L. Gossage and T. Eisen, Targeting Multiple Kinase Pathways: A Change In Paradigm, Clinical Cancer Research, vol.16, issue.7, pp.1973-1981, 2010.
DOI : 10.1158/1078-0432.CCR-09-3182

A. Larsen, D. Ouaret, E. Ouadrani, K. Petitprez, and A. , Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis, Pharmacology & Therapeutics, vol.131, issue.1, pp.80-90, 2011.
DOI : 10.1016/j.pharmthera.2011.03.012

E. Buck, A. Eyzaguirre, J. Haley, N. Gibson, P. Cagnoni et al., Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity, Molecular Cancer Therapeutics, vol.5, issue.8, pp.2051-2060, 2006.
DOI : 10.1158/1535-7163.MCT-06-0007

D. Amin, K. Hida, D. Bielenberg, and M. Klagsbrun, Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to
DOI : 10.1158/0008-5472.can-05-3387

K. Minakata, F. Takahashi, N. T. Hashimoto, M. Tajima, K. Murakami et al., Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors, Cancer Science, vol.20, issue.11, pp.1946-54, 2012.
DOI : 10.1111/j.1349-7006.2012.02408.x

O. Reilly, S. Leonard, M. Kieran, N. Comerford, K. Cummins et al., Hypoxia induces epithelial amphiregulin gene expression in a CREB-dependent manner, AJP: Cell Physiology, vol.290, issue.2, pp.592-600, 2006.
DOI : 10.1152/ajpcell.00278.2005

M. Bordoli, D. Stiehl, L. Borsig, G. Kristiansen, S. Hausladen et al., Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis, Oncogene, vol.59, issue.5, pp.548-60, 2011.
DOI : 10.1016/j.ccr.2009.09.029

N. Panupinthu, S. Yu, D. Zhang, F. Zhang, M. Gagea et al., Selfreinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer, Oncogene, 2013.

C. Allegra, J. Jessup, M. Somerfield, S. Hamilton, E. Hammond et al., Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti???Epidermal Growth Factor Receptor Monoclonal Antibody Therapy, Journal of Clinical Oncology, vol.27, issue.12
DOI : 10.1200/JCO.2009.21.9170

M. Span, P. Moerkerk, D. Goeij, A. Arends, and J. , A detailed analysis of K-ras point mutations in relation to tumor progression and survival in colorectal cancer patients, International Journal of Cancer, vol.75, issue.3, pp.241-246, 1996.
DOI : 10.1002/(SICI)1097-0215(19960621)69:3<241::AID-IJC15>3.0.CO;2-A

T. Winder, A. Mündlein, S. Rhomberg, K. Dirschmid, B. Hartmann et al., Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer, Oncology Reports, vol.21, issue.5
DOI : 10.3892/or_00000352

G. Pentheroudakis, V. Kotoula, D. Roock, W. Kouvatseas, G. Papakostas et al., Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction BIBLIOGRAPHIE 1 Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value, PLoS Med, issue.5, pp.10-1001453, 2013.

E. Sancho, E. Batlle, and H. Clevers, SIGNALING PATHWAYS IN INTESTINAL DEVELOPMENT AND CANCER, Annual Review of Cell and Developmental Biology, vol.20, issue.1, pp.695-723, 2004.
DOI : 10.1146/annurev.cellbio.20.010403.092805

W. Willett, The search for the causes of breast and colon cancer, Nature, vol.338, issue.6214, pp.338-389, 1989.
DOI : 10.1038/338389a0

M. Zavoral, Colorectal cancer screening: 20 years of development and recent progress, World Journal of Gastroenterology, vol.20, issue.14, pp.3825-3834, 2014.
DOI : 10.3748/wjg.v20.i14.3825

P. Hewitson, Screening for colorectal cancer using the faecal occult blood test, Hemoccult, Hemoccult. Cochrane Database Syst Rev, vol.329, issue.6, p.1216, 2007.
DOI : 10.1002/14651858.CD001216.pub2

W. S. Atkin, Improving colorectal cancer screening outcomes: Proceedings of the second meeting of the International Colorectal Cancer Screening Network, a global quality initiative, Journal of Medical Screening, vol.319, issue.3, pp.152-159, 2010.
DOI : 10.1258/jms.2010.010002

G. H. Barrows, Immunochemical Detection of Human Blood in Feces, American Journal of Clinical Pathology, vol.69, issue.3, pp.342-348, 1978.
DOI : 10.1093/ajcp/69.1.342

L. W. Day, T. Bhuket, and J. Allison, FIT Testing: An Overview, Current Gastroenterology Reports, vol.366, issue.Suppl, pp.15-357, 2013.
DOI : 10.1007/s11894-013-0357-x

J. Weitz, Colorectal cancer, The Lancet, vol.365, issue.9454, pp.365-153, 1991.
DOI : 10.1016/S0140-6736(05)17706-X

L. A. Aaltonen, Clues to the pathogenesis of familial colorectal cancer, Science, vol.260, issue.5109, pp.812-818, 1993.
DOI : 10.1126/science.8484121

M. Strand, Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair, Nature, vol.365, issue.6443, pp.365-274, 1993.
DOI : 10.1038/365274a0

J. Groden, Identification and characterization of the familial adenomatous polyposis coli gene, Cell, vol.66, issue.3, pp.589-600, 1991.
DOI : 10.1016/0092-8674(81)90021-0

N. Cancer-genome-atlas, Comprehensive molecular characterization of human colon and rectal cancer, Nature, issue.7407, pp.487-330, 2012.

F. A. Sinicrope, Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients, Gastroenterology, vol.131, issue.3, pp.729-766, 2006.
DOI : 10.1053/j.gastro.2006.06.005

M. F. Kane, Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines, Cancer Res, vol.57, issue.5, pp.808-819, 1997.

E. R. Fearon and B. Vogelstein, A genetic model for colorectal tumorigenesis, Cell, vol.61, issue.5, pp.61-759, 1990.
DOI : 10.1016/0092-8674(90)90186-I

V. Korinek, Constitutive Transcriptional Activation by a beta -Catenin-Tcf Complex in APC-/- Colon Carcinoma, Science, vol.275, issue.5307, pp.275-5307, 1997.
DOI : 10.1126/science.275.5307.1784

B. Vogelstein, Genetic Alterations during Colorectal-Tumor Development, New England Journal of Medicine, vol.319, issue.9, pp.525-557, 1988.
DOI : 10.1056/NEJM198809013190901

M. Malumbres and M. Barbacid, RAS oncogenes: The first 30 years, Nature Reviews Cancer, vol.245, issue.9, pp.459-65, 2003.
DOI : 10.1038/nrc1193

G. A. Repasky, E. J. Chenette, and C. J. Der, Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?, Trends in Cell Biology, vol.14, issue.11, pp.14-639, 2004.
DOI : 10.1016/j.tcb.2004.09.014

H. Ji, Mutations in BRAF and KRAS converge on activation of the mitogenactivated protein kinase pathway in lung cancer mouse models, Cancer Res, issue.10, pp.67-4933, 2007.

A. Bernet and P. Mehlen, Dependence receptors: when apoptosis controls tumor progression, Bull Cancer, vol.94, issue.4, pp.12-19, 2007.

