (LAD-1)/variant - a novel immunodeficiency syndrome characterized by dysfunctional β2 integrins. J Clin Invest 1997; 100:1725-1733.
20. Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M, Davidson D, Hynes RO. Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 2002; 22:927-933.
21. Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, et al. α3β1 Integrin has a crucial role in kidney and lung organogenesis. Development 1996; 122:3537-3547.
22. Ma GC, Liu CS, Chang SP, Yeh KT, Ke YY, Chen TH, et al. A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy. Prenat Diagn 2008; 28:1057-1063.
23. Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive integrin. Cell 1991; 65:359-362.
24. Niu H, Chen X, Gruppo RA, Li D, Wang Y, Zhang L, et al. Integrin αIIb-mediated PI3K/Akt activation in platelets. PLoS One 2012; 7:e47356.
25. Coller BS, Shattil SJ. The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood 2008; 112:3011-3025.
26. Lal H, Guleria RS, Foster DM, Lu G, Watson LE, Sanghi S, et al. Integrins: novel therapeutic targets for cardiovascular diseases. Cardiovasc Hematol Agents Med Chem 2007; 5:109-132.
27. Sakuma T, Sari I, Goodman CN, Lindner JR, Klibanov AL, Kaul S. Simultaneous integrin alphavbeta3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty. Cardiovasc Res 2005; 66:552-561.
28. Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest 1995; 95:713-724.
29. Coleman PJ, Brashear KM, Askew BC, Hutchinson JH, McVean CA, Duong le T, et al. Nonpeptide αvβ3 antagonists. Part 11: discovery and preclinical evaluation of potent αvβ3 antagonists for the prevention and treatment of osteoporosis. J Med Chem 2004; 47:4829-4837.
30. Liu Y, Zhao F, Gu W, Yang H, Meng Q, Zhang Y, et al. The roles of platelet GPIIb/IIIa and alphavbeta3 integrins during HeLa cells adhesion, migration, and invasion to monolayer endothelium under static and dynamic shear flow. J Biomed Biotechnol 2009; 2009:829243.
31. Trikha M, Tímár J, Zacharek M, Nemeth JA, Cai Y, Döme B, et al. Role for β3 integrins in human melanoma growth and survival. Int J Cancer 2002; 101:156-167.
32. Döme B, Rásó E, Dobos J, Mészáros L, Varga N, Puskás LG, et al. Parallel expression of alphaIIbbeta3 and alphavbeta3 integrins in human melanoma cells upregulates bFGF expression and promotes their angiogenic phenotype. Int J Cancer 2005; 116:27-35.
33. Timar J, Trikha M, Szekeres K, Bazaz R, Honn K. Expression and function of the high affinity alphaIIbbeta3 integrin in murine melanoma cells. Clin Exp Metastasis 1998; 16:437-445.
34. Bakewell SJ, Nestor P, Prasad S, Tomasson MH, Dowland N, Mehrotra M, et al. Platelet and osteoclast beta3 integrins are critical for bone metastasis. Proc Natl Acad Sci USA 2003; 100:14205-14210.
35. Parsons-Wingerter P, Kasman IM, Norberg S, Magnussen A, Zanivan S, Rissone A, et al. Uniform overexpression and rapid accessibility of alpha5beta1 integrin on blood vessels in tumors. Am J Pathol 2005; 167:193-211.
36. Morozevich GE, Kozlova NI, Ushakova NA, Preobrazhenskaya ME, Berman AE. Integrin α5β1 simultaneously controls EGFR-dependent proliferation and Akt-dependent pro-survival signaling in epidermoid carcinoma cells. Aging (Albany NY) 2012; 4:368-374.
37. Sayeed A, Fedele C, Trerotola M, Ganguly KK, Languino LR. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels. PLoS One 2013; 8:e76513.
38. Maglott A, Bartik P, Cosgun S, Klotz P, Rondé P, Fuhrmann G, et al. The small alpha5beta1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells. Cancer Res 2006; 66:6002-6007.
39. Bhaskar V, Fox M, Breinberg D, Wong MH, Wales PE, Rhodes S, et al. Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs 2008; 26:7-12.
40. Khalili P, Arakelian A, Chen G, Plunkett ML, Beck I, Parry GC, et al. A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther 2006; 5:2271-2280.
