• 中山大學(xué)孫逸仙紀(jì)念醫(yī)院(中山大學(xué)附屬第二醫(yī)院)肝膽外科(廣州 510120);

目的 通過(guò)檢測(cè)血管內(nèi)皮生長(zhǎng)因子-C(VEGF-C)及其受體Flt-4在肝癌組織中的表達(dá)，分析它們與肝癌脈管形成及臨床病理特征之間的關(guān)系，以了解VEGF-C在肝癌進(jìn)程中的作用。方法 采用免疫組化染色法檢測(cè)62例肝細(xì)胞肝癌(HCC)組織及15例正常肝組織中VEGF-C和Flt-4的表達(dá)，并計(jì)算以CD34為標(biāo)記的微血管密度(MVD)和以Flt-4為標(biāo)記的淋巴管密度(LVD)，分析它們相互之間及各自與HCC臨床病理特征之間的關(guān)系。結(jié)果 HCC組織中VEGF-C及Flt-4的陽(yáng)性表達(dá)率均明顯高于正常肝組織(P lt;0.05,P lt;0.01)。HCC組織中VEGF-C的表達(dá)與有無(wú)門靜脈癌栓、腫瘤組織學(xué)分化程度、術(shù)后復(fù)發(fā)及轉(zhuǎn)移有關(guān)(P lt;0.05,P lt;0.01)； Flt-4的表達(dá)與腫瘤組織學(xué)分化程度及術(shù)后復(fù)發(fā)有關(guān)(P lt;0.05,P lt;0.01)； MVD與腫瘤大小、TNM臨床分期、腫瘤組織學(xué)分化程度、有無(wú)門靜脈癌栓、術(shù)后復(fù)發(fā)和轉(zhuǎn)移有關(guān)(P lt;0.05,P lt;0.01)； LVD與腫瘤組織學(xué)分化程度、術(shù)后復(fù)發(fā)和轉(zhuǎn)移有關(guān)(P lt;0.05,P lt;0.01)。HCC組織中VEGF-C和Flt-4的表達(dá)及MVD和LVD這四者之間均兩兩呈正相關(guān)(P lt;0.01)。結(jié)論 VEGF-C和Flt-4在肝癌組織中高表達(dá)并與術(shù)后復(fù)發(fā)有關(guān)，且與MVD及LVD呈正相關(guān)，提示VEGF-C/Flt-4通路可能通過(guò)促進(jìn)肝癌血管和淋巴管的生成從而影響肝癌的進(jìn)展及預(yù)后。

引用本文： 葉義標(biāo),陳濤. VEGF-C在肝癌組織的表達(dá)及意義. 中國(guó)普外基礎(chǔ)與臨床雜志, 2010, 17(11): 1152-1157. doi: 復(fù)制

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. 陳自強(qiáng), 卞修武. 血管內(nèi)皮生長(zhǎng)因子家族 [J]. 國(guó)外醫(yī)學(xué)·生理、病理科學(xué)與臨床分冊(cè)， 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. 崔曉楠, 候力. 組織微陣列方法檢測(cè)CD105、VEGF-C在肝癌組織中的表達(dá) [J]. 醫(yī)學(xué)與哲學(xué)(臨床決策論壇版), 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, 溫玉明, 王昌美, 等. VEGFR-3表達(dá)與口腔癌淋巴道轉(zhuǎn)移的關(guān)系 [J]. 臨床口腔醫(yī)學(xué)雜志, 2001; 17(4): 243-245.
25. 蔣道榮, 姚登福, 祝勇, 等. 肝癌組織血管內(nèi)皮因子表達(dá)及其臨床意義 [J]. 中國(guó)醫(yī)師雜志, 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. 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. 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. 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. 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. 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. 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. 7. 陳自強(qiáng), 卞修武. 血管內(nèi)皮生長(zhǎng)因子家族 [J]. 國(guó)外醫(yī)學(xué)·生理、病理科學(xué)與臨床分冊(cè)， 2000; 20(3): 187-189.
  8. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 20. 崔曉楠, 候力. 組織微陣列方法檢測(cè)CD105、VEGF-C在肝癌組織中的表達(dá) [J]. 醫(yī)學(xué)與哲學(xué)(臨床決策論壇版), 2006; 27(5): 39-41， 48.
  21. 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. 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. 23. Clarijs R, Ruiter DJ, de Waal RM. Lymphangiogenesis in malignant tumours: Does it occur? [J]. J Pathol, 2001; 193(2): 143-146.
  24. 24. 于大海, 溫玉明, 王昌美, 等. VEGFR-3表達(dá)與口腔癌淋巴道轉(zhuǎn)移的關(guān)系 [J]. 臨床口腔醫(yī)學(xué)雜志, 2001; 17(4): 243-245.
  25. 25. 蔣道榮, 姚登福, 祝勇, 等. 肝癌組織血管內(nèi)皮因子表達(dá)及其臨床意義 [J]. 中國(guó)醫(yī)師雜志, 2004; 6(2): 158-160.
  26. 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. 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. 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.