D. P. Lane, Cancer. p53, guardian of the genome, Nature, issue.6381, pp.358-373, 1992.
URL : https://hal.archives-ouvertes.fr/hal-00868358

N. H. Chehab, Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage, Proceedings of the National Academy of Sciences, vol.96, issue.24, pp.96-13777, 1999.
DOI : 10.1073/pnas.96.24.13777

C. Kandoth, Mutational landscape and significance across 12 major cancer types, Nature, vol.339, issue.7471, pp.333-342, 2013.
DOI : 10.1038/nature12634

C. H. Heldin, K. Miyazono, and P. Ten-dijke, TGF-beta signalling from cell membrane to nucleus through SMAD proteins, Nature, issue.6659, pp.390-465, 1997.

R. Kalluri and E. G. Neilson, Epithelial-mesenchymal transition and its implications for fibrosis, Journal of Clinical Investigation, vol.112, issue.12, pp.1776-84, 2003.
DOI : 10.1172/JCI200320530

A. Puisieux, T. Brabletz, and J. Caramel, Oncogenic roles of EMT-inducing transcription factors, Nature Cell Biology, vol.11, issue.6, pp.488-94, 2014.
DOI : 10.1126/science.1164853

M. Jechlinger, S. Grunert, and H. Beug, Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling, Journal of Mammary Gland Biology and Neoplasia, vol.7, issue.4, pp.415-447, 2002.
DOI : 10.1023/A:1024090116451

T. Kokudo, Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells, J Cell Sci, issue.121, pp.3317-3341, 2008.

D. Medici, E. D. Hay, and B. R. Olsen, Snail and Slug promote epithelialmesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3, Mol Biol Cell, issue.11, pp.19-4875, 2008.

K. Niessen, Slug is a direct Notch target required for initiation of cardiac cushion cellularization, The Journal of Cell Biology, vol.122, issue.2, pp.315-340, 2008.
DOI : 10.1038/sj.emboj.7600069

H. Peinado, D. Olmeda, and A. Cano, Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer, pp.415-443, 2007.

J. P. Thiery, Epithelial???mesenchymal transitions in tumour progression, Nature Reviews Cancer, vol.59, issue.6, pp.442-54, 2002.
DOI : 10.1038/nrc822

S. H. Lim, Circulating tumour cells and the epithelial mesenchymal transition in colorectal cancer, Journal of Clinical Pathology, vol.138, issue.(Suppl 3), 2014.
DOI : 10.1136/jclinpath-2014-202499

A. Bhangu, Epithelial mesenchymal transition in colorectal cancer: Seminal role in promoting disease progression and resistance to neoadjuvant therapy, Surgical Oncology, vol.21, issue.4, pp.316-339, 2012.
DOI : 10.1016/j.suronc.2012.08.003

A. Loboda, EMT is the dominant program in human colon cancer, BMC Medical Genomics, vol.116, issue.3, p.9, 2011.
DOI : 10.1002/cncr.24760

H. Hugo, Epithelial???mesenchymal and mesenchymal???epithelial transitions in carcinoma progression, Journal of Cellular Physiology, vol.61, issue.2, pp.374-83, 2007.
DOI : 10.1002/jcp.21223

L. M. Coussens and Z. Werb, Inflammation and cancer, Nature, vol.2, issue.6917, pp.420-860, 2002.
DOI : 10.1006/cyto.1996.0074

S. Demaria, Cancer and Inflammation: Promise for Biologic Therapy, Journal of Immunotherapy, vol.33, issue.4, pp.335-51, 2010.
DOI : 10.1097/CJI.0b013e3181d32e74

D. P. Sarma, The Dukes classification of colorectal cancer): p. 1447. 43. Sobin, L.H. and I.D. Fleming, TNM Classification of Malignant Tumors, Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer, pp.256-80, 1986.

M. K. Connolly, Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor, Journal of Leukocyte Biology, vol.87, issue.4, pp.713-738, 2010.
DOI : 10.1189/jlb.0909607

R. Radinsky and I. J. Fidler, Regulation of tumor cell growth at organ-specific metastases, In Vivo, vol.6, issue.4, pp.325-356, 1992.

R. J. Rutman, A. Cantarow, and K. E. Paschkis, Studies in 2-acetylaminofluorene carcinogenesis. III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma, Cancer Res, vol.14, issue.2, pp.119-142, 1954.

C. Heidelberger, The comparative utilization of uracil-2-C14 by liver, intestinal mucosa, and Flexner-Jobling carcinoma in the rat, Cancer Res, vol.17, issue.5, pp.399-404, 1957.

J. Cassidy, XELOX (Capecitabine Plus Oxaliplatin): Active First-Line Therapy for Patients With Metastatic Colorectal Cancer, Journal of Clinical Oncology, vol.22, issue.11, pp.22-2084, 2004.
DOI : 10.1200/JCO.2004.11.069

R. Matuo, 5-Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line, Journal of Applied Toxicology, vol.2, issue.4, pp.308-324, 2009.
DOI : 10.1002/jat.1411

D. B. Longley, D. P. Harkin, and P. G. Johnston, 5-Fluorouracil: mechanisms of action and clinical strategies, Nature Reviews Cancer, vol.3, issue.5, pp.330-338, 2003.
DOI : 10.1038/nrc1074

M. Bertrand, High-dose continuous infusion folinic acid and bolus 5-fluorouracil in patients with advanced colorectal cancer: a phase II study., Journal of Clinical Oncology, vol.4, issue.7, pp.1058-61, 1986.
DOI : 10.1200/JCO.1986.4.7.1058

O. Capitain, The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer Leucovorin and fluorouracil with or without oxaliplatin as firstline treatment in advanced colorectal cancer, Pharmacogenomics J J Clin Oncol, vol.8, issue.416, pp.256-67, 2000.

E. Raymond, Oxaliplatin: a review of preclinical and clinical studies, Ann Oncol, issue.910, pp.1053-71, 1998.

M. A. Graham, Clinical pharmacokinetics of oxaliplatin: a critical review, Clin Cancer Res, vol.6, issue.4, pp.1205-1223, 2000.

D. M. Kweekel, H. Gelderblom, and H. J. Guchelaar, Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy, Cancer Treatment Reviews, vol.31, issue.2, pp.31-90, 2005.
DOI : 10.1016/j.ctrv.2004.12.006

L. Pendyala, Cytotoxicity, cellular accumulation and DNA binding of oxaliplatin isomers, Cancer Letters, vol.97, issue.2, pp.177-84, 1995.
DOI : 10.1016/0304-3835(95)03974-2

E. Cvitkovic, Ongoing and unsaid on oxaliplatin: the hope, British Journal of Cancer, vol.77, issue.4, pp.8-11, 1998.
DOI : 10.1038/bjc.1998.429

C. Tournigand, Adjuvant Therapy With Fluorouracil and Oxaliplatin in Stage II and Elderly Patients (between ages 70 and 75 years) With Colon Cancer: Subgroup Analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer Trial, Journal of Clinical Oncology, vol.30, issue.27, pp.30-3353, 2012.
DOI : 10.1200/JCO.2012.42.5645

M. E. Wall, M. C. Wani, and H. Taylor, Isolation and chemical characterization of antitumor agents from plants, Cancer Treat Rep, issue.8, pp.60-1011, 1976.

