Targeting angiogenesis in pancreatic cancer: Rationale and pitfalls

Langenbeck's Archives of Surgery

Volumn 393, Issue 6, 2008, Pages 901-910

  Whipple, Chery ^a   Korc, Murray ^a,b  

^a DARTMOUTH MEDICAL SCHOOL   (United States)

^b DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

Author keywords

Angiogenesis; Angiogenesis inhibitors; Invasion; Metastasis; Pancreatic ductal adenocarcinoma (PDAC)

Indexed keywords

1 TERT BUTYL 3 [6 (3,5 DIMETHOXYPHENYL) 2 (4 DIETHYLAMINOBUTYLAMINO)PYRIDO[2,3 D]PYRIMIDIN 7 YL]UREA; 2,4 DIMETHYL 5 (2 OXO 1H INDOL 3 YLMETHYLENE) 3 PYRROLEPROPIONIC ACID; 6 [4 (4 ETHYL 1 PIPERAZINYLMETHYL)PHENYL] 4 (ALPHA METHYLBENZYLAMINO) 7H PYRROLO[2,3 D]PYRIMIDINE; ANGIOGENESIS INHIBITOR; ANGIOPOIETIN; ANTINEOPLASTIC AGENT; AXITINIB; BEVACIZUMAB; CEDIRANIB; CETUXIMAB; CISPLATIN; CYTOKINE; ERLOTINIB; FLUOROURACIL; GEMCITABINE; GENISTEIN; GROWTH FACTOR; IMC 2C6; PROTEOHEPARAN SULFATE; SEMAXANIB; SORAFENIB; SUNITINIB; UNCLASSIFIED DRUG; VANDETANIB; VASCULOTROPIN TRAP; VATALANIB;

ANGIOGENESIS; BREAST CANCER; CANCER SURGERY; CANCER SURVIVAL; CARCINOGENESIS; CLINICAL FEATURE; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DEPRESSION; DIARRHEA; FATIGUE; HUMAN; HYPOXIA; LUNG METASTASIS; METASTASIS; MONOTHERAPY; NAUSEA; NONHUMAN; ONCOGENE SRC; PAIN; PANCREAS ADENOCARCINOMA; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; RASH; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; VOMITING; WEIGHT REDUCTION;

ANGIOGENESIS INHIBITORS; ANTINEOPLASTIC AGENTS; CARCINOMA, PANCREATIC DUCTAL; CELL HYPOXIA; CYTOKINES; DRUG THERAPY, COMBINATION; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; NEOVASCULARIZATION, PATHOLOGIC; PANCREATIC NEOPLASMS; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 53549092538     PISSN: 14352443     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00423-008-0280-z     Document Type: Review

References (113)