41. Zeng ZZ, Jia Y, Hahn NJ, Markwart SM, Rockwood KF, Livant DL. Role of focal adhesion kinase and phosphatidylinositol 3'-kinase in integrin fibronectin receptor-mediated, matrix metalloproteinase-1-dependent invasion by metastatic prostate cancer cells. Cancer Res 2006; 66:8091-8099.
42. Morozevich G, Kozlova N, Cheglakov I, Ushakova N, Berman A. Integrin alpha5beta1 controls invasion of human breast carcinoma cells by direct and indirect modulation of MMP-2 collagenase activity. Cell Cycle 2009; 8:2219-2225.
43. Imanishi Y, Hu B, Jarzynka MJ, Guo P, Elishaev E, Bar-Joseph I, Cheng SY. Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5) beta(1) integrin-mediated pathway. Cancer Res 2007; 67:4254-4263.
44. Tang BL, Ng EL. Rabs and cancer cell motility. Cell Motil Cytoskeleton 2009; 66:365-370.
45. Mitra AK, Sawada K, Tiwari P, Mui K, Gwin K, Lengyel E. Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis. Oncogene 2011; 30:1566-1576.
46. Roman J, Ritzenthaler JD, Roser-Page S, Sun X, Han S. Alpha5beta1-integrin expression is essential for tumor progression in experimental lung cancer. Am J Respir Cell Mol Biol 2010; 43:684-691.
47. Sil H, Sen T, Chatterjee A. Fibronectin-integrin (alpha5beta1) modulates migration and invasion of murine melanoma cell line B16F10 by involving MMP-9. Oncol Res 2011; 19:335-348.
48. Wang HY, Chen Z, Wang ZH, Wang H, Huang LM. Prognostic significance of α5β1-integrin expression in cervical cancer. Asian Pac J Cancer Prev 2013; 14:3891-3895.
49. Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 2011; 17:1359-1370.
50. Nemeth JA, Cher ML, Zhou Z, Mullins C, Bhagat S, Trikha M. Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clin Exp Metastasis 2003; 20:413-420.
51. Genersch E, Ferletta M, Virtanen I, Haller H, Ekblom P. Integrin alphavbeta3 binding to human alpha5-laminins facilitates FGF-2- and VEGF-induced proliferation of human ECV304 carcinoma cells. Eur J Cell Biol 2003; 82:105-117.
52. Tzukert K, Shimony N, Krasny L, Urieli-Shoval S, Gorodetsky R, Avrahami I, et al. Human melanoma cells expressing the alphavbeta3 integrin are partially protected from necrotic cell death induced by dynamic matrix detachment. Cancer Lett 2010; 290:174-181.
53. Vellon L, Menendez JA, Lupu R. A bidirectional 'alpha(v)beta(3) integrin-ERK1/ERK2 MAPK' connection regulates the proliferation of breast cancer cells. Mol Carcinog 2006; 45:795-804.
54. Kozlova NI, Morozevich GE, Chubukina AN, Berman AE. Integrin alphavbeta3 promotes anchorage-dependent apoptosis in human intestinal carcinoma cells. Oncogene 2001; 20:4710-4717.
55. Desgrosellier JS, Barnes LA, Shields DJ, Huang M, Lau SK, Prévost N, et al. An integrin alpha (v) beta (3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 2009; 15:1163-1169.
56. Lorger M, Krueger JS, O'Neal M, Staflin K, Felding-Habermann B. Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci USA 2009; 106:10666-10671.
57. Wang Y, Yan W, Lu X, Qian C, Zhang J, Li P, et al. Overexpression of osteopontin induces angiogenesis of endothelial progenitor cells via the αvβ3/PI3K/AKT/eNOS/NO signaling pathway in glioma cells. Eur J Cell Biol 2011; 90:642-648.
58. Montenegro CF, Salla-Pontes CL, Ribeiro JU, Machado AZ, Ramos RF, Figueiredo CC, et al. Blocking αvβ3 integrin by a recombinant RGD disintegrin impairs VEGF signaling in endothelial cells. Biochimie 2012; 94:1812-1820.
59. MacDonald TJ, Taga T, Shimada H, Tabrizi P, Zlokovic BV, Cheresh DA, Laug WE. Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 2001; 48:151-157.