L. Saltz, Irinotecan-based combinations for the adjuvant treatment of stage III colon cancer, Oncology, vol.12, issue.14, pp.47-50, 2000.

E. Guerin, In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1alpha target genes and decreases tumor angiogenesis, Mol Med, vol.18, pp.83-94, 2012.

J. Y. Douillard and V. S. Group, Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer, Oncology, vol.12, issue.14, pp.51-56, 2000.

J. Y. Douillard, Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial Adjuvant therapy for stage II and III colorectal cancer, Lancet Semin Oncol, vol.355, issue.92092, pp.34-37, 2000.

J. Folkman, Tumor angiogenesis: therapeutic implications, N Engl J Med, vol.285, issue.21, pp.1182-1188, 1971.

J. Folkman, Role of angiogenesis in tumor growth and metastasis, Semin Oncol, vol.296, pp.15-23, 2002.

M. M. Sholley, Mechanisms of neovascularization. Vascular sprouting can occur without proliferation of endothelial cells, Lab Invest, issue.6, pp.51-624, 1984.

C. Clapp, Peptide Hormone Regulation of Angiogenesis, Physiological Reviews, vol.89, issue.4, pp.1177-215, 2009.
DOI : 10.1152/physrev.00024.2009

J. Folkman, What Is the Evidence That Tumors Are Angiogenesis Dependent?, JNCI Journal of the National Cancer Institute, vol.82, issue.1, pp.4-6, 1990.
DOI : 10.1093/jnci/82.1.4

D. M. Mcdonald and P. Baluk, Significance of blood vessel leakiness in cancer, Cancer Res, vol.62, issue.18, pp.5381-5386, 2002.

D. M. Mcdonald and P. L. Choyke, Imaging of angiogenesis: from microscope to clinic, Nature Medicine, vol.9, issue.6, pp.713-738, 2003.
DOI : 10.1038/nm0603-713

D. M. Mcdonald and A. J. Foss, Endothelial cells of tumor vessels: abnormal but not absent, Cancer and Metastasis Reviews, vol.19, issue.1/2, pp.109-129, 2000.
DOI : 10.1023/A:1026529222845

S. Morikawa, Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors, The American Journal of Pathology, vol.160, issue.3, pp.985-1000, 2002.
DOI : 10.1016/S0002-9440(10)64920-6

H. Hashizume, Openings between Defective Endothelial Cells Explain Tumor Vessel Leakiness, The American Journal of Pathology, vol.156, issue.4, pp.1363-80, 2000.
DOI : 10.1016/S0002-9440(10)65006-7

Y. Huang, Vascular Normalization as an Emerging Strategy to Enhance Cancer Immunotherapy, Cancer Research, vol.73, issue.10, pp.73-2943, 2013.
DOI : 10.1158/0008-5472.CAN-12-4354

J. Folkman, New perspectives in clinical oncology from angiogenesis research, European Journal of Cancer, vol.32, issue.14, pp.32-2534, 1996.
DOI : 10.1016/S0959-8049(96)00423-6

J. Folkman, Induction of angiogenesis during the transition from hyperplasia to neoplasia, Nature, vol.339, issue.6219, pp.58-61, 1989.
DOI : 10.1038/339058a0

T. Filho and I. P. , Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice., Proceedings of the National Academy of Sciences, vol.91, issue.6, pp.2081-2086, 1994.
DOI : 10.1073/pnas.91.6.2081

R. Demicheli, Local Recurrences Following Mastectomy: Support for the Concept of Tumor Dormancy, JNCI Journal of the National Cancer Institute, vol.86, issue.1, pp.45-53, 1994.
DOI : 10.1093/jnci/86.1.45

J. W. Uhr, Cancer dormancy: Opportunities for new therapeutic approaches, Nature Medicine, vol.343, issue.5, pp.505-514, 1997.
DOI : 10.1038/nm0196-52

W. C. Black and H. G. Welch, Advances in Diagnostic Imaging and Overestimations of Disease Prevalence and the Benefits of Therapy, New England Journal of Medicine, vol.328, issue.17, pp.328-1237, 1993.
DOI : 10.1056/NEJM199304293281706

J. Folkman, R. Kalluri-ferrara, N. , H. P. Gerber, and J. Lecouter, Cancer without disease The biology of VEGF and its receptors, Nature Nat Med, vol.85, issue.6977 96, pp.427-787, 2003.

K. A. Houck, The Vascular Endothelial Growth Factor Family: Identification of a Fourth Molecular Species and Characterization of Alternative Splicing of RNA, Molecular Endocrinology, vol.5, issue.12, pp.1806-1820, 1991.
DOI : 10.1210/mend-5-12-1806

K. Suto, Crystal Structures of Novel Vascular Endothelial Growth Factors (VEGF) from Snake Venoms: INSIGHT INTO SELECTIVE VEGF BINDING TO KINASE INSERT DOMAIN-CONTAINING RECEPTOR BUT NOT TO fms-LIKE TYROSINE KINASE-1, Journal of Biological Chemistry, vol.280, issue.3, pp.280-2126, 2005.
DOI : 10.1074/jbc.M411395200

D. R. Senger, Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid, Science, vol.219, issue.4587, pp.219-983, 1983.
DOI : 10.1126/science.6823562

B. I. Rini and E. J. Small, Biology and Clinical Development of Vascular Endothelial Growth Factor???Targeted Therapy in Renal Cell Carcinoma, Journal of Clinical Oncology, vol.23, issue.5, pp.1028-1071, 2005.
DOI : 10.1200/JCO.2005.01.186

S. M. Uthoff, VEGF isoforms and mutations in human colorectal cancer, International Journal of Cancer, vol.100, issue.1, pp.32-38, 2002.
DOI : 10.1002/ijc.10552

Z. Poltorak, VEGF145, a Secreted Vascular Endothelial Growth Factor Isoform That Binds to Extracellular Matrix, Journal of Biological Chemistry, vol.272, issue.11, pp.272-7151, 1997.
DOI : 10.1074/jbc.272.11.7151

J. Woolard, VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant: Mechanism of Action, In vivo Effect On Angiogenesis and Endogenous Protein Expression, Cancer Research, vol.64, issue.21, pp.64-7822, 2004.
DOI : 10.1158/0008-5472.CAN-04-0934

B. Olofsson, Vascular endothelial growth factor B, a novel growth factor for endothelial cells., Proceedings of the National Academy of Sciences, vol.93, issue.6, pp.93-2576, 1996.
DOI : 10.1073/pnas.93.6.2576

B. Olofsson, Genomic Organization of the Mouse and Human Genes for Vascular Endothelial Growth Factor B (VEGF-B) and Characterization of a Second Splice Isoform, Journal of Biological Chemistry, vol.271, issue.32, pp.271-19310, 1996.
DOI : 10.1074/jbc.271.32.19310

A. Ristimaki, Proinflammatory Cytokines Regulate Expression of the Lymphatic Endothelial Mitogen Vascular Endothelial Growth Factor-C, Journal of Biological Chemistry, vol.273, issue.14, pp.273-8413, 1998.
DOI : 10.1074/jbc.273.14.8413

M. Bry, Vascular Endothelial Growth Factor-B in Physiology and Disease, Physiological Reviews, vol.94, issue.3, pp.779-794, 2014.
DOI : 10.1152/physrev.00028.2013