1. A Jemal R Siegel E Ward T Murray J Xu C Smigal MJ Thun 2006 Cancer statistics CA Cancer J Clin 56 106 130
2. M Wagner C Redaelli M Lietz CA Seiler H Friess MW Buchler 2004 Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma Br J Surg 91 586 594
3. M Korc 2007 Pancreatic cancer-associated stroma production Am J Surg 194 S84 S86
4. J Kleeff P Beckhove I Esposito S Herzig PE Huber JM Lohr H Friess 2007 Pancreatic cancer microenvironment Int J Cancer 121 699 705
5. N Bardeesy RA DePinho 2002 Pancreatic cancer biology and genetics Nat Rev Cancer 2 897 909
6. AF Hezel AC Kimmelman BZ Stanger N Bardeesy RA Depinho 2006 Genetics and biology of pancreatic ductal adenocarcinoma Genes Dev 20 1218 1249
7. AJ Aguirre N Bardeesy M Sinha L Lopez DA Tuveson J Horner MS Redston RA DePinho 2003 Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma Genes Dev 17 3112 3126
8. SP Thayer MP di Magliano PW Heiser CM Nielsen DJ Roberts GY Lauwers YP Qi S Gysin C Fernandez-del Castillo V Yajnik B Antoniu M McMahon AL Warshaw M Hebrok 2003 Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis Nature 425 851 856
9. DM Berman SS Karhadkar A Maitra R Montes De Oca MR Gerstenblith K Briggs AR Parker Y Shimada JR Eshleman DN Watkins PA Beachy 2003 Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours Nature 425 846 851
10. G Zeng M Germinaro A Micsenyi NK Monga A Bell A Sood V Malhotra N Sood V Midda DK Monga DM Kokkinakis SP Monga 2006 Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma Neoplasia 8 279 289
11. M Pasca di Magliano AV Biankin PW Heiser DA Cano PJ Gutierrez T Deramaudt D Segara AC Dawson JG Kench SM Henshall RL Sutherland A Dlugosz AK Rustgi M Hebrok 2007 Common activation of canonical wnt signaling in pancreatic adenocarcinoma PLoS ONE 2 e1155
12. WG Hu T Liu JX Xiong CY Wang 2007 Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells Acta Pharmacol Sin 28 1224 1230
13. JP Morton ME Mongeau DS Klimstra JP Morris YC Lee Y Kawaguchi CV Wright M Hebrok BC Lewis 2007 Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis Proc Natl Acad Sci U S A 104 5103 5108
14. Z Wang S Banerjee Y Li KM Rahman Y Zhang FH Sarkar 2006 Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells Cancer Res 66 2778 2784
15. Z Wang Y Zhang Y Li S Banerjee J Liao FH Sarkar 2006 Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells Mol Cancer Ther 5 483 493
16. T Welsch J Kleeff H Friess 2007 Molecular pathogenesis of pancreatic cancer: advances and challenges Curr Mol Med 7 504 521
17. MG Bachem M Schunemann M Ramadani 2005 Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells Gastroenterology 128 907 921
18. J Kleeff T Ishiwata A Kumbasar H Friess MW Buchler AD Lander M Korc 1998 The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer J Clin Invest 102 1662 1673
19. M Korc 2003 Pathways for aberrant angiogenesis in pancreatic cancer Mol Cancer 2 8
20. G Garcea TD Lloyd A Gescher AR Dennison WP Steward DP Berry 2004 Angiogenesis of gastrointestinal tumours and their metastases-a target for intervention? Eur J Cancer 40 1302 1313
21. N Reinmuth A Parkh S Ahamad W Liu O Stoeltzing F Fan 2003 Biology of angiogenesis in tumours of the gastrointestinal tract Microsc Res Tech 60 199 207
22. A John G Tuszynski 2001 The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis Pathol Oncol Res 7 14 23
23. S Curran GI Murray 2000 Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis Eur J Cancer 36 1621 1630
24. PK Goon GY Lip CJ Boos PS Stonelake AD Blann 2006 Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer Neoplasia 8 79 88
25. L Jussila K Alitalo 2002 Vascular growth factors and lymphangiogenesis Physiol Rev 82 673 700
26. GJ Caine AD Blann PS Stonelake P Ryan GY Lip 2003 Plasma angiopoietin-1, angiopoietin-2 and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1 Eur J Clin Invest 33 883 890
27. GL Semenza 2007 Hypoxia-inducible factor 1 (HIF-1) pathway Sci Signal Transduct Knowl Environ 2007 407 cm8
28. A Couvelard D O'Toole R Leek H Turley A Sauvanet C Degott P Ruszniewski J Belghiti AL Harris K Gatter F Pezzella 2005 Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas Histopathology 46 668 676
29. KY Detwiller NT Fernando NH Segal SW Ryeom PA D'Amore SS Yoon 2005 Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A Cancer Res 65 5881 5889
30. P Vaupel A Mayer 2007 Hypoxia in cancer: significance and impact on clinical outcome Cancer Metastasis Rev 26 225 239
