Expression and Significance of VEGF-C in Hepatocellular Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YE Yibiao , CHEN Tao.

Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital (The Second Affiliated Hospital) of Sun Yat-sen University, Guangzhou 510120, China;

Corresponding author：

Keywords：

Hepatocellular carcinoma; Vascular endothelial growth factor-C; FMS-like tyrosine kinase 4; CD34; Immunohistochemistry

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Objective To investigate the expressions of vascular endothelial growth factor-C (VEGF-C) and its receptor Flt-4 in hepatocellular carcinoma (HCC), in order to analyze the relationships among their expressions, angiogenesis, lymph-genesis, and clinicopathologic features of HCC. Methods Sixty-two cases of HCC and 15 cases of normal hepatic tissue were studied with immunohistochemical method in order to inspect the expressions of VEGF-C and Flt-4, and to calculate the microvessel density (MVD) marked by CD34 and the lymphatic vessel density (LVD) marked by Flt-4. Besides their correlations, their relations with clinicopathologic features of HCC were further analyzed. Results The positive rates of VEGF-C and Flt-4 were obviously higher in HCC than those in normal hepatic tissue (P lt;0.05, P lt;0.01). The expression of VEGF-C in HCC was remarkably related with portal vein tumor emboli, histological differentiation of HCC, and postoperative recurrence and metastasis (P lt;0.05, P lt;0.01). The expression of Flt-4 in HCC was also related with histological differentiation and postoperative recurrence (P lt;0.05, P lt;0.01). MVD was related with tumor size, TNM clinical stage, histological differentiation, portal vein tumor emboli, and postoperative recurrence and metastasis (P lt;0.05, P lt;0.01). LVD was related with histological differentiation, postoperative recurrence and metastasis (P lt;0.05, P lt;0.01). Additionally, there was positive correlation between VEGF-C and Flt-4, MVD or LVD, Flt-4 and MVD or LVD, MVD and LVD, respectively (P lt;0.01). Conclusions VEGF-C and Flt-4 are highly expressed in HCC, and are related with postoperative recurrence, are positive correlated with MVD and LVD. It suggests that VEGF-C/Flt-4 might has an effect on progression and prognosis of HCC through promoting angiogenesis and lymph-genesis.

Citation： YE Yibiao,CHEN Tao.. Expression and Significance of VEGF-C in Hepatocellular Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(11): 1152-1157. doi: Copy

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6.	Ogawa Y, Chung YS, Nakata B. Microvessel quantitation in invasive breast cancer by staining for factor Ⅷ-related antigen [J]. Br J Cancer, 1995; 71(6): 1297-1301.
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13.	Liu XE, Sun XD, Wu JM. Expression and significance of VEGF-C and FLT-4 in gastric cancer [J]. World J Gastroenterol, 2004; 10(3): 352-355.
14.	Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas [J]. Int J Cancer, 2001; 93(5): 662-666.
15.	Noguchi T, Takeno S, Shibata T, et al. VEGF-C expression correlates with histological differentiation and metastasis in squamous cell carcinoma of the esophagus [J]. Oncol Rep, 2002; 9(5): 995-999.
16.	Auvinen MI, Sihvo EI, Ruohtula T, et al. Incipient angiogenesis in Barrett’s epithelium and lymphangiogenesis in Barrett’s adenocarcinoma [J]. J Clin Oncol, 2002; 20(13): 2971-2979.
17.	Furudoi A, Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma [J]. Oncology, 2002; 62(2): 157-166.
18.	Akiyoshi F, Sata M, Suzuki H, et al. Serum vascular endothelial growth factor levels in various liver diseases [J]. Dig Dis Sci, 1998; 43(1): 41-45.
19.	El-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver [J]. Hepatology, 1998; 27(6): 1554-1562.
20.	崔晓楠, 候力. 组织微阵列方法检测CD105、VEGF-C在肝癌组织中的表达 [J]. 医学与哲学(临床决策论坛版), 2006; 27(5): 39-41， 48.
21.	Takahashi Y, Bucana CD, Cleary KR, et al. p53, vessel count, and vascular endothelial growth factor expression in human colon cancer [J]. Int J Cancer, 1998; 79(1): 34-38.
22.	Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas [J]. Int J Cancer, 2001; 93(5): 662-666.
23.	Clarijs R, Ruiter DJ, de Waal RM. Lymphangiogenesis in malignant tumours: Does it occur? [J]. J Pathol, 2001; 193(2): 143-146.
24.	于大海, 温玉明, 王昌美, 等. VEGFR-3表达与口腔癌淋巴道转移的关系 [J]. 临床口腔医学杂志, 2001; 17(4): 243-245.
25.	蒋道荣, 姚登福, 祝勇, 等. 肝癌组织血管内皮因子表达及其临床意义 [J]. 中国医师杂志, 2004; 6(2): 158-160.
26.	Sugimachi K, Tanaka S, Taguchi K, et al. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma [J]. J Clin Pathol, 2003; 56(11): 854-860.
27.	Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [J]. Science, 2002; 296(5574): 1883-1886.
28.	Stevenson DP, Milligan SR, Collins WP. Effects of platelet-derived endothelial cell growth factor/thymidine phosphorylase, substrate, and products in a three-dimensional model of angiogenesis [J]. Am J Pathol, 1998; 152(6): 1641-1646.