V. Joukov, Proteolytic processing regulates receptor specificity and activity of VEGF-C, The EMBO Journal, vol.16, issue.13, pp.3898-911, 1997.
DOI : 10.1093/emboj/16.13.3898

T. Tammela and K. Alitalo, Lymphangiogenesis: Molecular Mechanisms and Future Promise, Cell, vol.140, issue.4, pp.460-76, 2010.
DOI : 10.1016/j.cell.2010.01.045

URL : http://doi.org/10.1016/j.cell.2010.01.045

J. Fujimoto, Clinical implication of expression of vascular endothelial growth factor-C in metastatic lymph nodes of uterine cervical cancers, British Journal of Cancer, vol.5, issue.3, pp.91-466, 2004.
DOI : 10.1038/sj.bjc.6690356

F. Farnebo, F. Piehl, and J. Lagercrantz, Restricted Expression Pattern ofvegf-din the Adult and Fetal Mouse: High Expression in the Embryonic Lung, Biochemical and Biophysical Research Communications, vol.257, issue.3, pp.891-895, 1999.
DOI : 10.1006/bbrc.1999.0562

S. Takahashi, Vascular Endothelial Growth Factor (VEGF), VEGF Receptors and Their Inhibitors for Antiangiogenic Tumor Therapy, Biological & Pharmaceutical Bulletin, vol.34, issue.12, pp.34-1785, 2011.
DOI : 10.1248/bpb.34.1785

J. E. Park, Placenta growth factor Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk- 1/KDR, J Biol Chem, issue.41, pp.269-25646, 1994.

L. Xu and R. K. Jain, Down-Regulation of Placenta Growth Factor by Promoter Hypermethylation in Human Lung and Colon Carcinoma, Molecular Cancer Research, vol.5, issue.9, pp.873-80, 2007.
DOI : 10.1158/1541-7786.MCR-06-0141

A. Escudero-esparza, PGF isoforms, PLGF-1 and PGF-2, in colorectal cancer and the prognostic significance, Cancer Genomics Proteomics, vol.6, issue.4, pp.239-285, 2009.

D. J. Lyttle, Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus, J Virol, vol.68, issue.1, pp.84-92, 1994.

T. Andre, Vegf, vegf-B, vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa, International Journal of Cancer, vol.86, issue.2, pp.174-81, 2000.
DOI : 10.1002/(SICI)1097-0215(20000415)86:2<174::AID-IJC5>3.3.CO;2-5

S. A. Cunningham, Characterization of Vascular Endothelial Cell Growth Factor Interactions with the Kinase Insert Domain-containing Receptor Tyrosine Kinase: A REAL TIME KINETIC STUDY, Journal of Biological Chemistry, vol.274, issue.26, pp.274-18421, 1999.
DOI : 10.1074/jbc.274.26.18421

F. Fan, Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells, Oncogene, vol.135, issue.16, pp.24-2647, 2005.
DOI : 10.1038/sj.onc.1208246

I. Zachary and G. Gliki, Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family, Cardiovascular Research, vol.49, issue.3, pp.568-81, 2001.
DOI : 10.1016/S0008-6363(00)00268-6

B. Barleon, Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1, Blood, vol.87, issue.8, pp.3336-3379, 1996.

M. Clauss, The Vascular Endothelial Growth Factor Receptor Flt-1 Mediates Biological Activities: IMPLICATIONS FOR A FUNCTIONAL ROLE OF PLACENTA GROWTH FACTOR IN MONOCYTE ACTIVATION AND CHEMOTAXIS, Journal of Biological Chemistry, vol.271, issue.30, pp.271-17629, 1996.
DOI : 10.1074/jbc.271.30.17629

J. Lecouter, Angiogenesis-Independent Endothelial Protection of Liver: Role of VEGFR-1, Science, vol.299, issue.5608, pp.890-893, 2003.
DOI : 10.1126/science.1079562

R. L. Kendall and K. A. Thomas, Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor., Proceedings of the National Academy of Sciences, vol.90, issue.22, pp.90-10705, 1993.
DOI : 10.1073/pnas.90.22.10705

B. I. Terman, Identification of a new endothelial cell growth factor receptor tyrosine kinase, Oncogene, vol.6, issue.9, pp.1677-83, 1991.

S. F. Martins, Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer, Cancer Genomics Proteomics, vol.10, issue.2, pp.55-67, 2013.

T. Takahashi, A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells, The EMBO Journal, vol.20, issue.11, pp.20-2768, 2001.
DOI : 10.1093/emboj/20.11.2768

A. Kumanogoh and H. Kikutani, Immunological functions of the neuropilins and plexins as receptors for semaphorins, Nature Reviews Immunology, vol.174, issue.11, pp.802-816, 2013.
DOI : 10.1038/nri3545

A. Fantin, Neuropilin 1 (NRP1) hypomorphism combined with defective VEGF-A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis, Development, vol.141, issue.3, pp.141-556, 2014.
DOI : 10.1242/dev.103028

T. Cimato, Neuropilin-1 Identifies Endothelial Precursors in Human and Murine Embryonic Stem Cells Before CD34 Expression, Circulation, vol.119, issue.16, pp.2170-2178, 2009.
DOI : 10.1161/CIRCULATIONAHA.109.849596

P. Frankel, Chondroitin sulphate-modified neuropilin 1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line through a p130Cas-mediated pathway, EMBO reports, vol.53, issue.10, pp.983-992, 2008.
DOI : 10.1158/1535-7163.MCT-06-0082

F. Nakamura and Y. Goshima, Structural and Functional Relation of Neuropilins, Adv Exp Med Biol, vol.515, pp.55-69, 2002.
DOI : 10.1007/978-1-4615-0119-0_5

S. Djordjevic and P. C. Driscoll, Targeting VEGF signalling via the neuropilin coreceptor, Drug Discov Today, vol.18, pp.9-10, 2013.

Y. Herzog, Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins, Mechanisms of Development, vol.109, issue.1, pp.115-124, 2001.
DOI : 10.1016/S0925-4773(01)00518-4

A. Battaglia, Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer, Immunology, vol.163, issue.1, pp.129-167, 2008.
DOI : 10.1038/nri1919

S. Soker, VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding, Journal of Cellular Biochemistry, vol.97, issue.2, pp.357-68, 2002.
DOI : 10.1002/jcb.10140

G. Fuh, K. C. Garcia, and A. M. De-vos, The interaction of Neuropilin-1 with Vascular Endothelial Growth Factor and its receptor Flt-1, Journal of Biological Chemistry, issue.35, pp.275-26690, 2000.
DOI : 10.1074/jbc.M003955200

Q. Pan, Blocking Neuropilin-1 Function Has an Additive Effect with Anti-VEGF to Inhibit Tumor Growth, Cancer Cell, vol.11, issue.1, pp.53-67, 2007.
DOI : 10.1016/j.ccr.2006.10.018

A. Jarvis, Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction, Journal of Medicinal Chemistry, vol.53, issue.5, pp.2215-2241, 2010.
DOI : 10.1021/jm901755g

Y. Xin, Pharmacokinetic and Pharmacodynamic Analysis of Circulating Biomarkers of Anti-NRP1, a Novel Antiangiogenesis Agent, in Two Phase I Trials in Patients with Advanced Solid Tumors, Clinical Cancer Research, vol.18, issue.21, pp.18-6040, 2012.
DOI : 10.1158/1078-0432.CCR-12-1652