31. A Couvelard D O'Toole H Turley R Leek A Sauvanet C Degott P Ruszniewski J Belghiti AL Harris K Gatter F Pezzella 2005 Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression Br J Cancer 92 94 101
32. RH Wenger M Grassman 1997 Oxygen and the hypoxia-inducible factor 1 Biol Chem 378 609 616
33. P Buchler HA Reber M Buchler S Shrinkante MW Buchler H Firess 2003 Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in pancreatic cancer Pancreas 26 56 64
34. N Akakura M Kobayashi I Horiuchi A Suzuki GL Wang J Chen 2001 Constitutive expression of hypoxia-inducible factor-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation Cancer Res 61 6548 6554
35. NJ Gaspar L Li AM Kapoun S Medicherla M Reddy G Li G O'Young D Quon M Henson DL Damm GT Muiru A Murphy LS Higgins S Chakravarty DH Wong 2007 Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness Mol Pharmacol 72 152 161
36. Y Takahashi CD Bucana Y Akagi W Liu KR Cleary M Mai 1998 Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer Clin Cancer Res 4 429 434
37. N Boyer Arnold M Korc 2005 Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein J Biol Chem 280 21858 21866
38. P ten Dijke CS Hill 2004 New insights into TGF-beta-Smad signalling Trends Biochem Sci 29 265 273
39. F Ozawa H Friess A Tempia-Caliera J Kleeff MW Buchler 2001 Growth factors and their receptors in pancreatic cancer Teratog Carcinog Mutagen 21 27 44
40. HJ Zhu AW Burgess 2001 Regulation of transforming growth factor-beta signaling Mol Cell Biol Res Commun 4 321 330
41. Z Jia J Zhang D Wei L Wang P Yuan X Le Q Li J Yao K Xie 2007 Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A Cancer Res 67 4878 4885
42. Y Seo H Baba T Fukuda M Takashima K Sugimachi 2000 High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma Cancer Biol Ther 88 2239 2245
43. M Niedergethmann R Hildenbrand B Wostbrock M Hartel JW Sturm A Richter 2002 High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas Pancreas 25 122 129
44. K Xie D Wei S Huang 2006 Transcriptional anti-angiogenesis therapy of human pancreatic cancer Cytokine Growth Factor Rev 17 147 156
45. JE Nor J Christensen DJ Mooney PJ Polverini 1999 Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression Am J Pathol 154 375 384
46. DD Ku JK Zaleski S Liu TA Brock 1993 Vascular endothelial growth factor (VEGF) induces EDRF-dependent relaxation in coronary arteries Am J Pathol 265 H586 H592
47. F Bach FJ Uddin D Burke 2007 Angiopoietins in malignancy Eur J Surg Oncol 33 7 15
48. M Fukasawa M Korc 2004 Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines Clin Cancer Res 10 3327 3332
49. Y Hirokawa A Levitzki G Lessene J Baell C Xiao H Zhu H Maruta 2006 Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors) Cancer Lett 245 1-2 242 251
50. S Gengrinovitch B Berman G David L Witte G Neufeld D Ron 1999 Glypican-1 is a VEGF165 binding proteoglycan that acts as an extracellular chaperone for VEGF165 J Biol Chem 274 10816 10822
51. C Blancher JW Moore N Robertson AL Harris 2001 Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway Cancer Res 61 7349 7355
52. KN Meadows P Bryant K Pumiglia 2001 Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation J Biol Chem 276 49289 49298
53. F Okada JW Rak BS Croix B Lieubeau M Kaya L Roncari S Shirasawa T Sasazuki RS Kerbel 1998 Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells Proc Natl Acad Sci U S A 95 3609 3614
54. D Qiao K Meyer C Mundhenke SA Drew A Friedl 2003 Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 signaling in brain endothelial cells. Specific role for glypican-1 in glioma angiogenesis J Biol Chem 278 16045 16053
55. M Noda T Hattori H Kimura H Naitoh T Kodama K Kashima 1997 Expression of fibroblast growth factor 2 mRNA in early and advanced gastric cancer Acta Oncol 36 695 700
56. T Ueki T Koji S Tamiya PK Nakane M Tsuneyoshi 1995 Expression of basic fibroblast growth factor and fibroblast growth factor receptor in advanced gastric carcinoma J Pathol 177 353 361
57. GV Sperinde MA Nugent 1998 Heparan sulfate proteoglycans control intracellular processing of bFGF in vascular smooth muscle cells Biochemistry 37 13153 13164
58. GV Sperinde MA Nugent 2000 Mechanisms of fibroblast growth factor 2 intracellular processing: a kinetic analysis of the role of heparan sulfate proteoglycans Biochemistry 39 3788 3796
59. S Javerzat P Auguste A Bikfalvi 2002 The role of fibroblast growth factors in vascular development Trends Mol Med 8 483 489
