Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer

BMC Cancer

Volumn 13, Issue , 2013, Pages

  Khong, Tak L ^a   Thairu, Ngayu ^a   Larsen, Helene ^a,b   Dawson, Peter M ^a   Kiriakidis, Serafim ^a,b   Paleolog, Ewa M ^a,b  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Angiogenesis; Colorectal cancer; EGF; Hypoxia

Indexed keywords

BETA3 INTEGRIN; DIMETHYLOXALLYLGLYCINE; EOTAXIN; EPIDERMAL GROWTH FACTOR; EPIDERMAL GROWTH FACTOR RECEPTOR; GLYCINE DERIVATIVE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; INTERLEUKIN 8; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; TRANSFORMING GROWTH FACTOR ALPHA; TRANSFORMING GROWTH FACTOR BETA1; TYROSINE; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN RECEPTOR;

ANGIOGENIC GENE; ANGIOPOIETIN LIKE 4 GENE; ARTICLE; AUTOPHOSPHORYLATION; CANCER CELL; CELL HYPOXIA; CELL STRAIN; CELL STRAIN CACO 2; COLLAGEN TYPE IV ALPHA3 GENE; COLORECTAL CANCER; CONTROLLED STUDY; ENZYME ACTIVATION; EOTAXIN 1 GENE; EPHRIN 3 GENE; GENE; GENE CONTROL; GENE EXPRESSION REGULATION; GENE IDENTIFICATION; HUMAN; HUMAN CELL; INTEGRIN BETA3 CHAIN GENE; INTERLEUKIN 8 GENE; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR ALPHA GENE; TRANSFORMING GROWTH FACTOR BETA1 GENE; UPREGULATION; VASCULAR ENDOTHELIAL GROWTH FACTOR GENE; VEGF RECEPTOR GENE;

ANOXIA; CELL HYPOXIA; CELL LINE, TUMOR; COLORECTAL NEOPLASMS; EPIDERMAL GROWTH FACTOR; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; NEOVASCULARIZATION, PATHOLOGIC; RECEPTOR, EPIDERMAL GROWTH FACTOR; TRANSCRIPTOME;

EID: 84886736125     PISSN: None     EISSN: 14712407     Source Type: Journal    
DOI: 10.1186/1471-2407-13-518     Document Type: Article

References (91)