60. Sheldrake HM, Patterson LH. Function and antagonism of beta3 integrins in the development of cancer therapy. Curr Cancer Drug Targets 2009; 9:519-540.
61. Furger KA, Allan AL, Wilson SM, Hota C, Vantyghem SA, Postenka CO, et al. Beta(3) integrin expression increases breast carcinoma cell responsiveness to the malignancy-enhancing effects of osteopontin. Mol Cancer Res 2003; 1:810-819.
62. Huang J, Roth R, Heuser JE, Sadler JE. Integrin alpha(v)beta(3) on human endothelial cells binds von Willebrand factor strings under fluid shear stress. Blood 2009; 113:1589-1597.
63. Knowles LM, Gurski LA, Engel C, Gnarra JR, Maranchie JK, Pilch J. Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis. Cancer Res 2013; 73:6175-6184.
64. Yun Z, Menter DG, Nicolson GL. Involvement of integrin alphavbeta3 in cell adhesion, motility, and liver metastasis of murine RAW11 7 large cell lymphoma. Cancer Res 1996; 56:3103-3111.
65. Chatterjee N, Chatterjee A. Role of alphavbeta3 integrin receptor in the invasive potential of human cervical cancer (SiHa) cells. J Environ Pathol Toxicol Oncol 2001; 20:211-221.
66. Kaur S, Kenny HA, Jagadeeswaran S, Zillhardt MR, Montag AG, Kistner E, et al. {beta}3-Integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer. Am J Pathol 2009; 175:2184-2196.
67. Li F, Liu Y, Kan X, Li Y, Liu M, Lu JG. Elevated expression of integrin αv and β5 subunit in laryngeal squamous-cell carcinoma associated with lymphatic metastasis and angiogenesis. Pathol Res Pract 2013; 209:105-109.
68. Vogetseder A, Thies S, Ingold B, Roth P, Weller M, Schraml P, et al. αv-Integrin isoform expression in primary human tumors and brain metastases. Int J Cancer 2013; 133:2362-2371.
69. Zhu L, Wang X, Wu J, Mao D, Xu Z, He Z, et al. Cooperation of protease-activated receptor 1 and integrin αvβ5 in thrombin-mediated lung cancer cell invasion. Oncol Rep 2012; 28:553-560.
70. Breuss JM, Gillett N, Lu L, Sheppard D, Pytela R. Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues. J Histochem Cytochem 1993; 41:1521-1527.
71. Zhang ZY, Xu KS, He QS, Niu WB, Wang JY, Mi YT, et al. Signaling and regulatory mechanisms of integrin alphavbeta6 on the apoptosis of colon cancer cells. Cancer Lett 2008; 266:209-215.
72. Cantor D, Slapetova I, Kan A, McQuade LR, Baker MS. Overexpression of αvβ6 integrin alters the colorectal cancer cell proteome in favor of elevated proliferation and a switching in cellular adhesion that increases invasion. J Proteome Res 2013; 12:2477-2490.
73. Xue H, Atakilit A, Zhu W, Li X, Ramos DM, Pytela R. Role of the alpha(v) beta6 integrin in human oral squamous cell carcinoma growth in vivo and in vitro. Biochem Biophys Res Commun 2001; 288:610-618.
74. Allen MD, Thomas GJ, Clark S, Dawoud MM, Vallath S, Payne SJ, et al. Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. Clin Cancer Res 2014; 20:344-357.
75. Regezi JA, Ramos DM, Pytela R, Dekker NP, Jordan RC. Tenascin and beta 6 integrin are overexpressed in floor of mouth in situ carcinomas and invasive squamous cell carcinomas. Oral Oncol 2002; 38:332-336.
76. Sipos B, Hahn D, Carceller A, Piulats J, Hedderich J, Kalthoff H, et al. Immunohistochemical screening for beta6-integrin subunit expression in adenocarcinomas using a novel monoclonal antibody reveals strong up-regulation in pancreatic ductal adenocarcinomas in vivo and in vitro. Histopathology 2004; 45:226-236.
77. Ahmed N, Riley C, Rice GE, Quinn MA, Baker MS. Alpha(v)beta(6) integrin - A marker for the malignant potential of epithelial ovarian cancer. J Histochem Cytochem 2002; 50:1371-1380.
