- Volume 16 Issue 11
DOI QR Code
Endothelial Cell Proliferation and Vascular Endothelial Growth Factor Expression in Primary Colorectal Cancer and Corresponding Liver Metastases
- Raluca, Balica Amalia (Department of Histology, Angiogenesis Research Center) ;
- Cimpean, Anca Maria (Department of Histology, Angiogenesis Research Center) ;
- Cioca, Andreea (Department of Pathology, Iuliu Hatieganu University of Medicine and Pharmacy) ;
- Cretu, Octavian (Department of Surgery, "Victor Babes" University of Medicine and Pharmacy) ;
- Mederle, Ovidiu (Department of Histology, Angiogenesis Research Center) ;
- Ciolofan, Alexandru (Department of Surgery, "Victor Babes" University of Medicine and Pharmacy) ;
- Gaje, Pusa (Department of Histology, Angiogenesis Research Center) ;
- Raica, Marius (Department of Histology, Angiogenesis Research Center)
- Published : 2015.06.26
Background: Colorectal carcinoma (CRC) is one of the major causes of cancer death worldwide. Data from the literature indicate differences between the proliferation rate of endothelial cells relative to the morphology growth type, possibly due to origin of specimens (autopsy material, surgery fragments) or quantification methods. Vascular endothelial growth factor (VEGF) is a factor that stimulates the proliferation of endothelial cells. It is expressed in more than 90% of cases of metastatic CRC. Aim: The aim of this study was to evaluate the endothelial cell proliferation and VEGF expression in primary tumors and corresponding liver metastases. Materials and Methods: Our study included 24 recent biopsies of primary tumors and corresponding liver metastases of CRC cases. CD34/Ki67 double immunostaining and RNA scope assay for VEGF were performed. Results: In the primary tumors analysis of VEGFmRNA expression indicated no significant correlation with differentiation grade, proliferative and non-proliferative vessels in the intratumoral and peritumoral areas. In contrast, in the corresponding liver metastases, VEGFmRNA expression significantly correlated with the total number of non-proliferative vessels and total number of vessels. CD34/Ki67 double immunostaining in the cases with poorly differentiated carcinoma indicated a high number of proliferating endothelial cells in the peritumoral area and a low number in the intratumoral area for the primary tumor. Moderately differentiated carcinomas of colon showed no proliferating endothelial cells in the intratumoral area in half of the cases included in the study, for both, primary tumor and liver metastasis. In well differentiated CRCs, in primary tumors, a high proliferation rate of endothelial cells in the intratumoral area and a lower proliferation rate in the peritumoral area were found. A low value was found in corresponding liver metastasis. Conclusions: The absence of proliferative endothelial cells in half of the cases for the primary tumors and liver metastases in moderately differentiated carcinoma suggest a vascular mimicry phenomenon. The mismatch between the total number of vessels and endothelial proliferation in primary tumors indicate that a functional vascular network is already formed or the existence of some mechanisms influenced by other angiogenic factors.
Colon carcinoma;endothelial cell proliferation;metastasis
- Baena R, Salinas P. (2015). Diet and colorectal cancer. Maturitas, 80, 258-64. https://doi.org/10.1016/j.maturitas.2014.12.017
- Bates DO, Catalano PJ, Symonds KE, et al (2012). Association between VEGF Splice Isoforms and Progression-Free Survival in Metastatic Colorectal Cancer Patients Treated with Bevacizumab, Clin Cancer Res, 18, 6384-91. https://doi.org/10.1158/1078-0432.CCR-12-2223
- Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999). Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest, 103, 159-65. https://doi.org/10.1172/JCI5028
- Cao D, Hou M, Guan YS, et al (2009). Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer, 9, 432. https://doi.org/10.1186/1471-2407-9-432
- Choi J, Chang H (2012). The expression of MAGE and SSX, and correlation of COX2, VEGF, and survivin in colorectal cancer. Anticancer Res, 32, 559-64.
- Colpaert CG, Vermeulen PB, Benoy I, et al (2003). Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression. Br J Cancer, 88, 718-25. https://doi.org/10.1038/sj.bjc.6600807
- Dirican A, Varol U, Kucukzeybek Y, et al (2014). Treatment of metastatic colorectal cancer with or without bevacizumab: can the neutrophil/lymphocyte ratio predict the efficiency of bevacizumab? Asian Pac J Cancer Prev, 15, 4781-6. https://doi.org/10.7314/APJCP.2014.15.12.4781
- Eefsen RL, Van den Eynden GC, Hoyer-Hansen G, et al (2012). Histopathological growth pattern, proteolysis and angiogenesis in chemonaive patients resected for multiple colorectal liver metastases. J Oncol, 2012, 907971.