1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005, 55:74-108. 10.3322/canjclin.55.2.74, 15761078.
2. Khong TL, Larsen H, Raatz Y, Paleolog E. Angiogenesis as a therapeutic target in arthritis: learning the lessons of the colorectal cancer experience. Angiogenesis 2007, 10:243-258. 10.1007/s10456-007-9081-1, 17805984.
3. Thairu N, Kiriakidis S, Dawson P, Paleolog E. Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience. Angiogenesis 2011, Epub ahead of print.
4. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, Wykoff CC, Maher ER, Harris AL, Ratcliffe PJ, Maxwell PH. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 2002, 1:459-468. 10.1016/S1535-6108(02)00071-5, 12124175.
5. Goethals L, Debucquoy A, Perneel C, Geboes K, Ectors N, De Schutter H, Penninckx F, McBride WH, Begg AC, Haustermans KM. Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers. Int J Radiat Oncol Biol Phys 2006, 65:246-254. 10.1016/j.ijrobp.2006.01.007, 16618579.
6. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 2002, 64:993-998. 10.1016/S0006-2952(02)01168-1, 12213597.
7. Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med 2004, 36:1-12. 10.1038/emm.2004.1, 15031665.
8. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001, 107:43-54. 10.1016/S0092-8674(01)00507-4, 11595184.
9. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA 2002, 99:13459-13464. 10.1073/pnas.192342099, 129695, 12351678.
10. Bracken CP, Fedele AO, Linke S, Balrak W, Lisy K, Whitelaw ML, Peet DJ. Cell-specific regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment. J Biol Chem 2006, 281:22575-22585. 10.1074/jbc.M600288200, 16760477.
11. Giles RH, Lolkema MP, Snijckers CM, Belderbos M, van der Groep P, Mans DA, van Beest M, van Noort M, Goldschmeding R, van Diest PJ, et al. Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis. Oncogene 2006, 25:3065-3070. 10.1038/sj.onc.1209330, 16407833.
12. Simiantonaki N, Taxeidis M, Jayasinghe C, Kurzik-Dumke U, Kirkpatrick CJ. Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression. BMC Cancer 2008, 8:320. 10.1186/1471-2407-8-320, 2584660, 18983642.
13. Kuwai T, Kitadai Y, Tanaka S, Onogawa S, Matsutani N, Kaio E, Ito M, Chayama K. Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. Int J Cancer 2003, 105:176-181. 10.1002/ijc.11068, 12673675.
14. Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC. Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res 2004, 64:1765-1772. 10.1158/0008-5472.CAN-03-3017, 14996738.
15. Rasheed S, Harris AL, Tekkis PP, Turley H, Silver A, McDonald PJ, Talbot IC, Glynne-Jones R, Northover JM, Guenther T. Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis. Br J Cancer 2009, 100:1666-1673. 10.1038/sj.bjc.6605026, 2696753, 19436307.
16. Imamura T, Kikuchi H, Herraiz MT, Park DY, Mizukami Y, Mino-Kenduson M, Lynch MP, Rueda BR, Benita Y, Xavier RJ, Chung DC. HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J Cancer 2009, 124:763-771. 10.1002/ijc.24032, 2682346, 19030186.
17. Yoshimura H, Dhar DK, Kohno H, Kubota H, Fujii T, Ueda S, Kinugasa S, Tachibana M, Nagasue N. Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin Cancer Res 2004, 10:8554-8560. 10.1158/1078-0432.CCR-0946-03, 15623639.
18. Cleven AH, van Engeland M, Wouters BG, de Bruine AP. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol 2007, 29:229-240.
19. Lockhart AC, Berlin JD. The epidermal growth factor receptor as a target for colorectal cancer therapy. Semin Oncol 2005, 32:52-60. 10.1053/j.seminoncol.2004.09.036, 15726506.
20. Akagi M, Kawaguchi M, Liu W, McCarty MF, Takeda A, Fan F, Stoeltzing O, Parikh AA, Jung YD, Bucana CD, et al. Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer 2003, 88:796-802. 10.1038/sj.bjc.6600811, 2376351, 12618892.
21. Okamura K, Morimoto A, Hamanaka R, Ono M, Kohno K, Uchida Y, Kuwano M. A model system for tumor angiogenesis: involvement of transforming growth factor-alpha in tube formation of human microvascular endothelial cells induced by esophageal cancer cells. Biochem Biophys Res Commun 1992, 186:1471-1479. 10.1016/S0006-291X(05)81572-4, 1380804.
22. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 1993, 4:121-133. 10.1091/mbc.4.1.121, 300905, 7680247.
23. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, Radinsky R, Dinney CP. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 1999, 5:257-265.
24. Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997, 151:1523-1530. 1858348, 9403702.
25. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Bianco AR, Tortora G. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001, 7:1459-1465.
26. Francoual M, Etienne-Grimaldi MC, Formento JL, Benchimol D, Bourgeon A, Chazal M, Letoublon C, Andre T, Gilly N, Delpero JR, et al. EGFR in colorectal cancer: more than a simple receptor. Ann Oncol 2006, 17:962-967. 10.1093/annonc/mdl037, 16524971.
27. Johnston JB, Navaratnam S, Pitz MW, Maniate JM, Wiechec E, Baust H, Gingerich J, Skliris GP, Murphy LC, Los M. Targeting the EGFR pathway for cancer therapy. Curr Med Chem 2006, 13:3483-3492. 10.2174/092986706779026174, 17168718.
28. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007, 25:1658-1664. 10.1200/JCO.2006.08.1620, 17470858.
29. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999, 274:32631-32637. 10.1074/jbc.274.46.32631, 10551817.
30. Shafee N, Kaluz S, Ru N, Stanbridge EJ. PI3K/Akt activity has variable cell-specific effects on expression of HIF target genes, CA9 and VEGF, in human cancer cell lines. Cancer Lett 2009, 282:109-115. 10.1016/j.canlet.2009.03.004, 2706285, 19342157.
31. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001, 21:3995-4004. 10.1128/MCB.21.12.3995-4004.2001, 87062, 11359907.
32. Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 2006, 281:25903-25914. 10.1074/jbc.M603414200, 3132567, 16847054.
33. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000, 60:1541-1545.
34. Denekamp J. Vascular attack as a therapeutic strategy for cancer. Cancer Metastasis Rev 1990, 9:267-282. 10.1007/BF00046365, 2292139.
35. Keese M, Magdeburg RJ, Herzog T, Hasenberg T, Offterdinger M, Pepperkok R, Sturm JW, Bastiaens PI. Imaging epidermal growth factor receptor phosphorylation in human colorectal cancer cells and human tissues. J Biol Chem 2005, 280:27826-27831. 10.1074/jbc.M504485200, 15908435.
36. Fogh J, Fogh JM, Orfeo T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst 1977, 59:221-226.
37. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25:402-408. 10.1006/meth.2001.1262, 11846609.
38. Muz B, Larsen H, Madden L, Kiriakidis S, Paleolog EM. Prolyl hydroxylase domain enzyme 2 is the major player in regulating hypoxic responses in rheumatoid arthritis. Arthritis Rheum 2012, 64:2856-2867. 10.1002/art.34479, 22488178.
39. Larsen H, Muz B, Khong TL, Feldmann M, Paleolog EM. Differential effects of Th1 versus Th2 cytokines in combination with hypoxia on HIFs and angiogenesis in RA. Arthritis Res Ther 2012, 14:R180. 10.1186/ar3934, 3580575, 22866899.
40. Buzzi N, Colicheo A, Boland R, de Boland AR. MAP kinases in proliferating human colon cancer Caco-2 cells. Mol Cell Biochem 2009, 328:201-208. 10.1007/s11010-009-0090-9, 19301097.
41. Laprise P, Chailler P, Houde M, Beaulieu JF, Boucher MJ, Rivard N. Phosphatidylinositol 3-kinase controls human intestinal epithelial cell differentiation by promoting adherens junction assembly and p38 MAPK activation. J Biol Chem 2002, 277:8226-8234. 10.1074/jbc.M110235200, 11756422.
42. CRUK (Cancer Research UK) Cancer Stats: Colorectal Cancer 2006, CRUK.
43. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182-1186. 10.1056/NEJM197111182852108, 4938153.
44. Caro I, Boulenc X, Rousset M, Meunier V, Bourrié M, Julian B, Joyeux H, Roques C, Berger Y, Zweibaum A, Fabre G. Characterisation of a newly isolated Caco-2 clone (TC-7), as a model of transport processes and biotransformation of drugs. Int J Pharm 1995, 116:147-158.
45. Bockmann S, Nebe B. The in vitro effects of H-89, a specific inhibitor of protein kinase A, in the human colonic carcinoma cell line Caco-2. Eur J Cancer Prev 2003, 12:469-478. 10.1097/00008469-200312000-00005, 14639124.
46. Wang S, Basson MD. Identification of functional domains in AKT responsible for distinct roles of AKT isoforms in pressure-stimulated cancer cell adhesion. Exp Cell Res 2008, 314:286-296. 10.1016/j.yexcr.2007.08.005, 2180395, 17825284.
47. Liu Y, Bodmer WF. Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. Proc Natl Acad Sci USA 2006, 103:976-981. 10.1073/pnas.0510146103, 1327731, 16418264.
