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The Role of Vascular Endothelial Growth Factor (VEGF) and p53 Status for Angiogenesis in Gastric Cancer  

Joo, Young-Eun (Departments of Internal Medicine, Chonnam National University Medical School)
Sohn, Young-Hae (Departments of Internal Medicine, Chonnam National University Medical School)
Joo, So-Young (Departments of Internal Medicine, Chonnam National University Medical School)
Lee, Wan-Sik (Departments of Internal Medicine, Chonnam National University Medical School)
Min, Sang-Woon (Departments of Internal Medicine, Chonnam National University Medical School)
Park, Chang-Hwan (Departments of Internal Medicine, Chonnam National University Medical School)
Rew, Jong-Sun (Departments of Internal Medicine, Chonnam National University Medical School)
Choi, Sung-Kyu (Departments of Internal Medicine, Chonnam National University Medical School)
Park, Chang-Soo (Departments of Internal Medicine, Pathology Chonnam National University Medical School)
Kim, Young-Jin (Departments of General Surgery, Chonnam National University Medical School)
Kim, Sei-Jong (Departments of Internal Medicine, Chonnam National University Medical School)
Publication Information
The Korean journal of internal medicine / v.17, no.4, 2002 , pp. 211-219 More about this Journal
Abstract
Background : Angiogenesis is of crucial importance for tumor growth and development of metastases. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity and mutations of the p53 gene has been thought to upregulate VEGF. The purpose of our study was to evaluate the prognostic significance of these tumor biomarkers for angiogenesis relative to the information derived from established clinicopathological parameters in gastric cancer. Methods : In this study, we conducted an immunohistochemical investigation of VEGF and p53 expression in 145 tissue samples obtained from gastric cancer patients undergoing curative surgical treatment. To evaluate angiogenesis, microvessel density (MVD) was counted by staining endothelial cells immunohistochemically using anti-CD34 monoclonal antibody. Results : High MVD was significantly associated with depth of tumor invasion and distant metastasis (p=0.004, 0.021, respectively). Moreover, overall survival for patients with high MVD were significantly lower than that of low MVD (p=0.048). Positive expression of VEGF correlated significantly with lymph node and distant etastasis (p=0.040, 0.048, respectively). However, no significant correlation was found between p53 expression and various clinicopathologica parameters. VEGF positive tumors showed a higher MVD than VEGF negative tumors (p=0.028). The expression of p53 did not correlate with VEGF expression. Also, the relationship between the status of p53 expression and MVD had not statistically significant differences. In the multivariate analysis, status of VEGF, p53 expression and MVD were not an independent prognostic factor. Conclusion : VEGF seems to be an important, clinically relevant inducer of angiogenesis and angiogenesis assessed by the MVD may be a useful marker or predicting metastasis in gastric cancer. However, further studies are warranted to clarify the impact of p53.
Keywords
Angiogenesis; Genes; p53; Stomach Neoplasms; Immunohistochemistry;
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1 Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582-1584, 1994.   DOI   PUBMED
2 Macchiarini P, Fontanini G, Hardin MJ, Squartini F, Angeletti CA. Relation of neovascularization to metastasis of non-small cell lung cancer. Lancet 340:145-147, 1992.   DOI   ScienceOn
3 Weider N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401-409, 1993.   PUBMED
4 Takahashi Y, Kitadai Y, Bucana CD, Cleary K, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis and proliferation of human colon cancer. Cancer Res 55:3964-3968, 1995.   PUBMED
5 Watanabe H, Jass JR, Sobin LH. Histologic typing of oesophageal and gastric tumors. WHO International Histologic Classification of Tumors. Berlin, Heidelberg, New York, Paris, Tokyo, Hong Kong, Springer-Verlag, 1990.
6 American Joint Committee on Cancer. Manual for staging cancer. In: Stomach cancer. 71-76 Philadelphia, Lippincott-Raven, 1997.
7 Reed JA, Manahan LJ, Park CS, Brigati DJ. Complete one-hour immunohistochemistry based on capillary action. Biotechniques 13:434-443, 1992.   PUBMED
8 Ellis LM, Fidler IJ. Angiogenesis and metastasis. Eur J Cancer 32:2451-2460, 1996.   DOI   ScienceOn
9 Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T, Horiuchi T, Muraoka R, Iki M. Extent of tumor vascularization correlates with prognosis and hematogenous metastasis in gastric carcinomas. Cancer Res 56:2671-2676, 1996.   PUBMED
10 Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306-1309, 1989.   DOI   PUBMED
11 Dix B, Robbins P, Carrello S, Howe A, Iacopetta B. Comparison of p 53 gene mutation and protein overexpression in colorectal carcinomas. Br J Cancer 70:585-590, 1990.