60. LW Feurino Y Zhang U Bharadwaj R Zhang F Li WE Fisher FC Brunicardi C Chen Q Yao M Li 2007 IL-6 Stimulates Th2 Type Cytokine Secretion and Upregulates VEGF and NRP-1 Expression in Pancreatic Cancer Cells Cancer Biol Ther 6 7 1096 1100
61. KE Hedin 2002 Chemokines: new, key players in the pathobiology of pancreatic cancer Int J Gastrointest Cancer 31 23 29
62. MN Wente MP Keane MD Burdick H Friess MW Buchler GO Ceyhan HA Reber RM Strieter OJ Hines 2006 Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis Cancer Lett 241 221 227
63. Q Shi JL Abbruzzese S Huang IJ Fidler Q Xiong K Xie 1999 Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic Clin Cancer Res 5 3711 3721
64. Y kitadai Y Takahashi K Haruma K Naka K Sumii H Yokozaki 1998 Transfection of interlukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cell s in nude mice Br J Cancer 81 647 653
65. K Xie D Wei Q Shi S Huang 2004 Constitutive and inducible expression and regulation of vascular endothelial growth factor Cytokine Growth Factor Rev 15 297 324
66. RL Chen AD Lander 2001 Mechanisms underlying preferential assembly of heparan sulfate on glypican-1 J Biol Chem 276 7507 7517
67. J Kleeff S Wildi A Kumbasar H Friess AD Lander M Korc 1999 Stable transfection of a glypican-1 antisense construct decreases tumorigenicity in PANC-1 pancreatic carcinoma cells Pancreas 19 281 288
68. K Ding M Lopez-Burks JA Sanchez-Duran M Korc AD Lander 2005 Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells J Cell Biol 171 729 738
69. T Aikawa CA Whipple ME Lopez J Gunn A Young AD Lander M Korc 2008 Glypican-1 modulates the angiogenic and metastatic potential of cancer cells J Clin Invest 118 89 99
70. MM Fuster L Wang J Castagnola L Sikora K Reddi PH Lee KA Radek M Schuksz JR Bishop RL Gallo P Sriramarao JD Esko 2007 Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis J Cell Biol 177 539 549
71. S Niedzwiecki T Stepien K Kopec K Kuzdak J Komorowski R Krupinski H Stepien 2006 Angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2) and Tie-2 (a receptor tyrosine kinase) concentrations in peripheral blood of patients with thyroid cancers Cytokine 36 291 295
72. T Asahara D Chen T Takahashi K Fujikawa M Kearney M Magner GD Yancopoulos JM Isner 1998 Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization Circ Res 83 233 240
73. CR Tait PF Jones 2004 Angiopoietins in tumours: the angiogenic switch J Pathol 204 1 10
74. RB Irby TJ Yeatman 2000 Role of Src expression and activation in human cancer Oncogene 19 5636 5642
75. M Maa T Leu DJ McCarley RC Schatzman SJ Parsons 1995 Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers Proc Natl Acad Sci 92 6981 6985
76. JM Summy JG Trevino CH Baker GE Gallick 2005 c-Src regulates constitutive and EGF-mediated VEGF expression in pancreatic tumor cells through activation of phosphatidyl inositol-3 kinase and p38 MAPK Pancreas 31 263 274
77. MV Yezhelyev G Koehl M Guba T Brabletz KW Jauch A Ryan A Barge T Green M Fennell CJ Bruns 2004 Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice Clin Cancer Res 10 8028 8036
78. I Ischenko M Guba M Yezhelyev A Papyan G Schmid T Green M Fennell KW Jauch CJ Bruns 2007 Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer Angiogenesis 10 167 182
79. D Mukhadopathyay L Tsiokas XM Zhou D Foster JS Brugge VP Sukhatme 1995 Hypoxic induction of human vascular endothelial growth factor expression through c-src activation Nature 375 577 581
80. D Coppola 2000 Molecular prognostic markers in pancreatic cancer Cancer Control 7 421 427
81. Y Yang V Macleod M Bendre Y Huang AM Theus HQ Miao P Kussie S Yaccoby J Epstein LJ Suva T Kelly RD Sanderson 2005 Heparanase promotes the spontaneous metastasis of myeloma cells to bone Blood 105 1303 1309
82. S Curran SR Dundas J Buxton MF Leeman R Ramsay GI Murray 2004 Matrix metalloproteinase/tissue inhibitors of matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers Clin Cancer Res 10 8229 8234
83. A Zetser Y Bashenko E Edovitsky F Levy-Adam I Vlodavsky N Ilan 2006 Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation Cancer Res 66 1455 1463
84. A Koliopanos H Friess J Kleeff X Shi Q Liao I Pecker I Vlodavsky A Zimmermann MW Buchler 2001 Heparanase expression in primary and metastatic pancreatic cancer Cancer Res 61 4655 4659
85. SK Das DM Vasudevan 2007 Essential factors associated with hepatic angiogenesis Life Sci 81 1555 1564