48. Brink M, de Goeij AF, Weijenberg MP, Roemen GM, Lentjes MH, Pachen MM, Smits KM, de Bruine AP, Goldbohm RA, van den Brandt PA. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis 2003, 24:703-710. 10.1093/carcin/bgg009, 12727799.
49. Kikuchi H, Pino MS, Zeng M, Shirasawa S, Chung DC. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer. Cancer Res 2009, 69:8499-8506. 10.1158/0008-5472.CAN-09-2213, 2811371, 19843849.
50. Baba Y, Huttenhower C, Nosho K, Tanaka N, Shima K, Hazra A, Schernhammer ES, Hunter DJ, Giovannucci EL, Fuchs CS, Ogino S. Epigenomic diversity of colorectal cancer indicated by LINE-1 methylation in a database of 869 tumors. Mol Cancer 2010, 9:125. 10.1186/1476-4598-9-125, 2892454, 20507599.
51. Damstrup L, Kuwada SK, Dempsey PJ, Brown CL, Hawkey CJ, Poulsen HS, Wiley HS, Coffey RJ. Amphiregulin acts as an autocrine growth factor in two human polarizing colon cancer lines that exhibit domain selective EGF receptor mitogenesis. Br J Cancer 1999, 80:1012-1019. 10.1038/sj.bjc.6690456, 2363033, 10362109.
52. Yonezawa M, Wada K, Tatsuguchi A, Akamatsu T, Gudis K, Seo T, Mitsui K, Nagata K, Tanaka S, Fujimori S, Sakamoto C. Heregulin-induced VEGF expression via the ErbB3 signaling pathway in colon cancer. Digestion 2009, 80:215-225. 10.1159/000229775, 19797898.
53. Gentile LB, Piva B, Diaz BL. Hypertonic stress induces VEGF production in human colon cancer cell line Caco-2: inhibitory role of autocrine PGE(2). PLoS One 2011, 6:e25193. 10.1371/journal.pone.0025193, 3182186, 21980393.
54. Bu XD, Li N, Tian XQ, Huang PL. Caco-2 and LS174T cell lines provide different models for studying mucin expression in colon cancer. Tissue Cell 2011, 43:201-206. 10.1016/j.tice.2011.03.002, 21470648.
55. Dhawan P, Ahmad R, Chaturvedi R, Smith JJ, Midha R, Mittal MK, Krishnan M, Chen X, Eschrich S, Yeatman TJ, et al. Claudin-2 expression increases tumorigenicity of colon cancer cells: role of epidermal growth factor receptor activation. Oncogene 2011, 30:3234-3247. 10.1038/onc.2011.43, 3591522, 21383692.
56. de Bruine AP, de Vries JE, Dinjens WN, Moerkerk PT, van der Linden EP, Pijls MM, ten Kate J, Bosman FT. Human Caco-2 cells transfected with c-Ha-Ras as a model for endocrine differentiation in the large intestine. Differentiation 1993, 53:51-60. 10.1111/j.1432-0436.1993.tb00645.x, 8508948.
57. Zgouras D, Wachtershauser A, Frings D, Stein J. Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1alpha nuclear translocation. Biochem Biophys Res Commun 2003, 300:832-838. 10.1016/S0006-291X(02)02916-9, 12559948.
58. Matsuo Y, Sawai H, Ma J, Xu D, Ochi N, Yasuda A, Takahashi H, Funahashi H, Takeyama H. IL-1alpha secreted by colon cancer cells enhances angiogenesis: the relationship between IL-1alpha release and tumor cells' potential for liver metastasis. J Surg Oncol 2009, 99:361-367. 10.1002/jso.21245, 19204921.
59. Franovic A, Holterman CE, Payette J, Lee S. Human cancers converge at the HIF-2alpha oncogenic axis. Proc Natl Acad Sci USA 2009, 106:21306-21311. 10.1073/pnas.0906432106, 2795516, 19955413.
60. Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 2000, 275:26765-26771.
61. Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 2006, 66:3197-3204. 10.1158/0008-5472.CAN-05-3090, 16540671.
62. Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 2003, 278:14013-14019. 10.1074/jbc.M209702200, 12588875.
63. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001, 15:2675-2686. 10.1101/gad.924501, 312814, 11641274.
64. Katoh Y, Katoh M. Comparative integromics on Angiopoietin family members. Int J Mol Med 2006, 17:1145-1149.
65. Galaup A, Cazes A, Le Jan S, Philippe J, Connault E, Le Coz E, Mekid H, Mir LM, Opolon P, Corvol P, et al. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci USA 2006, 103:18721-18726. 10.1073/pnas.0609025103, 1693729, 17130448.
66. Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P, Germain S. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 2003, 162:1521-1528. 10.1016/S0002-9440(10)64285-X, 1851201, 12707035.
67. Oike Y, Ito Y, Maekawa H, Morisada T, Kubota Y, Akao M, Urano T, Yasunaga K, Suda T. Angiopoietin-related growth factor (AGF) promotes angiogenesis. Blood 2004, 103:3760-3765. 10.1182/blood-2003-04-1272, 14764539.
