• 四川大學華西醫(yī)院普外科（成都610041）;

【摘要】目的 介紹VEGFC和VEGFD在淋巴管生成及消化道腫瘤淋巴轉(zhuǎn)移中的作用的有關研究進展。
方法 對近年來VEGFC和VEGFD的結構功能特點、及其在淋巴管生成和消化道腫瘤淋巴轉(zhuǎn)移中的作用的研究進展進行綜述和分析。
結果 VEGFC和VEGFD可促進血管、淋巴管生成和淋巴轉(zhuǎn)移。胃癌中VEGFC mRNA及其蛋白表達與淋巴侵犯、靜脈侵犯、淋巴結轉(zhuǎn)移及低的5年生存率相關； VEGFC在食管癌和結直腸癌中的作用以及VEGFD在結直腸癌中的作用有待進一步研究。
結論 VEGFC、VEGFD/VEGFR3信號通路可能成為控制腫瘤生長轉(zhuǎn)移的理想靶點，抗新生淋巴管治療有望成為腫瘤生物治療新模式。

引用本文： 達明緒,伍曉汀,羅婷. 淋巴管生成因子與消化道腫瘤. 中國普外基礎與臨床雜志, 2005, 12(6): 630-633. doi: 復制

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1. 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(7)1751.
2. Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGFD) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) [J]. Proc Natl Acad Sci USA, 1998; 95(2)548.
3. McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGFC and VEGFD [J]. J Exp Med, 2003; 198(6)86.
4. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGFC promotes breast cancer metastasis [J]. Nat Med, 2001; 7(2)192.
5. Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factorCmediated lymphangiogenesis promotes tumour metastasis [J]. EMBO J, 2001; 20(4)672.
6. Stacker SA, Caesar C, Baldwin ME, et al. VEGFD promotes the metastatic spread of tumor cells via the lymphatics [J]. Nat Med, 2001; 7(2)186.
7. Veikkola T, Jussila L, Makinen T, et al. Signalling via vascular endothelial growth factor receptor3 is sufficient for lymphangiogenesis in transgenic mice [J]. EMBO J, 2001; 20(6)1223.
8. Krishnan J, Kirkin V, Steffen A, et al. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)C and VEGFD in tumors and its relationship to lymphatic metastasis in immunocompetent rats [J]. Cancer Res, 2003; 63(3)713.
9. Leu AJ, Berk DA, Lymboussaki A, et al. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation [J]. Cancer Res, 2000; 60(16)4324.
10. Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [J]. Science, 2002; 296(5574)1883.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. George ML, Tutton MG, Janssen F, et al. VEGFA, VEGFC, and VEGFD in colorectal cancer progression [J]. Neoplasia, 2001; 3(5)420.
22. Andre T, Kotelevets L, Vaillant JC, et al. Vegf, VegfB, VegfC and their receptors KDR, FLT1 and FLT4 during the neoplastic progression of human colonic mucosa [J]. Int J Cancer, 2000; 86(2)174.
23. White JD, Hewett PW, Kosuge D, et al. Vascular endothelial growth factorD expression is an independent prognostic marker for survival in colorectal carcinoma [J]. Cancer Res, 2002; 62(6)1669.
24. Kawakami M, Furuhata T, Kimura Y, et al. Quantification of vascular endothelial growth factorC and its receptor3 messenger RNA with realtime quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer [J]. Surgery, 2003; 133(3)300.
25. Witte D, Thomas A, Ali N, et al. Expression of the vascular endothelial growth factor receptor3 (VEGFR3) and its ligand VEGFC in human colorectal adenocarcinoma [J]. Anticancer Res, 2002; 22(3)1463.
  1. 1. 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(7)1751.
  2. 2. Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGFD) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) [J]. Proc Natl Acad Sci USA, 1998; 95(2)548.
  3. 3. McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGFC and VEGFD [J]. J Exp Med, 2003; 198(6)86.
  4. 4. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGFC promotes breast cancer metastasis [J]. Nat Med, 2001; 7(2)192.
  5. 5. Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factorCmediated lymphangiogenesis promotes tumour metastasis [J]. EMBO J, 2001; 20(4)672.
  6. 6. Stacker SA, Caesar C, Baldwin ME, et al. VEGFD promotes the metastatic spread of tumor cells via the lymphatics [J]. Nat Med, 2001; 7(2)186.
  7. 7. Veikkola T, Jussila L, Makinen T, et al. Signalling via vascular endothelial growth factor receptor3 is sufficient for lymphangiogenesis in transgenic mice [J]. EMBO J, 2001; 20(6)1223.
  8. 8. Krishnan J, Kirkin V, Steffen A, et al. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)C and VEGFD in tumors and its relationship to lymphatic metastasis in immunocompetent rats [J]. Cancer Res, 2003; 63(3)713.
  9. 9. Leu AJ, Berk DA, Lymboussaki A, et al. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation [J]. Cancer Res, 2000; 60(16)4324.
  10. 10. Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [J]. Science, 2002; 296(5574)1883.
  11. 11. 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.
  12. 12. 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.
  13. 13. 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.
  14. 14. 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.
  15. 15. 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.
  16. 16. 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.
  17. 17. 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.
  18. 18. 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.
  19. 19. 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.
  20. 20. 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.
  21. 21. George ML, Tutton MG, Janssen F, et al. VEGFA, VEGFC, and VEGFD in colorectal cancer progression [J]. Neoplasia, 2001; 3(5)420.
  22. 22. Andre T, Kotelevets L, Vaillant JC, et al. Vegf, VegfB, VegfC and their receptors KDR, FLT1 and FLT4 during the neoplastic progression of human colonic mucosa [J]. Int J Cancer, 2000; 86(2)174.
  23. 23. White JD, Hewett PW, Kosuge D, et al. Vascular endothelial growth factorD expression is an independent prognostic marker for survival in colorectal carcinoma [J]. Cancer Res, 2002; 62(6)1669.
  24. 24. Kawakami M, Furuhata T, Kimura Y, et al. Quantification of vascular endothelial growth factorC and its receptor3 messenger RNA with realtime quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer [J]. Surgery, 2003; 133(3)300.
  25. 25. Witte D, Thomas A, Ali N, et al. Expression of the vascular endothelial growth factor receptor3 (VEGFR3) and its ligand VEGFC in human colorectal adenocarcinoma [J]. Anticancer Res, 2002; 22(3)1463.