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Changes of Plasma and Liver Tissue Levels of VEGF, bFGF and Endostatin in the N,NDiethylnitrosamine-induced Hepatocarcinogenesis and Progression in Rat Liver  

Kim, Beom-Gyu (Departments of Surgery, College of Medicine, Chung-Ang University)
Cha, Seong-Jae (Departments of Surgery, College of Medicine, Chung-Ang University)
Park, Sung-Jun (Departments of Surgery, College of Medicine, Chung-Ang University)
Lim, Hyun-Muk (Departments of Surgery, College of Medicine, Chung-Ang University)
Park, Eon-Sub (Departments of Pathology, College of Medicine, Chung-Ang University)
Publication Information
Annals of Surgical Treatment and Research / v.68, no.5, 2005 , pp. 422-429 More about this Journal
Abstract
Purpose: Proangiogenic and antiangiogenic growth factors are related to control of cancer progression and metastasis. The expression of Factor VIII-Related antigen in liver, that is marker of the vascular endothelial cell antigen, may be an indicator of neovascularization. This study aimed to monitor the change of plasma and tissue levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and endostatin in rat liver carcinogenesis and to determine the possibility of the future predictive indicator and antiangiogenic therapy application. Methods: Sprague-Dawley Rats received 120 ppm concentration diethylnitrosamine (DEN) in drinking water as a carcinogen and in control and experimental groups, sequentially sacrificed by three and seven rats at 3, 6, 9, 12, 15 and 18 weeks, respectively. The liver tissue was examined with light microscopy, immunohistochemistry and enzyme immunoassay method. Results: In hepatocarcinogenesis, the preneoplastic nodules appeared at 6 weeks after oral 120 ppm concentration DEN administration. The hepatocellular carcinomas and their pulmonary metastatic foci developed at 15 weeks and 18 weeks, respectively. The immunohistochemical staining of Factor VIII-Related antigen was negative in all sinusoids in normal control livers, but focal or scattered expression in preneoplastic nodules and diffuse expression were found in hepatocellular carcinomas. The tissue levels of VEGF and bFGF were found to have a direct correlation with the plasma levels, but not endostatin. The levels of VEGF and bFGF increased slightly in preneoplastic nodules and markedly elevated in hepatocellular carcinoma. However, there was no significant difference between the levels of VEGF and bFGF and the state of metastasis. There was no significant relation between the levels of endostatin and carcinogenesis and progression of the rat liver. Conclusion: From the above results, it could be suggested that VEGF and bFGF may play an important role in initiation and progression of hepatocellular carcinomas in rat liver, but not endostatin. Also, there was no correlation between the levels of VEGF and bFGF and the state of metastasis. Therefore, further study to determine the relationship between the angiogenic regulators and its receptors will serve as a promising research in the predictive indicator and antiangiogenic therapy.
Keywords
Hepatocarcinogenesis; FactorVIII-related antigen; VEGF; bFGF; Endostatin;
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1 Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, et al. Induction of vascular endothelial growth factor gene expression by interleukin-$1{\beta}$ in rat aortic smooth muscle cells. J Biol Cem 1995;270:308-12
2 Salgado R, Benoy I, Weytjens R, Vermenlen PB, Dirix LY. Serum vascular endothelial growth factor load and ilterleukin-6 in cancer patients-replay. Bri J Cancer 2000;82:1895-6   DOI   ScienceOn
3 Motto Y, Sawabu N, Yamaguchi Y, Terada T, Nakamura Y. Sinusoidal capillarization of human hepatocellular carcinoma: Possible promotion by fibroblast growth factor. Oncology 1993;50:270-4   DOI   ScienceOn
4 Folkman J, Satoson K, Ingber D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989;339:58-61   DOI   ScienceOn
5 Shichiri M, Hirata Y. Antiangiogenesis signals by endostatin. FASEB J 2001;15:1044-53   DOI   ScienceOn