86. S Indraccolo E Gola A Rosato S Minuzzo W Habeler V Tisato V Roni G Esposito M Morini A Albini DM Noonan M Ferrantini A Amadori L Chieco-Bianchi 2002 Differential effects of angiostatin, endostatin and interferon-alpha(1) gene transfer on in vivo growth of human breast cancer cells Gene Ther 9 867 878
87. VK Puduvalli R Sawaya 2000 Antiangiogenesis-therapeutic strategies and clinical implications for brain tumors J Neurooncol 50 189 200
88. A Kleespies KW Jauch CJ Bruns 2006 Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer? Drug Resist Updat 9 1 18
89. V Heinemann H Wilke HG Mergenthaler M Clemens H Konig HJ Illiger M Arning A Schalhorn K Possinger U Fink 2000 Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer Ann Oncol 11 1399 1403
90. ST Cha D Talavera E Demir AK Nath MR Sierra-Honigmann 2005 A method of isolation and culture of microvascular endothelial cells from mouse skin Microvasc Res 70 198 204
91. TA Fong LK Shawver L Sun C Tang H App TJ Powell YH Kim R Schreck X Wang W Risau A Ullrich KP Hirth G McMahon 1999 SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types Cancer Res 59 99 106
92. J Glade-Bender JJ Kandel DJ Yamashiro 2003 VEGF blocking therapy in the treatment of cancer Expert Opin Biol Ther 3 263 276
93. DW Davis R Takamori CP Raut HQ Xiong RS Herbst WM Stadler JV Heymach GD Demetri A Rashid Y Shen S Wen JL Abbruzzese DJ McConkey 2005 Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668 Clin Cancer Res 11 678 689
94. P Buchler HA Reber MW Buchler H Friess OJ Hines 2002 VEGF-RII influences the prognosis of pancreatic cancer Ann Surg 236 738 49 discussion 749
95. P Buchler HA Reber MM Roth M Shiroishi H Friess OJ Hines 2007 Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer Neoplasia 9 119 127
96. J Harding B Burtness 2005 Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody Drugs Today (Barc) 41 107 127
97. E Cabebe GA Fisher 2007 Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer Expert Opin Investig Drugs 16 467 476
98. MJ Moore D Goldstein J Hamm A Figer JR Hecht S Gallinger HJ Au P Murawa D Walde RA Wolff D Campos R Lim K Ding G Clark T Voskoglou-Nomikos M Ptasynski W Parulekar 2007 Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 25 1960 1966
99. WW Ma M Hidalgo 2007 Exploiting novel molecular targets in gastrointestinal cancers World J Gastroenterol 13 5845 5856
100. BF El-Rayes S Ali IF Ali PA Philip J Abbruzzese FH Sarkar 2006 Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB Cancer Res 66 10553 10559
101. P Buchler HA Reber MW Buchler H Friess RS Lavey OJ Hines 2004 Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression Cancer 100 201 210
102. Y Li F Ahmed S Ali PA Philip O Kucuk FH Sarkar 2005 Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells Cancer Res 65 6934 6942
103. S Banerjee Y Zhang S Ali M Bhuiyan Z Wang PJ Chiao PA Philip J Abbruzzese FH Sarkar 2005 Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer Cancer Res 65 9064 9072
104. MS Sakla NS Shenouda PJ Ansell RS Macdonald DB Lubahn 2007 Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells Endocrine 32 69 78
105. AJ Singh RD Meyer G Navruzbekov R Shelke L Duan H Band SE Leeman N Rahimi 2007 A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCgamma1 activation and angiogenesis Proc Natl Acad Sci U S A 104 5413 5418
106. P Carmeliet 2005 Angiogenesis in life, disease and medicine Nature 438 932 936
107. F Shojaei N Ferrara 2007 Antiangiogenic therapy for cancer: an update Cancer J 13 345 348
108. H Kurahara S Takao K Maemura H Shinchi S Natsugoe T Aikou 2004 Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: its relationship to lymph node metastasis Clin Cancer Res 10 8413 8420
109. RF Tang J Itakura T Aikawa K Matsuda H Fujii M Korc Y Matsumoto 2001 Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer Pancreas 22 285 292
110. RF Tang SX Wang L Peng M Zhang ZF Li ZM Zhang Y Xiao FR Zhang 2006 Expression of vascular endothelial growth factors A and C in human pancreatic cancer World J Gastroenterol 12 280 286
111. K Fukahi M Fukasawa G Neufeld J Itakura M Korc 2004 Aberrant expression of neuropilin-1 and -2 in human pancreatic cancer cells Clin Cancer Res 10 581 590
112. T Cohen Y Herzog A Brodzky JK Greenson S Eldar Z Gluzman-Poltorak G Neufeld MB Resnick 2002 Neuropilin-2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours J Pathol 198 77 82
113. A Couvelard J Hu G Steers D O'Toole A Sauvanet J Belghiti P Bedossa K Gatter P Ruszniewski F Pezzella 2006 Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors Gastroenterology 131 1597 1610