C. D. Weekes, A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors, Investigational New Drugs, vol.411, issue.10, 2014.
DOI : 10.1007/s10637-014-0071-z

R. Ross, A Platelet-Dependent Serum Factor That Stimulates the Proliferation of Arterial Smooth Muscle Cells In Vitro, Proceedings of the National Academy of Sciences, vol.71, issue.4, pp.1207-1217, 1974.
DOI : 10.1073/pnas.71.4.1207

B. Westermark and A. Wasteson, A platelet factor stimulating human normal glial cells, Experimental Cell Research, vol.98, issue.1, pp.170-174, 1976.
DOI : 10.1016/0014-4827(76)90476-6

N. Kohler and A. Lipton, Platelets as a source of fibroblast growth-promoting activity, Experimental Cell Research, vol.87, issue.2, pp.297-301, 1974.
DOI : 10.1016/0014-4827(74)90484-4

S. G. Ball, C. A. Shuttleworth, and C. M. Kielty, Vascular endothelial growth factor can signal through platelet-derived growth factor receptors, The Journal of Cell Biology, vol.13, issue.3, pp.489-500, 2007.
DOI : 10.1016/S0008-6363(00)00268-6

S. Pennock and A. Kazlauskas, Vascular Endothelial Growth Factor A Competitively Inhibits Platelet-Derived Growth Factor (PDGF)-Dependent Activation of PDGF Receptor and Subsequent Signaling Events and Cellular Responses, Molecular and Cellular Biology, vol.32, issue.10, pp.32-1955, 2012.
DOI : 10.1128/MCB.06668-11

J. Andrae, R. Gallini, and C. Betsholtz, Role of platelet-derived growth factors in physiology and medicine, Genes & Development, vol.22, issue.10, pp.22-1276, 2008.
DOI : 10.1101/gad.1653708

J. B. Demoulin and A. Essaghir, PDGF receptor signaling networks in normal and cancer cells, Cytokine & Growth Factor Reviews, vol.25, issue.3, 2014.
DOI : 10.1016/j.cytogfr.2014.03.003

N. Papadopoulos, Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab, Angiogenesis, vol.28, issue.281, pp.171-85, 2012.
DOI : 10.1007/s10456-011-9249-6

R. C. Bates, Flt-1-Dependent Survival Characterizes the Epithelial-Mesenchymal Transition of Colonic Organoids, Current Biology, vol.13, issue.19, pp.13-1721, 2003.
DOI : 10.1016/j.cub.2003.09.002

A. Giatromanolaki, Activated Vegfr2/kdr Pathway In Tumour Cells And Tumour Associated Vessels Of Colorectal Cancer, European Journal of Clinical Investigation, vol.25, issue.11, pp.37-878, 2007.
DOI : 10.1016/j.yexcr.2005.05.022

M. Calvani, Differential Involvement of Vascular Endothelial Growth Factor in the Survival of Hypoxic Colon Cancer Cells, Cancer Research, vol.68, issue.1, pp.285-91, 2008.
DOI : 10.1158/0008-5472.CAN-07-5564

M. P. Morelli, Targeting vascular endothelial growth factor receptor-1 and -3 with cediranib (AZD2171): effects on migration and invasion of gastrointestinal cancer cell lines, Molecular Cancer Therapeutics, vol.8, issue.9, pp.2546-58, 2009.
DOI : 10.1158/1535-7163.MCT-09-0380

V. Poindessous, EGFR- and VEGF(R)-Targeted Small Molecules Show Synergistic Activity in Colorectal Cancer Models Refractory to Combinations of Monoclonal Antibodies, Clinical Cancer Research, vol.17, issue.20, pp.17-6522, 2011.
DOI : 10.1158/1078-0432.CCR-11-1607

Y. Yin, Blocking effects of siRNA on VEGF expression in human colorectal cancer cells, World Journal of Gastroenterology, vol.16, issue.9, pp.1086-92, 2010.
DOI : 10.3748/wjg.v16.i9.1086

M. Eppenberger, Role of the VEGF ligand to receptor ratio in the progression of mismatch repair-proficient colorectal cancer, BMC Cancer, vol.14, issue.26, p.93, 2010.
DOI : 10.3748/wjg.14.4156

N. T. Okita, Vascular Endothelial Growth Factor Receptor Expression as a Prognostic Marker for Survival in Colorectal Cancer, Japanese Journal of Clinical Oncology, vol.39, issue.9, pp.595-600, 2009.
DOI : 10.1093/jjco/hyp066

C. Munaut, Hypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast, Human Reproduction, vol.23, issue.6, pp.1407-1422, 2008.
DOI : 10.1093/humrep/den114

C. Bais, PlGF Blockade Does Not Inhibit Angiogenesis during Primary Tumor Growth, Cell, vol.141, issue.1, pp.166-77, 2010.
DOI : 10.1016/j.cell.2010.01.033

K. Masuda, A Novel Tumor-Promoting Function Residing in the 5??? Non-coding Region of vascular endothelial growth factor mRNA, PLoS Medicine, vol.12, issue.5, p.94, 2008.
DOI : 10.1371/journal.pmed.0050094.st002

D. P. Lesslie, Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases, British Journal of Cancer, vol.269, issue.11, pp.94-1710, 2006.
DOI : 10.1038/sj.onc.1205989

S. Samuel, Intracrine vascular endothelial growth factor signaling in survival and chemoresistance of human colorectal cancer cells, Oncogene, vol.65, issue.10, pp.30-1205, 2011.
DOI : 10.1126/science.6823562

D. Shweiki, Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis., Proceedings of the National Academy of Sciences, vol.92, issue.3, pp.92-768, 1995.
DOI : 10.1073/pnas.92.3.768

P. H. Maxwell, Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth, Proceedings of the National Academy of Sciences, vol.94, issue.15, pp.94-8104, 1997.
DOI : 10.1073/pnas.94.15.8104

P. Carmeliet, Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis, Nature, issue.6692, pp.394-485, 1998.

C. J. Hu, The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha, Mol Biol Cell, issue.11, pp.18-4528, 2007.

G. L. Semenza, Hypoxia-Inducible Factors in Physiology and Medicine, Cell, vol.148, issue.3, pp.399-408, 2012.
DOI : 10.1016/j.cell.2012.01.021

I. Stein, Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes., Molecular and Cellular Biology, vol.15, issue.10, pp.15-5363, 1995.
DOI : 10.1128/MCB.15.10.5363

K. Shen, c-Jun N-Terminal Kinase Mediated VEGFR2 Sustained Phosphorylation is Critical for VEGFA-Induced Angiogenesis In Vitro and In Vivo, Cell Biochemistry and Biophysics, vol.20, issue.1, pp.17-27, 2012.
DOI : 10.1007/s12013-012-9363-0

H. P. Gerber, Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes: Flt-1, BUT NOT Flk-1/KDR, IS UP-REGULATED BY HYPOXIA, Journal of Biological Chemistry, vol.272, issue.38, pp.272-23659, 1997.
DOI : 10.1074/jbc.272.38.23659