6 Rifkin D, Mostakelli DS. Recent development in the cell biology of basic fibroblast growth factor. J Cell Biol 1989;109:1-6   DOI   ScienceOn
7 Ding I, Sun JZ, Fenton B, Liu WM, Kimsely P, Okunieff P, et al. Intratumoral administration of endostatin plasmid inhibits vascular growth and perfusion in MCa-4 murine mammary carcinomas. Cancer Res 2001;61:526-31
8 Petrovic LM, Burroughs A, Scheuer PJ. Hepatic sinusoidal endothelium Ulex lectin binding. Histopathology 1989;14:233-43   DOI   PUBMED
9 Ikebe T, Yamamoto T, Kubo S, Hirohashi K, Kinoshita K, Kaneda K, et al. Suppressive effect of the angiogenesis inhibitor TNP-470 on the development of carcinogen-induced hepatic nodules in Rats. Jpn J Can Res 1998;89:143-9   DOI
10 Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995;95:1789-97   DOI   ScienceOn
11 Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, et al. Endostatin induces endothelial cell apoptosis. J Biol Chem 1999;274:11721-6   DOI   ScienceOn
12 Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, et al. Quantification of angiogenesis in solid human tumors: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 1996;32A:2474-84
13 Mise M, Arii DS, Higashituji H, Furutani M, Niwano M. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 1996;23:455-63   DOI   PUBMED
14 Hata K, Dhar DK, Kanasaki H, Nakayama K, Fujiwaki R, Katabuchi H, et al. Serum endostatin levels in patients with epithelial ovarian cancer. Anticancer Res 2003;23:1907-12
15 Tischer E, Mitchell R, Hartman T, Silva S, Gospodarowicz D, Fiddes JC, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991;266:11947-54
16 Yamamoto T, Kaneda K, Hirohashi K, Kinoshita H, Sakurai M. Sinusoidal capillarization and arterial blood supply continuously proceed with the advance of the stages of hepatocarcinogenesis in the rat. Jpn J Cancer Res 1996;87:442-50   DOI
17 Folkman J, Klagsburm M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I. A heparin-binding angiogenic protein (basic fibroblast growth factor) is stored within basement membrane. Am J Pathol 1989;130:393-400
18 Deininger MH, Wybranietz WA, Graepler FTC, Lauer UM, Meyermann R, Schlueesenger HJ. Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway. FASEB J 2003;17:1267-76   DOI   ScienceOn
19 O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin an endogenous inhibitor of angiogenesis and tumor growth. Cell 1989;88:277-85
20 Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306-9   DOI   PUBMED
21 Kuroiwa M, Takeuchi T, Lee JH, Yoshizawa J, Hirato J, Kaneko S, et al. Continous versus intermittent administration of human Endostatin in xenografted Human Neuroblastoma. J Pediatric Surg 2003;38:1499-505   DOI   ScienceOn
22 Tate RL, Alexander M. Stability of nitrosamines in samples of lake water, soil, and sewage. J Natl Cancer Inst 1975;54:327-30
23 Mahadevan V, Hart IR. Metastasis and angiogenesis. Acta Oncol 1990;29:97-103   DOI   ScienceOn
24 Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Meds 1998;49:407-24   DOI   ScienceOn
25 Dhar DK, Ono T, Yamanoi A, Soda Y, Yamaguchi E, Rahman MA, et al. Serum endostatin predicts tumor vascularity in Hepatocellular Carcinoma. Cancer 2002;95:2189-95
26 Haratake J, Scheuer PJ. An immunohistochemical and ultrastructural study of the sinusoids of hepatocellular carcinoma. Cancer 1990;65:1985-93   DOI   PUBMED   ScienceOn
27 Ellis LM, Staley CA, Liu W, Fleming RYD, Parikh N, Bucana CA, et al. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem 1998;273:1052-7   DOI   ScienceOn
28 Du Z, Hou S. The anti-angiogenic activity of human endostatin inhibits bladder cancer growth and its mechanism. J Urology 2003;170:2000-3   DOI   ScienceOn
29 Cortinovis C, Kimeck F, Nogueira E. Rat hepatocarcinogenesis induced by N-nitrosodiethylamine and N-nitrosomorphine continuously administered at low doses. Am J Pathol 1991;139:1157-71
30 Hanahan D, Folkman J. Patterns and emerging mechanisms of angiogenic switch during tumorigenesis. Cell 1996;86:353-64   DOI   ScienceOn