Eppenberger et al. BMC Cancer 2010, 10:93 http://www.biomedcentral.com/1471-2407/10/93 in events occurring at the invasive tumour front and highlight a possible prognostic role of VEGFR1 expres- sion in mismatch repair-proficient colorectal cancers. Authors’ contributions ME participated in acquisition of data, data analysis, and manuscript writing. IZ carried out the conception and design, the interpretation of data, and manuscript writing while DB participated in data acquisition and analysis. LT was active in conception and design and AL was responsible for conception and design, data acquisition and analysis, and interpretation of findings. All authors have read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Received: 23 March 2009 Accepted: 11 March 2010 Published: 11 March 2010 References 1. Crawford Y, Ferrara N: VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res 2009, 335(1):261-269. 2. Liao D, Johnson RS: Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 2007, 26(2):281-290. 3. Mukhopadhyay D, Datta K: Multiple regulatory pathways of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in tumors. Semin Cancer Biol 2004, 14(2):123-130. 4. Ellis LM, Hicklin DJ: VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008, 8(8):579-591. 5. Fischer C, Mazzone M, Jonckx B, Carmeliet P: FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?. Nat Rev Cancer 2008, 8(12):942-956. 6. Roskoski R Jr: VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun 2008, 375(3):287-291. 7. Su JL, Yen CJ, Chen PS, Chuang SE, Hong CC, Kuo IH, Chen HY, Hung MC, Kuo ML: The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer 2007, 96(4):541-545. 8. Eubank TD, Roberts RD, Khan M, Curry JM, Nuovo GJ, Kuppusamy P, Marsh CB: Granulocyte Macrophage Colony-Stimulating Factor Inhibits Breast Cancer Growth and Metastasis by Invoking an Anti-Angiogenic Program in Tumor-Educated Macrophages. Cancer Res 2009, 69(5):2133-2140. 9. Gonzalez FJ, Vicioso L, Alvarez M, Sevilla I, Marques E, Gallego E, Alonso L, Matilla A, Alba E: Association between VEGF expression in tumour- associated macrophages and elevated serum VEGF levels in primary colorectal cancer patients. Cancer Biomark 2007, 3(6):325-333. 10. Murdoch C, Muthana M, Coffelt SB, Lewis CE: The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008, 8(8):618-631. 11. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285(21):1182-1186. 12. Folkman J, Merler E, Abernathy C, Williams G: Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971, 133(2):275-288. 13. Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005, 307(5706):58-62. 14. Ribatti D: The discovery of antiangiogenic molecules: a historical review. Curr Pharm Des 2009, 15(4):345-352. 15. Sessa C, Guibal A, Del Conte G, Ruegg C: Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?. Nat Clin Pract Oncol 2008, 5(7):378-391. 16. Andre T, Kotelevets L, Vaillant JC, Coudray AM, Weber L, Prevot S, Parc R, Gespach C, Chastre E: Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. Int J Cancer 2000, 86(2):174-181. 17. Ghanem MA, van Steenbrugge GJ, Sudaryo MK, Mathoera RB, Nijman JM, Kwast van der TH: Expression and prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor (FLT-1) in nephroblastoma. J Clin Pathol 2003, 56(2):107-113. 18. Plate KH, Breier G, Weich HA, Mennel HD, Risau W: Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF Page 9 of 10 receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 1994, 59(4):520-529. 19. Sauter G, Simon R, Hillan K: Tissue microarrays in drug discovery. Nat Rev Drug Discov 2003, 2(12):962-972. 20. Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PA, Robinson BA, Fox SB: The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. J Pathol 2003, 200(2):183-194. 21. Angelo LS, Kurzrock R: Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res 2007, 13(10):2825-2830. 22. Min JK, Lee YM, Kim JH, Kim YM, Kim SW, Lee SY, Gho YS, Oh GT, Kwon YG: Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway. Circ Res 2005, 96(3):300-307. 23. Zlobec I, Baker K, Minoo P, Hayashi S, Terracciano L, Lugli A: Tumor border configuration added to TNM staging better stratifies stage II colorectal cancer patients into prognostic subgroups. Cancer 2009, 115(17):4021-4029. 24. Jass JR, Love SB, Northover JM: A new prognostic classification of rectal cancer. Lancet 1987, 1(8545):1303-1306. 25. Zlobec I, Lugli A, Baker K, Roth S, Minoo P, Hayashi S, Terracciano L, Jass JR: Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. J Pathol 2007, 212(3):260-268. 26. Compton CC: Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003, 16(4):376-388. 27. Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, Bucana CD, Hicklin DJ, Ellis LM: Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 2000, 89(3):488-499. 28. Kang SM, Maeda K, Onoda N, Chung YS, Nakata B, Nishiguchi Y, Sowa M: Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int J Cancer 1997, 74(5):502-507. 29. Kondo Y, Arii S, Mori A, Furutani M, Chiba T, Imamura M: Enhancement of angiogenesis, tumor growth, and metastasis by transfection of vascular endothelial growth factor into LoVo human colon cancer cell line. Clin Cancer Res 2000, 6(2):622-630. 30. Lee JC, Chow NH, Wang ST, Huang SM: Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer 2000, 36(6):748-753. 31. Nakata S, Ito K, Fujimori M, Shingu K, Kajikawa S, Adachi W, Matsuyama I, Tsuchiya S, Kuwano M, Amano J: Involvement of vascular endothelial growth factor and urokinase-type plasminogen activator receptor in microvessel invasion in human colorectal cancers. Int J Cancer 1998, 79(2):179-186. 32. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM: Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995, 55(18):3964-3968. 33. Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, et al: Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 1998, 77(6):998-1002. 34. Bates RC, Goldsmith JD, Bachelder RE, Brown C, Shibuya M, Oettgen P, Mercurio AM: Flt-1-dependent survival characterizes the epithelial- mesenchymal transition of colonic organoids. Curr Biol 2003, 13(19):1721-1727. 35. Yang AD, Camp ER, Fan F, Shen L, Gray MJ, Liu W, Somcio R, Bauer TW, Wu Y, Hicklin DJ, et al: Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res 2006, 66(1):46-51. 36. Neuchrist C, Erovic BM, Handisurya A, Steiner GE, Rockwell P, Gedlicka C, Burian M: Vascular endothelial growth factor receptor 2 (VEGFR2) expression in squamous cell carcinomas of the head and neck. Laryngoscope 2001, 111(10):1834-1841. 37. Hu WG, Li JW, Feng B, Beveridge M, Yue F, Lu AG, Ma JJ, Wang ML, Guo Y, Jin XL, et al: Vascular endothelial growth factors C and D represent novel