Y. Han, Hypoxia Influences the Vascular Expansion and Differentiation of Embryonic Stem Cell Cultures Through the Temporal Expression of Vascular Endothelial Growth Factor Receptors in an ARNT-Dependent Manner, STEM CELLS, vol.218, issue.Suppl 1, pp.799-809, 2010.
DOI : 10.1002/stem.316

K. Suzuma, Increased Expression of KDR/Flk-1 (VEGFR-2) in Murine Model of Ischemia-Induced Retinal Neovascularization, Microvascular Research, vol.56, issue.3, pp.183-91, 1998.
DOI : 10.1006/mvre.1998.2111

J. Kanellis, Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1 expression, Kidney International, vol.61, issue.5, pp.61-1696, 2002.
DOI : 10.1046/j.1523-1755.2002.00329.x

T. G. Graeber, Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status., Molecular and Cellular Biology, vol.14, issue.9, pp.6264-77, 1994.
DOI : 10.1128/MCB.14.9.6264

D. Menendez, A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network, Proceedings of the National Academy of Sciences, vol.103, issue.5, pp.1406-1417, 2006.
DOI : 10.1073/pnas.0508103103

I. Hwang, J. Kim, and S. Jeong, beta-Catenin and peroxisome proliferator-activated receptor-delta coordinate dynamic chromatin loops for the transcription of vascular endothelial growth factor A gene in colon cancer cells, J Biol Chem, issue.49, pp.287-41364, 2012.

S. Naik, Vascular Endothelial Growth Factor Receptor-1 Is Synthetic Lethal to Aberrant {beta}-Catenin Activation in Colon Cancer, Clin Cancer Res, issue.24, pp.15-7529, 2009.

M. Selvakumaran, Antitumor effect of the angiogenesis inhibitor bevacizumab is dependent on susceptibility of tumors to hypoxia-induced apoptosis, Biochemical Pharmacology, vol.75, issue.3, pp.75-627, 2008.
DOI : 10.1016/j.bcp.2007.09.029

M. P. Barr, D. J. Bouchier-hayes, and J. J. Harmey, Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia, International Journal of Oncology, vol.32, issue.1, pp.41-49, 2008.
DOI : 10.3892/ijo.32.1.41

G. Nardo, Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization, Cancer Research, vol.71, issue.12, pp.71-4214, 2011.
DOI : 10.1158/0008-5472.CAN-11-0242

L. G. Presta, Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders, Cancer Res, issue.20, pp.57-4593, 1997.

H. Wildiers, Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11, British Journal of Cancer, vol.88, issue.12, pp.1979-86, 2003.
DOI : 10.1038/sj.bjc.6601005

T. H. Lee, Vascular Endothelial Growth Factor Modulates the Transendothelial Migration of MDA-MB-231 Breast Cancer Cells through Regulation of Brain Microvascular Endothelial Cell Permeability, Journal of Biological Chemistry, vol.278, issue.7, pp.278-5277, 2003.
DOI : 10.1074/jbc.M210063200

C. G. Willett, Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer, Nature Medicine, vol.10, issue.2, pp.145-152, 2004.
DOI : 10.1038/nm988

A. De-gramont, Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial, The Lancet Oncology, vol.13, issue.12, pp.13-1225, 2012.
DOI : 10.1016/S1470-2045(12)70509-0

C. Aghajanian, OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinumsensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer, J Clin Oncol, issue.17, pp.30-2039, 2012.

D. Stark, Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial, The Lancet Oncology, vol.14, issue.3, pp.236-279, 2013.
DOI : 10.1016/S1470-2045(12)70567-3

F. Hilberg, BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy, Cancer Research, vol.68, issue.12, pp.68-4774, 2008.
DOI : 10.1158/0008-5472.CAN-07-6307

A. Gaya and V. Tse, A preclinical and clinical review of aflibercept for the management of cancer, Cancer Treatment Reviews, vol.38, issue.5, pp.484-93, 2012.
DOI : 10.1016/j.ctrv.2011.12.008

J. Holash, VEGF-Trap: A VEGF blocker with potent antitumor effects, Proceedings of the National Academy of Sciences, vol.99, issue.17, pp.99-11393, 2002.
DOI : 10.1073/pnas.172398299

M. Fukasawa and M. Korc, Vascular Endothelial Growth Factor-Trap Suppresses Tumorigenicity of Multiple Pancreatic Cancer Cell Lines, Clinical Cancer Research, vol.10, issue.10, pp.3327-3359, 2004.
DOI : 10.1158/1078-0432.CCR-03-0820

E. Van-cutsem, Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen, Journal of Clinical Oncology, vol.30, issue.28, pp.30-3499, 2012.
DOI : 10.1200/JCO.2012.42.8201

G. Carpenter and S. Cohen, Epidermal Growth Factor, Annual Review of Biochemistry, vol.48, issue.1, pp.193-216, 1979.
DOI : 10.1146/annurev.bi.48.070179.001205

P. Casalini, Role of HER receptors family in development and differentiation, Journal of Cellular Physiology, vol.94, issue.3, pp.343-50, 2004.
DOI : 10.1002/jcp.20007

E. Tzahar, ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms, J Biol Chem, issue.40, pp.269-25226, 1994.

D. Graus-porta, ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling, The EMBO Journal, vol.16, issue.7, pp.16-1647, 1997.
DOI : 10.1093/emboj/16.7.1647

H. Xie, EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCgamma signaling pathway, J Cell Sci, issue.111, pp.615-639, 1998.

J. E. De-larco and G. J. Todaro, Epithelioid and fibroblastic rat kidney cell clones: Epidermal growth factor (EGF) receptors and the effect of mouse sarcoma virus transformation, Journal of Cellular Physiology, vol.69, issue.3, pp.94-335, 1978.
DOI : 10.1002/jcp.1040940311

J. J. Peschon, An Essential Role for Ectodomain Shedding in Mammalian Development, Science, vol.282, issue.5392, pp.1281-1285, 1998.
DOI : 10.1126/science.282.5392.1281

S. Kasina, ADAM-mediated amphiregulin shedding and EGFR transactivation, Cell Proliferation, vol.13, issue.6, pp.799-812, 2009.
DOI : 10.1111/j.1365-2184.2009.00645.x

N. Bles, ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion, Blood, vol.116, issue.17, pp.3219-3245, 2010.
DOI : 10.1182/blood-2010-01-265611

G. R. Johnson, Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor and p185erbB2. Evidence that amphiregulin acts exclusively through the epidermal growth factor receptor at the surface of human epithelial cells

Y. L. Hsu, Lung Tumor-Associated Dendritic Cell-Derived Amphiregulin Increased Cancer Progression, The Journal of Immunology, vol.187, issue.4, pp.1733-1777, 2011.
DOI : 10.4049/jimmunol.1100996

N. Eckstein, Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells, Journal of Biological Chemistry, vol.283, issue.2, pp.739-50, 2008.
DOI : 10.1074/jbc.M706287200

W. H. Fiske, D. Threadgill, and R. J. Coffey, ERBBs in the gastrointestinal tract: Recent progress and new perspectives, Experimental Cell Research, vol.315, issue.4, pp.315-583, 2009.
DOI : 10.1016/j.yexcr.2008.10.043

P. J. Miettinen, Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor, Nature, vol.376, issue.6538, pp.337-378, 1995.
DOI : 10.1038/376337a0

R. R. Nair, B. B. Warner, and B. W. Warner, Role of Epidermal Growth Factor and Other Growth Factors in the Prevention of Necrotizing Enterocolitis, Seminars in Perinatology, vol.32, issue.2, pp.107-120, 2008.
DOI : 10.1053/j.semperi.2008.01.007

A. K. Larsen, Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis, Pharmacology & Therapeutics, vol.131, issue.1, pp.80-90, 2011.
DOI : 10.1016/j.pharmthera.2011.03.012

C. K. Goldman, Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology., Molecular Biology of the Cell, vol.4, issue.1, pp.121-154, 1993.
DOI : 10.1091/mbc.4.1.121

M. Detmar, Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis, Journal of Experimental Medicine, vol.180, issue.3, pp.1141-1147, 1994.
DOI : 10.1084/jem.180.3.1141

F. Ciardiello, Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells, Clin Cancer Res, vol.6, issue.9, pp.3739-3786, 2000.