- Eefsen RL, Vermeulen PB, Christensen IJ, et al (2015). Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin Exp Metastasis, 32, 369-81. https://doi.org/10.1007/s10585-015-9715-4
- Frankel TL, D'Angelica MI (2014). Hepatic resection for colorectal metastases. J Surg Oncol, 109, 2-7 https://doi.org/10.1002/jso.23371
- Giantonio BJ, Catalano PJ, Meropol NJ, et al (2007). Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol, 25, 1539-44. https://doi.org/10.1200/JCO.2006.09.6305
- Hobson B, Denekamp J (1984). Endothelial proliferation in tumours and normal tissues: Continuous labelling studies. Br J Cancer, 49, 405-13. https://doi.org/10.1038/bjc.1984.66
- Hugen N, van de Velde CJ, de Wilt JH, et al. (2014) Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol, 25, 651-7 https://doi.org/10.1093/annonc/mdt591
- Hurwitz H, Fehrenbacher L, Novotny W, et al (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 350, 2335-42. https://doi.org/10.1056/NEJMoa032691
- Imura S, Miyake H, Izumi K, Tashiro S, Uehara H (2004). Correlation of vascular endothelial cell proliferation with microvessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in hepatocellular carcinoma. J Mes Invest, 51, 202-9. https://doi.org/10.2152/jmi.51.202
- Jubb AM, Cesario A, Ferguson M, et al (2011). Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. Br J Cancer, 104, 1877-81. https://doi.org/10.1038/bjc.2011.147
- Jubb AM, Hurwitz HI, Bai W, et al (2006). Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol, 24, 217-27. https://doi.org/10.1200/JCO.2005.01.5388
- Kendall RL, Rutledge RZ, Mao X, et al (1999). Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues. J Biol Chem, 274, 6453-60. https://doi.org/10.1074/jbc.274.10.6453
- Lamalice L, Le Boeuf F, Huot J (2007). Endothelial cell migration during angiogenesis. Circ Res, 100, 782-94. https://doi.org/10.1161/01.RES.0000259593.07661.1e
- Nielsen K, Rolff HC, Eefsen RL, Vainer B (2014). The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod Pathol, 27, 1641-8. https://doi.org/10.1038/modpathol.2014.4
- Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT (1993). Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci USA, 90, 7533-7.
- Rasool S, Kadla SA, Rasool V, et al. (2013) A comparative overview of general risk factors associated with the incidence of colorectal cancer. Tumour Biol, 34, 2469-76. https://doi.org/10.1007/s13277-013-0876-y
- Schwartz SM, Benditt EP (1973). Cell replication in the aortic endothelium: A new method for study of the problem. Lab Invest, 28, 699-707.
- Tokunaga T, Oshika Y, Abe Y, et al (1998). Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer, 77, 998-1002. https://doi.org/10.1038/bjc.1998.164
- Vermeulen PB, Gasparini G, Fox SB, et al (1996). Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. J Cancer, 32, 2474-84.
- Vermeulen PB, Colpaert C, Salgado R, et al (2001). Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol, 195, 336-42. https://doi.org/10.1002/path.966
- Vermeulen PB, Gasparini G, Fox SB, et al (2002). Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. J Cancer, 38, 1564-79.
- Vermeulen PB, Verhoeven D, Fierens H, Hubens G, et al (1995). Micro vessel density, endothelial cell proliferation and tumour cell proliferation in human colorectaladenocarcinomas. Ann Oncol, 6, 59-64. https://doi.org/10.1093/oxfordjournals.annonc.a059043
- Yu T, Hou F, Liu M, et al (2012). Norcantharidin antiangiogenesis activity possibly through an endothelial cell pathway in human colorectal cancer. Asian Pac J Cancer Prev, 13, 499-503. https://doi.org/10.7314/APJCP.2012.13.2.499
- Zecchin A, Borgers G, Carmeliet P (2015). Endothelial cells and cancer cells: metabolic partners in crime? Curr Opin Hematol, 22, 234-42 https://doi.org/10.1097/MOH.0000000000000138
- Zhou LH, Hu Q, Sui H, et al (2012). Tanshinone II--a inhibits angiogenesis through down regulation of COX-2 in human colorectal cancer. Asian Pac J Cancer Prev, 13, 4453-8. https://doi.org/10.7314/APJCP.2012.13.9.4453
- Zhu LM, Zhao YZ, Ju HX et al (2014). Efficacy and safety of bevacizumab in Chinese patients with metastatic colorectal cancer. Asian Pac J Cancer Prev, 15, 6559-64. https://doi.org/10.7314/APJCP.2014.15.16.6559