78. Arihiro K, Kaneko M, Fujii S, Inai K, Yokosaki Y. Significance of alpha 9 beta 1 and alpha v beta 6 integrin expression in breast carcinoma. Breast Cancer 2000; 7:19-26.
79. Elayadi AN, Samli KN, Prudkin L, Liu YH, Bian A, Xie XJ, et al. A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for non-small cell lung cancer. Cancer Res 2007; 67:5889-5895.
80. Zhao R, Liu XQ, Wu XP, Liu YF, Zhang ZY, Yang GY, et al. Vascular endothelial growth factor (VEGF) enhances gastric carcinoma invasiveness via integrin alpha(v)beta6. Cancer Lett 2010; 287:150-156.
81. Marsh D, Dickinson S, Neill GW, Marshall JF, Hart IR, Thomas GJ. alpha vbeta 6 Integrin promotes the invasion of morphoeic basal cell carcinoma through stromal modulation. Cancer Res 2008; 68:3295-3303.
82. Yang GY, Xu KS, Pan ZQ, Zhang ZY, Mi YT, Wang JS, et al. Integrin alpha v beta 6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver. Cancer Sci 2008; 99:879-887.
83. Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J 2002; 21:3919-3926.
84. Tran T, Barlow B, O'Rear L, Jarvis B, Li Z, Dickeson K, et al. Loss of the α2β1 integrin alters human papilloma virus-induced squamous carcinoma progression in vivo and in vitro. PLoS One 2011; 6:e26858.
85. Grzesiak JJ, Bouvet M. Determination of the ligand-binding specificities of the alpha2beta1 and alpha1beta1 integrins in a novel 3-dimensional in vitro model of pancreatic cancer. Pancreas 2007; 34:220-228.
86. Bartolomé RA, Barderas R, Torres S, Fernandez-Aceñero MJ, Mendes M, García-Foncillas J, et al. Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis. Oncogene 2014; 33:1658-1669.
87. Zhang Z, Ramirez NE, Yankeelov TE, Li Z, Ford LE, Qi Y, et al. alpha2beta1 Integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner. Blood 2008; 111:1980-1988.
88. Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R. Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res 2003; 63:8312-8317.
89. Fishman DA, Kearns A, Chilukuri K, Bafetti LM, O'Toole EA, Georgacopoulos J, et al. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen. Invasion Metastasis 1998; 18:15-26.
90. Van Slambrouck S, Hilkens J, Bisoffi M, Steelant WF. AsialoGM1 and integrin alpha2beta1 mediate prostate cancer progression. Int J Oncol 2009; 35:693-699.
91. Zou CY, Wen FQ, Chen YX, Liu ZP, Zhang ZX. Effect of integrin alpha2beta1 on invasion and migration of neuroblastoma cells. Zhongguo Dang Dai Er Ke Za Zhi 2008; 10:386-390.
92. Cagnet S, Faraldo MM, Kreft M, Sonnenberg A, Raymond K, Glukhova MA. Signaling events mediated by α3β1 integrin are essential for mammary tumorigenesis. Oncogene 2013; doi: 10.1038/onc.2013.391. [Epub ahead of print].
93. Yoon HJ, Cho YR, Joo JH, Seo DW. Knockdown of integrin α3β1 expression induces proliferation and migration of non-small cell lung cancer cells. Oncol Rep 2013; 29:662-668.
94. Mitchell K, Svenson KB, Longmate WM, Gkirtzimanaki K, Sadej R, Wang X, et al. Suppression of integrin alpha3beta1 in breast cancer cells reduces cyclooxygenase-2 gene expression and inhibits tumorigenesis, invasion, and cross-talk to endothelial cells. Cancer Res 2010; 70:6359-6367.
95. Mizuno H, Ogura M, Saito Y, Sekine W, Sano R, Gotou T, et al. Changes in adhesive and migratory characteristics of hepatocellular carcinoma (HCC) cells induced by expression of alpha3beta1 integrin. Biochim Biophys Acta 2008; 1780:564-570.
96. Tsuji T, Kawada Y, Kai-Murozono M, Komatsu S, Han SA, Takeuchi K, et al. Regulation of melanoma cell migration and invasion by laminin-5 and alpha3beta1 integrin (VLA-3). Clin Exp Metastasis 2002; 19:127-134.
97. Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, et al. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer 2000; 87:336-342.
98. Kawataki T, Yamane T, Naganuma H, Rousselle P, Andurén I, Tryggvason K, Patarroyo M. Laminin isoforms and their integrin receptors in glioma cell migration and invasiveness: evidence for a role of alpha5-laminin(s) and alpha3beta1 integrin. Exp Cell Res 2007; 313:3819-3831.
99. Yoshimasu T, Sakurai T, Oura S, Hirai I, Tanino H, Kokawa Y, et al. Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line. Cancer Sci 2004; 95:142-148.
100. Zhou B, Gibson-Corley KN, Herndon ME, Sun Y, Gustafson-Wagner E, Teoh-Fitzgerald M, et al. Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma. Mol Cancer Res 2014; 12:143-154.
101. Varzavand A, Drake JM, Svensson RU, Herndon ME, Zhou B, Henry MD, et al. Integrin α3β1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization. Clin Exp Metastasis 2013; 30:541-552.
102. Lipscomb EA, Simpson KJ, Lyle SR, Ring JE, Dugan AS, Mercurio AM. The alpha6beta4 integrin maintains the survival of human breast carcinoma cells in vivo. Cancer Res 2005; 65:10970-10976.
103. Ding YB, Deng B, Huang YS, Xiao WM, Wu J, Zhang YQ, et al. A high level of integrin α6 expression in human intrahepatic cholangiocarcinoma cells is associated with a migratory and invasive phenotype. Dig Dis Sci 2013; 58:1627-1635.
104. Cruz-Monserrate Z, O'Connor KL Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation. Neoplasia 2008; 10:408-417.
105. Kim TH, Kim HI, Soung YH, Shaw LA, Chung J. Integrin (alpha6beta4) signals through Src to increase expression of S100A4, a metastasis-promoting factor: implications for cancer cell invasion. Mol Cancer Res 2009; 7:1605-1612.
106. Chao C, Lotz MM, Clarke AC, Mercurio AM. A function for the integrin alpha6beta4 in the invasive properties of colorectal carcinoma cells. Cancer Res 1996; 56:4811-4819.
107. Rossen K, Dahlstrøm KK, Mercurio AM, Wewer UM. Expression of the alpha 6 beta 4 integrin by squamous cell carcinomas and basal cell carcinomas: possible relation to invasive potential? Acta Derm Venereol 1994; 74:101-105.
108. Gilcrease MZ. Integrin signaling in epithelial cells. Cancer Lett 2007; 247:1-25.
109. Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59:1295-1300.
110. Hussain AF, Tur MK, Barth S. An aptamer-siRNA chimera silences the eukaryotic elongation factor 2 gene and induces apoptosis in cancers expressing αvβ3 integrin. Nucleic Acid Ther 2013; 23:203-212.
111. Danen EH. Integrins: regulators of tissue function and cancer progression. Curr Pharm Des 2005; 11:881-891.
112. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 2008; 8:604-617.
113. Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003; 301:94-96.
114. Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA. Differential αv integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol 2003; 162:933-943.
115. Jia J, Starodub A, Cushman I, Liu Y, Marshall DJ, Hurwitz HI, et al. Dual inhibition of αV integrins and Src kinase activity as a combination therapy strategy for colorectal cancer. Anticancer Drugs 2013; 24:237-250.
116. Kumar CC, Malkowski M, Yin Z, Tanghetti E, Yaremko B, Nechuta T, et al. Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha (v)beta3 and alpha(v)beta5 integrin receptor antagonist. Cancer Res 2001; 61:2232-2238.
117. Cascone I, Napione L, Maniero F, Serini G, Bussolino F. Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J Cell Biol 2005; 170:993-1004.
118. Li L, Liu F, Welser-Alves JV, McCullough LD, Milner R. Upregulation of fibronectin and the α5β1 and αvβ3 integrins on blood vessels within the cerebral ischemic penumbra. Exp Neurol 2012; 233:283-291.
119. Li L, Welser-Alves J, van der Flier A, Boroujerdi A, Hynes RO, Milner R. An angiogenic role for the α5β1 integrin in promoting endothelial cell proliferation during cerebral hypoxia. Exp Neurol 2012; 237:46-54.
120. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE. A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 2007; 5:61.