N. Pore, EGFR Tyrosine Kinase Inhibitors Decrease VEGF Expression by Both Hypoxia-Inducible Factor (HIF)-1-Independent and HIF-1-Dependent Mechanisms, Cancer Research, vol.66, issue.6, pp.66-3197, 2006.
DOI : 10.1158/0008-5472.CAN-05-3090

A. M. Petit, 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, issue.6, pp.151-1523, 1997.

X. Li, Requirement of hypoxia-inducible factor-1?? down-regulation in mediating the antitumor activity of the anti-epidermal growth factor receptor monoclonal antibody cetuximab, Molecular Cancer Therapeutics, vol.7, issue.5, pp.1207-1224, 2008.
DOI : 10.1158/1535-7163.MCT-07-2187

G. N. Naumov, Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance, Clinical Cancer Research, vol.15, issue.10, pp.15-3484, 2009.
DOI : 10.1158/1078-0432.CCR-08-2904

R. M. Shaheen, Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms, Cancer Res, issue.4, pp.61-1464, 2001.

P. Sini, The Antitumor and Antiangiogenic Activity of Vascular Endothelial Growth Factor Receptor Inhibition Is Potentiated by ErbB1 Blockade, Clinical Cancer Research, vol.11, issue.12, pp.4521-4553, 2005.
DOI : 10.1158/1078-0432.CCR-04-1954

J. R. Tonra, Synergistic Antitumor Effects of Combined Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor-2 Targeted Therapy, Clinical Cancer Research, vol.12, issue.7, pp.2197-207, 2006.
DOI : 10.1158/1078-0432.CCR-05-1682

K. Yokoi, Dual Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation by AEE788 Reduces Growth and Metastasis of Human Colon Carcinoma in an Orthotopic Nude Mouse Model, Cancer Research, vol.65, issue.9, pp.65-3716, 2005.
DOI : 10.1158/0008-5472.CAN-04-3700

C. J. Punt and J. Tol, More is less???combining targeted therapies in metastatic colorectal cancer, Nature Reviews Clinical Oncology, vol.97, issue.12, pp.731-734, 2009.
DOI : 10.1038/nrclinonc.2009.168

J. Tol, Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer, New England Journal of Medicine, vol.360, issue.6, pp.563-72, 2009.
DOI : 10.1056/NEJMoa0808268

J. R. Hecht, A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer, Journal of Clinical Oncology, vol.27, issue.5, pp.672-80, 2009.
DOI : 10.1200/JCO.2008.19.8135

A. Franovic, Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer, Proceedings of the National Academy of Sciences, vol.104, issue.32, pp.13092-13099, 2007.
DOI : 10.1073/pnas.0702387104

K. Y. Chung, Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry, Journal of Clinical Oncology, vol.23, issue.9, pp.1803-1813, 2005.
DOI : 10.1200/JCO.2005.08.037

H. J. Lenz, Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines, Journal of Clinical Oncology, vol.24, issue.30, pp.24-4914, 2006.
DOI : 10.1200/JCO.2006.06.7595

M. Moroni, Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study, The Lancet Oncology, vol.6, issue.5, pp.279-86, 2005.
DOI : 10.1016/S1470-2045(05)70102-9

A. D. Roth, in Stage II and III Resected Colon Cancer: Results of the Translational Study on the PETACC-3, EORTC 40993, SAKK 60-00 Trial, Journal of Clinical Oncology, vol.28, issue.3, pp.28-466, 2010.
DOI : 10.1200/JCO.2009.23.3452

G. Smith, Activating K-Ras mutations outwith ???hotspot??? codons in sporadic colorectal tumours ??? implications for personalised cancer medicine, British Journal of Cancer, vol.59, issue.4, pp.693-703, 2010.
DOI : 10.1126/science.1174229

C. J. Allegra, Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti???Epidermal Growth Factor Receptor Monoclonal Antibody Therapy, Journal of Clinical Oncology, vol.27, issue.12, pp.27-2091, 2009.
DOI : 10.1200/JCO.2009.21.9170

S. Ardekani and G. , The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis, PLoS One, issue.710, p.47054, 2012.

W. De-roock, Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis, The Lancet Oncology, vol.11, issue.8, pp.11-753, 2010.
DOI : 10.1016/S1470-2045(10)70130-3

D. Nicolantonio and F. , Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer, Journal of Clinical Oncology, vol.26, issue.35, pp.26-5705, 2008.
DOI : 10.1200/JCO.2008.18.0786

P. Laurent-puig, Metastatic Colon Cancer, Journal of Clinical Oncology, vol.27, issue.35, pp.27-5924, 2009.
DOI : 10.1200/JCO.2008.21.6796

URL : https://hal.archives-ouvertes.fr/hal-00618089

A. Dasari and W. A. Messersmith, New Strategies in Colorectal Cancer: Biomarkers of Response to Epidermal Growth Factor Receptor Monoclonal Antibodies and Potential Therapeutic Targets in Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Pathways, Clinical Cancer Research, vol.16, issue.15, pp.16-3811, 2010.
DOI : 10.1158/1078-0432.CCR-09-2283

N. I. Goldstein, Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model, Clin Cancer Res, issue.111, pp.1311-1319, 1995.

H. Sunada, Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation., Proceedings of the National Academy of Sciences, vol.83, issue.11, pp.83-3825, 1986.
DOI : 10.1073/pnas.83.11.3825

URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC323616

D. Li, BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models, Oncogene, vol.6, issue.34, pp.27-4702, 2008.
DOI : 10.1016/j.ccr.2006.05.023

S. A. Perera, HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy, Proceedings of the National Academy of Sciences, vol.106, issue.2
DOI : 10.1073/pnas.0808930106

L. V. Sequist, Mutations, Journal of Clinical Oncology, vol.31, issue.27, pp.31-3327, 2013.
DOI : 10.1200/JCO.2012.44.2806

D. A. Karnofsky, The bases for cancer chemotherapy, Stanford Med Bull, vol.6, issue.1, pp.257-69, 1948.

A. De-gramont, [Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD], Rev Med Interne, issue.10, pp.18-769, 1997.

T. Andre, CPT-11 (Irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer, European Journal of Cancer, vol.35, issue.9, pp.1343-1350, 1999.
DOI : 10.1016/S0959-8049(99)00150-1

R. B. Corcoran, TORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in BRAF-Mutant Melanoma, Science Translational Medicine, vol.5, issue.196, pp.196-98, 0196.
DOI : 10.1126/scitranslmed.3005753

M. Elkabets, mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer, Sci Transl Med, issue.5, pp.196-99, 0196.

M. Y. Koh and G. Powis, Passing the baton: the HIF switch, Trends in Biochemical Sciences, vol.37, issue.9, pp.364-72, 2012.
DOI : 10.1016/j.tibs.2012.06.004

F. Fan, Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration, British Journal of Cancer, vol.59, issue.8, pp.1270-1277, 2011.
DOI : 10.1002/cncr.21145

N. Yamagishi, Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells, BMC Cancer, vol.8, issue.10, p.229, 2013.
DOI : 10.1586/14737140.8.10.1545

B. Das, A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma, Cancer Res, issue.16, pp.65-7267, 2005.

H. Harada, The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose-and reoxygenation-dependent manner in irradiated tumors, J Biol Chem, issue.8, pp.284-5332, 2009.