68. Nakayama T, Hirakawa H, Shibata K, Nazneen A, Abe K, Nagayasu T, Taguchi T. Expression of angiopoietin-like 4 (ANGPTL4) in human colorectal cancer: ANGPTL4 promotes venous invasion and distant metastasis. Oncol Rep 2011, 25:929-935.
69. Merlos-Suarez A, Batlle E. Eph-ephrin signalling in adult tissues and cancer. Curr Opin Cell Biol 2008, 20:194-200. 10.1016/j.ceb.2008.01.011, 18353626.
70. Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 2004, 15:419-433. 10.1016/j.cytogfr.2004.09.002, 15561600.
71. Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, Thorpe PE, Muraoka RS, Cerretti DP, Pozzi A, Jackson D, et al. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 2002, 21:7011-7026. 10.1038/sj.onc.1205679, 12370823.
72. Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, Dietmaier W, Landthaler M, Vogt T. Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem 2004, 50:490-499. 10.1373/clinchem.2003.026849, 14726470.
73. Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M, Malats N, Sancho E, Boon E, Pawson T, et al. EphB receptor activity suppresses colorectal cancer progression. Nature 2005, 435:1126-1130. 10.1038/nature03626, 15973414.
74. Javelaud D, Mauviel A. Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles. Int J Biochem Cell Biol 2004, 36:1161-1165. 10.1016/S1357-2725(03)00255-3, 15109563.
75. Robson H, Anderson E, James RD, Schofield PF. Transforming growth factor beta 1 expression in human colorectal tumours: an independent prognostic marker in a subgroup of poor prognosis patients. Br J Cancer 1996, 74:753-758. 10.1038/bjc.1996.432, 2074698, 8795578.
76. Gulubova M, Manolova I, Ananiev J, Julianov A, Yovchev Y, Peeva K. Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer. Int J Colorectal Dis 2010, 25:591-599. 10.1007/s00384-010-0906-9, 20165854.
77. Berger AP, Kofler K, Bektic J, Rogatsch H, Steiner H, Bartsch G, Klocker H. Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate 2003, 57:57-65. 10.1002/pros.10279, 12886524.
78. Xiong B, Gong LL, Zhang F, Hu MB, Yuan HY. TGF beta1 expression and angiogenesis in colorectal cancer tissue. World J Gastroenterol 2002, 8:496-498.
79. Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 2006, 12:7242-7251. 10.1158/1078-0432.CCR-06-0646, 17189395.
80. Fujimoto K, Sheng H, Shao J, Beauchamp RD. Transforming growth factor-beta1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells. Exp Cell Res 2001, 266:239-249. 10.1006/excr.2000.5229, 11399052.
81. Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000, 19:2474-2488. 10.1038/sj.onc.1203527, 10851046.
82. Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 2001, 98:10983-10985. 10.1073/pnas.211430998, 58668, 11572954.
83. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 2001, 3:245-252. 10.1038/35060032, 11231573.
84. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1999, 68:965-1014. 10.1146/annurev.biochem.68.1.965, 10872470.
85. Thant AA, Nawa A, Kikkawa F, Ichigotani Y, Zhang Y, Sein TT, Amin AR, Hamaguchi M. Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. Clin Exp Metastasis 2000, 18:423-428. 10.1023/A:1010921730952, 11467775.
86. Engebraaten O, Bjerkvig R, Pedersen PH, Laerum OD. Effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain-tumour biopsies in vitro. Int J Cancer 1993, 53:209-214. 10.1002/ijc.2910530206, 8381111.
87. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Kohne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012, 48:1466-1475. 10.1016/j.ejca.2012.02.057, 22446022.
88. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009, 360:1408-1417. 10.1056/NEJMoa0805019, 19339720.
89. Thairu N, Kiriakidis S, Dawson P, Paleolog E. HIF-Isoforms have divergent roles in the angiogenesis of colorectal cancer. Colorectal Dis 2011, 13:20 (P034).
90. Thairu N, Kiriakidis S, Dawson P, Paleolog E. Short-term cultures of tumour-derived colorectal cancer cells - a novel in vitro model for the evaluation of angiogenesis in colorectal cancer. Br J Surg 2012, 99:7 (abstract O637).
91. Thairu N, Kiriakidis S, Dawson P, Paleolog E. Short-term cultures of tumour-derived colorectal cancer cells - a novel in vitro model for the evaluation of angiogenesis in colorectal cancer. Colorectal Dis 2012, 14:16 (P027).