121. Kapp TG, Rechenmacher F, Sobahi TR, Kessler H. Integrin modulators: a patent review. Expert Opin Ther Pat 2013; 23:1273-1295.
122. Bell-McGuinn KM, Matthews CM, Ho SN, Barve M, Gilbert L, Penson RT, et al. A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol Oncol 2011; 121:273-279.
123. Brooks PC, Klemke RL, Schon S, Lewis JM, Schwartz MA, Cheresh DA. Insulin-like growth factor receptor cooperates with integrin αvβ5 to promote tumor cell dissemination in vivo. J Clin Invest 1997; 99:1390-1398.
124. Ricono JM, Huang M, Barnes LA, Lau SK, Weis SM, Schlaepfer DD, et al. Specific cross-talk between epidermal growth factor receptor and integrin alphavbeta5 promotes carcinoma cell invasion and metastasis. Cancer Res 2009; 69:1383-1391.
125. Lonsdorf AS, Krämer BF, Fahrleitner M, Schönberger T, Gnerlich S, Ring S, et al. Engagement of αIIbβ3 (GPIIb/IIIa) with αvβ3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis. J Biol Chem 2012; 287:2168-2178.
126. Lorger M, Krueger JS, O'Neal M, Staflin K, Felding-Habermann B. Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci USA 2009; 106:10666-10671.
127. Zhao Y, Miao G, Li Y, Isaji T, Gu J, Li J, et al. Microrna 130b suppresses migration and invasion of colorectal cancer cells through downregulation of integrin β1. PLoS One 2014; 9:e87938.
128. Zha R, Guo W, Zhang Z, Qiu Z, Wang Q, Ding J, et al. Genome-wide screening identified That miR-134 acts as a metastasis suppressor by targeting integrin β1 in hepatocellular carcinoma. PLoS One 2014; 9: e87665.
129. Kinoshita T, Nohata N, Hanazawa T, Kikkawa N, Yamamoto N, Yoshino H, et al. Tumour-suppressive microRNA-29s inhibit cancer cell migration and invasion by targeting laminin-integrin signalling in head and neck squamous cell carcinoma. Br J Cancer 2013; 109:2636-2645.
130. Chang CC, Yang YJ, Li YJ, Chen ST, Lin BR, Wu TS, et al. MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma. Oral Oncol 2013; 49:923-931.
131. Valastyan S, Chang A, Benaich N, Reinhardt F, Weinberg RA. Concurrent suppression of integrin alpha5, radixin, and RhoA phenocopies the effects of miR-31 on metastasis. Cancer Res 2010; 70:5147-5154.
132. Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szász AM, Wang ZC, et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 2009; 137:1032-1046.
133. Hunt S, Jones AV, Hinsley EE, Whawell SA, Lambert DW. MicroRNA-124 suppresses oral squamous cell carcinoma motility by targeting ITGB1. FEBS Lett 2011; 585:187-192.
134. De la Fuente MT, Casanova B, Cantero E, Hernández del Cerro M, Garcia Marco J, Silva A, Garcia-Pardo A. Involvement of p53 in alpha4beta1 integrin-mediated resistance of B-CLL cells to fludarabine. Biochem Biophys Res Commun 2003; 311:708-712.
135. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93:1658-1667.
136. De la Fuente MT, Casanova B, Moyano JV, Garcia-Gila M, Sanz L, GarciaMarco J, et al. Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine. J Leukoc Biol 2002; 71:495-502.
137. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 2000; 19:4319-4327.
138. Kasahara T, Koguchi E, Funakoshi M, Aizu-Yokota E, Sonoda Y. Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation. Antioxid Redox Signal 2002; 4:491-499.
139. Zhang H, Ozaki I, Mizuta T, Matsuhashi S, Yoshimura T, Hisatomi A, et al. Beta 1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway. Cancer 2002; 95:896-906.
140. Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene 2001; 20:4995-5004.
141. Lesniak D, Xu Y, Deschenes J, Lai R, Thoms J, Murray D, et al. Beta1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer. Cancer Res 2009; 69:8620-8628.
142. Cordes N, Beinke C, Plasswilm L, van Beuningen D. Irradiation and various cytotoxic drugs enhance tyrosine phosphorylation and beta(1)-integrin clustering in human A549 lung cancer cells in a substratum-dependent manner in vitro. Strahlenther Onkol 2004; 180:157-164.
143. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 1999; 5:662-668.
144. Ju L, Zhou C, Li W, Yan L. Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. J Cell Biochem 2010; 111:1565-1574.
145. Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, et al. Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res 2013; 73:6243-6253.
146. Thomas F, Holly JM, Persad R, Bahl A, Perks CM. Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor. Prostate 2010; 70:856-865.
147. Hazlehurst LA, Valkov N, Wisner L, Storey JA, Boulware D, Sullivan DM, Dalton WS. Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood 2001; 98:1897-1903.
148. Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK. β1 Integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res 2013; 73:3145-3154.
149. Zhang CJ, Shen ZJ, Pan CW, Zhong S, Li T, Zhang MG. Engagement of integrinβ1 induces resistance of bladder cancer cells to mitomycin-C. Urology 2012; 79:638-643.
150. Mori R, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Tomoda K, et al. Targeting beta1 integrin restores sensitivity to docetaxel of esophageal squamous cell carcinoma. Oncol Rep 2008; 20:1345-1351.
151. Hazlehurst LA, Argilagos RF, Dalton WS. Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells. Br J Haematol 2007; 136:269-275.
152. Estrugo D, Fischer A, Hess F, Scherthan H, Belka C, Cordes N. Ligand bound beta1 integrins inhibit procaspase-8 for mediating cell adhesion-mediated drug and radiation resistance in human leukemia cells. PLoS One 2007; 2:e269.
153. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003; 9:1158-1165.
154. Mraz M, Zent CS, Church AK, Jelinek DF, Wu X, Pospisilova S, et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol 2011; 155:53-64.
155. Scalici JM, Harrer C, Allen A, Jazaeri A, Atkins KA, McLachlan KR, et al. Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin. Gynecol Oncol 2014; 132:455-461.
156. Hsieh YT, Gang EJ, Geng H, Park E, Huantes S, Chudziak D, et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 2013; 121:1814-1818.
157. Damiano JS, Hazlehurst LA, Dalton WS. Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia 2001; 15:1232-1239.
158. Janouskova H, Maglott A, Leger DY, Bossert C, Noulet F, Guerin E, et al. Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma. Cancer Res 2012; 72:3463-3470.
159. Sebens Müerköster S, Kötteritzsch J, Geismann C, Gast D, Kruse ML, Altevogt P, et al. alpha5-Integrin is crucial for L1CAM-mediated chemoresistance in pancreatic adenocarcinoma. Int J Oncol 2009; 34:243-253.
160. Gendron S, Couture J, Aoudjit F. Collagen type I signaling reduces the expression and the function of human receptor activator of nuclear factorkappa B ligand (RANKL) in T lymphocytes. Eur J Immunol 2005; 35:3673-3682.
161. Naci D, El Azreq MA, Chetoui N, Lauden L, Sigaux F, Charron D, et al. α2β1 integrin promotes chemoresistance against doxorubicin in cancer cells through extracellular signal-regulated kinase (ERK). J Biol Chem 2012; 287:17065-17076.
162. Zheng Y, Yang J, Qian J, Qiu P, Hanabuchi S, Lu Y, et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia 2013; 27:702-710.
163. Wu RC, Wang Z, Liu MJ, Chen DF, Yue XS. beta2-Integrins mediate a novel form of chemoresistance in cycloheximide-induced U937 apoptosis. Cell Mol Life Sci 2004; 61:2071-2082.
164. Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL. Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 1999; 5:1587-1594.
165. Shin DH, Lee HJ, Min HY, Choi SP, Lee MS, Lee JW, et al. Combating resistance to anti-IGFR antibody by targeting the integrin β3-Src pathway. J Natl Cancer Inst 2013; 105:1558-1570.
166. Brozovic A, Majhen D, Roje V, Mikac N, Jakopec S, Fritz G, et al. alpha(v) beta(3) Integrin-mediated drug resistance in human laryngeal carcinoma cells is caused by glutathione-dependent elimination of drug-induced reactive oxidative species. Mol Pharmacol 2008; 74:298-306.