K. Minakata, Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors, Cancer Science, vol.20, issue.11, pp.1946-54, 2012.
DOI : 10.1111/j.1349-7006.2012.02408.x

R. Longo and G. Gasparini, Challenges for patient selection with VEGF inhibitors, Cancer Chemotherapy and Pharmacology, vol.6, issue.11, pp.151-70, 2007.
DOI : 10.1007/s00280-006-0403-6

J. M. Jurgensmeier, Prognostic and predictive value of VEGF, sVEGFR-2 and CEA in mCRC studies comparing cediranib, bevacizumab and chemotherapy, British Journal of Cancer, vol.2, issue.6, pp.1316-1339, 2013.
DOI : 10.1016/S0022-5347(05)00736-6

M. I. Koukourakis, Prognostic and Predictive Role of Lactate Dehydrogenase 5 Expression in Colorectal Cancer Patients Treated with PTK787/ZK 222584 (Vatalanib) Antiangiogenic Therapy, Clinical Cancer Research, vol.17, issue.14, pp.17-4892, 2011.
DOI : 10.1158/1078-0432.CCR-10-2918

M. Scartozzi, Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients, British Journal of Cancer, vol.22, issue.5, pp.799-804, 2012.
DOI : 10.1038/bjc.2012.17

A. Mcintyre, Carbonic Anhydrase IX Promotes Tumor Growth and Necrosis In Vivo and Inhibition Enhances Anti-VEGF Therapy, Clinical Cancer Research, vol.18, issue.11, pp.18-3100, 2012.
DOI : 10.1158/1078-0432.CCR-11-1877

L. Richeldi, Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis, New England Journal of Medicine, vol.370, issue.22, pp.2071-82, 2014.
DOI : 10.1056/NEJMoa1402584

M. Reck, Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial, The Lancet Oncology, vol.15, issue.2, pp.143-55, 2014.
DOI : 10.1016/S1470-2045(13)70586-2

O. Reilly and S. M. , Hypoxia induces epithelial amphiregulin gene expression in a CREB-dependent manner, AJP: Cell Physiology, vol.290, issue.2, pp.592-600, 2006.
DOI : 10.1152/ajpcell.00278.2005

M. R. Bordoli, Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis, Oncogene, vol.59, issue.5, pp.548-60, 2011.
DOI : 10.1016/j.ccr.2009.09.029

A. Petitprez and A. K. Larsen, Irinotecan resistance is accompanied by upregulation of EGFR and Src signaling in human cancer models, Curr Pharm Des, vol.19, issue.5, pp.958-64, 2013.

S. H. Lee, HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress, Carcinogenesis, vol.30, issue.12, pp.30-1997, 2009.
DOI : 10.1093/carcin/bgp233

Y. Wang, Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1, Proceedings of the National Academy of Sciences, vol.109, issue.13, pp.4892-4899
DOI : 10.1073/pnas.1112129109

Y. Wang, Regulation of endocytosis via the oxygen-sensing pathway, Nature Medicine, vol.11, issue.3, pp.319-343, 2009.
DOI : 10.1126/science.1134389

P. Perrotte, Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice, Clin Cancer Res, vol.5, issue.2, pp.257-65, 1999.

C. J. Bruns, Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms, Clin Cancer Res, vol.6, issue.5, pp.1936-1984, 2000.

D. N. Amin, Tumor Endothelial Cells Express Epidermal Growth Factor Receptor (EGFR) but not ErbB3 and Are Responsive to EGF and to EGFR Kinase Inhibitors, Cancer Research, vol.66, issue.4, pp.2173-80, 2006.
DOI : 10.1158/0008-5472.CAN-05-3387

T. Sasaki, Modification of the Primary Tumor Microenvironment by Transforming Growth Factor ??-Epidermal Growth Factor Receptor Signaling Promotes Metastasis in an Orthotopic Colon Cancer Model, The American Journal of Pathology, vol.173, issue.1, pp.205-221, 2008.
DOI : 10.2353/ajpath.2008.071147

T. Kuwai, Phosphorylated Epidermal Growth Factor Receptor on Tumor-Associated Endothelial Cells Is a Primary Target for Therapy with Tyrosine Kinase Inhibitors, Neoplasia, vol.10, issue.5, pp.489-500, 2008.
DOI : 10.1593/neo.08200

R. J. Coffey and . Jr, Production and auto-induction of transforming growth factoralpha in human keratinocytes, Nature, issue.6133, pp.328-817, 1987.

N. Panupinthu, Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer, Oncogene, vol.320, issue.22, pp.33-2846, 2014.
DOI : 10.1073/pnas.95.25.14863

N. Normanno, Implications for KRAS status and EGFR-targeted therapies in metastatic CRC, Nature Reviews Clinical Oncology, vol.276, issue.9, pp.519-546, 2009.
DOI : 10.1038/nrclinonc.2009.111

P. J. Roberts and T. E. Stinchcombe, Mutation: Should We Test for It, and Does It Matter?, Journal of Clinical Oncology, vol.31, issue.8, pp.31-1112, 2013.
DOI : 10.1200/JCO.2012.43.0454

B. B. Ma, Intermittent versus continuous erlotinib with concomitant modified ???XELOX??? (q3W) in first-line treatment of metastatic colorectal cancer, Cancer, vol.23, issue.suppl 4, pp.119-4145, 2013.
DOI : 10.1002/cncr.28327

A. K. Larsen, V. Poindessous, and E. Alexandre, Escargueil and Paul Mésange Angiogenesis inhibitors: accomplishments and challenges

P. Mésange, . Poindessous, . Battistella, F. Dumont, A. Merabtene et al., Angiogenesis inhibition triggers a survival response in colorectal tumor models

V. Poindessous, . Mésange, . Batistella, M. Afchain, . Forgue-lafitte et al., AK Larsen Exposure to nintedanib, a triple angiokinase inhibitor, is accompanied by activation of EGFR and other ErbB/HER-family members in colorectal cancer (CRC) models, providing a rational for combinations of nintedanib with the ErbB family blocker afatinib

P. Mésange, . Poindessous, . Batistella, . Savina, . Tournigand et al., Larsen Bevacizumab exposure is accompanied by EGFR activation in colorectal cancer (CRC) models providing a rational for combinations of bevacizumab and erlotinib in the GERCOR DREAM phase III trial