1. Jeng KS, Sheen IS, Wang YC, et al. Is the vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma of prognostic value after resection? [J]. World J Gastroenterol， 2004; 10(5): 676-681.
2. Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease [J]. Cancer， 1999; 85(1): 178-187.
3. Yamaguchi R, Yano H, Nakashima O, et al. Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma [J]. J Gastroenterol Hepatol, 2006; 21(1 Pt 1): 152-160.
4. Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases [J]. EMBO J, 1996; 15(2): 290-298.
5. Hagedorn M, Bikfalvi A. Target molecules for anti-angiogenic therapy: from basic research to clinical trials [J]. Crit Rev Oncol Hematol, 2000; 34(2): 89-110.
6. Ogawa Y, Chung YS, Nakata B. Microvessel quantitation in invasive breast cancer by staining for factor Ⅷ-related antigen [J]. Br J Cancer, 1995; 71(6): 1297-1301.
7. 陈自强, 卞修武. 血管内皮生长因子家族 [J]. 国外医学·生理、病理科学与临床分册， 2000; 20(3): 187-189.
8. Yonemura Y, Endo Y, Fujita H, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer [J]. Clin Cancer Res, 1999; 5(7): 1823-1829.
9. Yonemura Y, Fushida S, Bando E, et al. Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer [J]. Eur J Cancer, 2001; 37(7): 918-923.
10. Ichikura T, Tomimatsu S, Ohkura E, et al. Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma [J]. J Surg Oncol, 2001; 78(2): 132-137.
11. Takahashi A, Kono K, Itakura J, et al. Correlation of vascular endothelial growth factor-C expression with tumor-infiltrating dendritic cells in gastric cancer [J]. Oncology, 2002; 62(2): 121-127.
12. Ishikawa M, Kitayama J, Kazama S, et al. Expression of vascular endothelial growth factor C and D (VEGF-C and -D) is an important risk factor for lymphatic metastasis in undifferentiated early gastric carcinoma [J]. Jpn J Clin Oncol, 2003; 33(1): 21-27.
13. Liu XE, Sun XD, Wu JM. Expression and significance of VEGF-C and FLT-4 in gastric cancer [J]. World J Gastroenterol, 2004; 10(3): 352-355.
14. Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas [J]. Int J Cancer, 2001; 93(5): 662-666.
15. Noguchi T, Takeno S, Shibata T, et al. VEGF-C expression correlates with histological differentiation and metastasis in squamous cell carcinoma of the esophagus [J]. Oncol Rep, 2002; 9(5): 995-999.
16. Auvinen MI, Sihvo EI, Ruohtula T, et al. Incipient angiogenesis in Barrett’s epithelium and lymphangiogenesis in Barrett’s adenocarcinoma [J]. J Clin Oncol, 2002; 20(13): 2971-2979.
17. Furudoi A, Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma [J]. Oncology, 2002; 62(2): 157-166.
18. Akiyoshi F, Sata M, Suzuki H, et al. Serum vascular endothelial growth factor levels in various liver diseases [J]. Dig Dis Sci, 1998; 43(1): 41-45.
19. El-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver [J]. Hepatology, 1998; 27(6): 1554-1562.
20. 崔晓楠, 候力. 组织微阵列方法检测CD105、VEGF-C在肝癌组织中的表达 [J]. 医学与哲学(临床决策论坛版), 2006; 27(5): 39-41， 48.
21. Takahashi Y, Bucana CD, Cleary KR, et al. p53, vessel count, and vascular endothelial growth factor expression in human colon cancer [J]. Int J Cancer, 1998; 79(1): 34-38.
22. Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas [J]. Int J Cancer, 2001; 93(5): 662-666.
23. Clarijs R, Ruiter DJ, de Waal RM. Lymphangiogenesis in malignant tumours: Does it occur? [J]. J Pathol, 2001; 193(2): 143-146.
24. 于大海, 温玉明, 王昌美, 等. VEGFR-3表达与口腔癌淋巴道转移的关系 [J]. 临床口腔医学杂志, 2001; 17(4): 243-245.
25. 蒋道荣, 姚登福, 祝勇, 等. 肝癌组织血管内皮因子表达及其临床意义 [J]. 中国医师杂志, 2004; 6(2): 158-160.
26. Sugimachi K, Tanaka S, Taguchi K, et al. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma [J]. J Clin Pathol, 2003; 56(11): 854-860.
27. Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [J]. Science, 2002; 296(5574): 1883-1886.
28. Stevenson DP, Milligan SR, Collins WP. Effects of platelet-derived endothelial cell growth factor/thymidine phosphorylase, substrate, and products in a three-dimensional model of angiogenesis [J]. Am J Pathol, 1998; 152(6): 1641-1646.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression and Significance of VEGF-C in Hepatocellular Carcinoma

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