167. Gao J, Hu Z, Liu D, Liu J, Liu C, Hou R, et al. Expression of Lewis y antigen and integrin αv, β3 in ovarian cancer and their relationship with chemotherapeutic drug resistance. J Exp Clin Cancer Res 2013; 32:36.
168. Folgiero V, Avetrani P, Bon G, Di Carlo SE, Fabi A, Nisticò C, et al. Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas. PLoS One 2008; 3:e1592.
169. Yang XH, Flores LM, Li Q, Zhou P, Xu F, Krop IE, Hemler ME. Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists. Cancer Res 2010; 70:2256-2263.
170. Hersey P, Sosman J, O'Day S, Richards J, Bedikian A, Gonzalez R, et al. Etaracizumab Melanoma Study Group. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma. Cancer 2010; 116:1526-1534.
171. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 2000; 6:3056-3061.
172. Rosenthal MA, Davidson P, Rolland F, Campone M, Xue L, Han TH, 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. Asia Pac J Clin Oncol 2010; 6:42-48.
173. 99mTc-NC100692. Acta Radiol 2010; 51:40-46.
174. Heidenreich A, Rawal SK, Szkarlat K, Bogdanova N, Dirix L, Stenzl A, et al. A randomized, double-blind, multicenter, phase 2 study of a human monoclonal antibody to human αν integrins (intetumumab) in combination with docetaxel and prednisone for the first-line treatment of patients with metastatic castration-resistant prostate cancer. Ann Oncol 2013; 24:329-336.
175. O'Day S, Pavlick A, Loquai C, Lawson D, Gutzmer R, Richards J, et al. A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma. Br J Cancer 2011; 105:346-352.
176. Wirth M, Heidenreich A, Gschwend JE, Gil T, Zastrow S, Laniado M, et al. A multicenter phase 1 study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody targeting αv integrins, in progressive castration-resistant prostate cancer with bone metastases after chemotherapy. Eur Urol 2014; 65:897-904.
177. Uhl W, Zühlsdorf M, Koernicke T, Forssmann U, Kovar A. Safety, tolerability, and pharmacokinetics of the novel αv-integrin antibody EMD 525797 (DI17E6) in healthy subjects after ascending single intravenous doses. Invest New Drugs 2014; 32:347-354.
178. Gilbert MR, Kuhn J, Lamborn KR, Lieberman F, Wen PY, Mehta M, et al. Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery. J Neurooncol 2012; 106:147-153.
179. Stupp R, Hegi ME, Gorlia T, Erridge S, Grujicic D, Steinbach JP, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study. J Clin Oncol 2013; 13:LBA2009.
180. Reardon DA, Neyns B, Weller M, Tonn JC, Nabors LB, Stupp R. Cilengitide: an RGD-pentapeptide avb3 and avb5 inhibitor in development for gliobastoma and other malignancies. Future Oncol 2011; 7:339-354.
181. 18F-AH111585 in breast cancer patients. J Nucl Med 2008; 49:879-886.
182. Keifer JA, Guttridge DC, Ashburner BP, Jr Baldwin AS. Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 2001; 276:22382-22387.
183. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173:699-703.
184. Li X, Liu X, Wang J, Wang Z, Jiang W, Reed E, et al. Thalidomide down-regulates the expression of VEGF and bFGF in cisplatin-resistant human lung carcinoma cells. Anticancer Res 2003; 23:2481-2487.
185. Eleutherakis-Papaiakovou V, Bamias A, Dimopoulos MA. Thalidomide in cancer medicine. Ann Oncol 2004; 15:1151-1160.
186. Besse B, Tsao LC, Chao DT, Fang Y, Soria JC, Almokadem S, et al. Phase Ib safety and pharmacokinetic study of volociximab, an anti-α5β1 integrin antibody, in combination with carboplatin and paclitaxel in advanced non-small-cell lung cancer. Ann Oncol 2013; 24:90-96.
187. Keizer RJ, Funahashi Y, Semba T, Wanders J, Beijnen JH, Schellens JH, et al. Evaluation of α2-integrin expression as a biomarker for tumor growth inhibition for the investigational integrin inhibitor E7820 in preclinical and clinical studies. AAPS J 2011; 13:230-239.
188. Cianfrocca ME, Kimmel KA, Gallo J, Cardoso T, Brown MM, Hudes G, et al. Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours. Br J Cancer 2006; 94:1621-1626.