12 Bossi P, Viale G, Lee AK, Alfano R, Coggi G, Bosari S. Angiogenesis in colorectal tumors: microvessel quantitation in adenomas and carcinomas with clinicopathological correlations. Cancer Res 55:5049-5053, 1995.   PUBMED
13 Mooteri S, Rubin D, Leurgans S, Jakate S, Drabe E, Saclarides T. Tumor angiogenesis in primary and metastatic colorectal cancers. Dis Colon Rectum 39:1073-1080, 1996.   DOI   ScienceOn
14 Weidner N. Angiogenesis as a predictor of clinical outcome in cancer patients. Hum Pathol 31:403-405, 2000.   DOI   PUBMED   ScienceOn
15 Weider N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metatstasis: correlation in invasive breast carcinoma. N Engl J Med 324:1-8, 1991.   DOI   ScienceOn
16 Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezzella F, Viale G, Weidner N, Harris AL, Dirix LY. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32:2474-2484, 1996.   DOI   ScienceOn
17 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353-364, 1996.   DOI   ScienceOn
18 Maeda K, Kang SM, Onoda N, Ogawa M, Sawada T, Nakata B, Kato Y, Chung YS, Sowa M. Expression of p53 and vascular endothelial growth factor associated with tumor angiogenesis and prognosis in gastric cancer. Oncology 55:594-599, 1998.   DOI   ScienceOn
19 Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CC. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 22:3551-3555, 1994.   PUBMED
20 Hall PA, Going JJ. Review. Predicting the future: a critical appraisal of cancer prognosis studies. Histopathology 35:489-494, 1999.   DOI   ScienceOn
21 Bouck N. p53 and angiogenesis. Biochem Biophys Acta 1287:63-66, 1996.
22 Kahlenberg MS, Stoler DL, Rodriguez-Bigas MA, Weber TK, Driscoll DL, Anderson GR, Petrelli NJ. p53 tumor suppressor gene mutations predict decreased survival of patients with sporadic colorectal carcinoma. Cancer 88:1814-1819, 2000.   DOI   ScienceOn
23 Lauren P. The two histologic main types of gastric carcinoma. Acta Pathol Microbiol Scand 63:31-49, 1965.
24 Ferrara N, Heinsohn H, Walder CE, Bunting S, Thomas GR. The regulation of blood vessel growth by vascular endothelial growth factor. Ann NY Acad Sci 752:246-256, 1995.   DOI
25 Giatromanolaki A, Koukourakis MI, Stathopoulos GP, Kapsoritakis A, Paspatis G, Kakolyris S, Sivridis E, Georgoulias V, Harris AL, Gatter KC. Angiogenic interactions of vascular endothelial growth factor, of thymidine phosphorylase and of p53 protein expression in locally advanced gastric cancer. Oncol Res 12:33-41, 2000.   PUBMED
26 Folkman J, Shing Y. Angiogenesis. J Biol Chem 267:10931-10934,1992.
27 Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36:127-137, 1995.   DOI   PUBMED   ScienceOn
28 Van Meir EG, Polverini P, Chazin VR, Su Huang HJ, de Tribolet N, Cavenee WK. Release of an inhibitor of angiogenesis upon induction of wild-type p53 expression in glioblastoma cells. Nat Genet 8:171-176, 1994.   DOI   ScienceOn
29 Folkman J. Clinical application of research on angiogenesis. N Engl J Med 333:1757-1763, 1995.   DOI   ScienceOn
30 Kolch W, Martiny-Baron G, Kieser A, Marme D. Regulation of the expression of the VEGF/VPS and its receptors: role in tumor angiogenesis. Breast Cancer Res Treat 36:139-155, 1995.   DOI   ScienceOn
31 Salvesen HB, Iversen OE, Akslen LA. Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study. J Clin Oncol 17:1382-1390, 1999.   DOI   PUBMED
32 Kieser A, Weich HA, Brandner G, Marme D, Lolch W. Mutant p53 potentiates protein kinase C production of vascular endothelial growth factor expression. Oncogene 9:963-969, 1994.   PUBMED
33 Fujimoto K, Hosotani R, Wada M, Lee JU, Koshiba T, Miyamoto Y, Tsuji S, Nakajima S, Doi R, Imamura M. Expression of two angiogenic factors, vascular endothelial growth factor and platelet-derived endothelial cell growth factor in human pancreatic cancer, and its relationship to angiogenesis. Eur J Cancer 34:1439-1447, 1998.   DOI   ScienceOn
34 Saito H, Tujitani S, Ikeguchi M, Maeta M, Kaibara N. Neoangiogenesis and relationship to nuclear p53 accumulation and vascular endothelial growth factor expression in advanced gastric carcinoma. Oncology 57:164-172, 1999.   DOI   ScienceOn
35 Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4-6, 1990.
36 Risau W. Mechanisms of angiogenesis. Nature 386:671-674, 1997.   DOI   PUBMED   ScienceOn
37 Maehara Y, Kabashima A, Koga T, Tokunaga E, Takeuchi H, Kakeji Y, Sugimachi K. Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma. Surgery 128:408-416, 2000.   DOI   ScienceOn