Researching Progress of Tumor Lymphangiogenesis and Lymphatic Metastasis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Qinghua , WU Xiaoting

Department of General Surgery， West China Hospital， Sichuan University， Chengdu 610041， China;

Corresponding author：

Keywords：

Tumor metastasis,Lymphangiogenesis,Vascular endothelial growth factor,Vascular endothelial growth factor receptor

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【Abstract】Objective To understand the features of lymphatic vessel, and to summarize the foundation and mechanism of the promotion and inhibition of tumor lymphangiogenesis recorded on the current studies of animal experiments and clinical researches. Methods The related literatures of the structural features of lymphatic vessel, lymphatic endothelial molecular markers, the origin of lymphatic tumors, the molecular mechanisms and regulatory factors were reviewed, and the relationship between tumor lymphangiogenesis and lymphatic metastasis, the treatment targeting at the formation of the anti-tumor lymphatic vessel and its existing problems were also analyzed. Results Hyperplasia of lymphatic vessels occurred during the process of tumor formation and progression. The structural features of the lymphatic vessels in the tumor were conducive to tumor lymphatic metastasis. In recent years, methods of anti-lymphangiogenesis and inhibition of tumor lymphatic metastasis had achieved considerable success in animal experiments. However, there were still a lot of problems need to be solved. Conclusion Tumor lymphangiogenesis has a significantly positive correlation between tumor lymphatic metastasis and patients’ prognosis, which may indicate that treatment against the formation of tumor lymphatic vessel maybe effective.

Citation： ZHANG Qinghua,WU Xiaoting. Researching Progress of Tumor Lymphangiogenesis and Lymphatic Metastasis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2008, 15(3): 223-226. doi: Copy

1.	Pepper MS, Tille JC, Nisato R, et al. Lymphangiogenesis and tumor metastasis [J]. Cell Tissue Res, 2003; 314(1)∶167.
2.	Folkman J, Kaipainen A. Genes tell lymphatics to sprout or not [J]. Nat Immunol, 2004; 5(1)∶11.
3.	Schneider M, Büchler P, Giese N, et al. Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread [J]. Int J Oncol, 2006; 28(4)∶883.
4.	Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [J]. Science, 2002; 296(5574)∶1883.
5.	Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice [J]. Science, 1997; 276(5317)∶1423.
6.	Jones A, Fujiyama C, Turner K, et al. Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis [J]. BJU Int, 2000; 86(1)∶80.
7.	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.
8.	Valtola R, Salven P, Heikkila P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer [J]. Am J Pathol, 1999; 154(5)∶1381.
9.	敬静，李宏江，朱炜炜，等. 乳腺疾病中血管内皮生长因子的表达及其意义[J]. 中国普外基础与临床杂志， 2001； 8（5）∶322.
10.	Liersch R, Nay F, Lu L, et al. Induction of lymphatic endothelial cell differentiation in embryoid bodies [J]. Blood, 2006; 107(3)∶1214.
11.	Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype [J]. EMBO J, 2002; 21(7)∶1505.
12.	Witmer AN, van Blijswijk BC, Dai J, et al. VEGFR-3 in adult angiogenesis [J]. J Pathol, 2001; 195(4)∶490.
13.	Ny A, Koch M, Schneider M, et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis [J]. Nat Med, 2005; 11(9)∶998.
14.	Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation [J]. Nature, 2000; 407(6801)∶242.
15.	Makinen T, Veikkola T, Mustjoki S, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3 [J]. EMBO J, 2001; 20(17)∶4762.
16.	Stacker SA, Stenvers K, Caesar C, et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers [J]. J Biol Chem, 1999; 274(45)∶32127.
17.	Tsai PW, Shiah SG, Lin MT, et al. Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway [J]. J Biol Chem, 2003; 278(8)∶5750.
18.	Su JL, Shih JY, Yen ML, et al. Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma [J]. Cancer Res, 2004; 64(2)∶554.
19.	Tang RF, Wang SX, Zhang FR, et al. Interleukin-1alpha, 6 regulate the secretion of vascular endothelial growth factor A, C in pancreatic cancer [J].Hepatobiliary Pancreat Dis Int, 2005; 4(3)∶460.
20.	Jenny B, Harrison JA, Baetens D, et al. Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas [J]. J Pathol, 2006; 209(1)∶34.
21.	Liao X, Tang W, Cai Q, et al. Lymphangiogenesis in tumor tissues and 5’-nase, Flt-4, Flk-1 expressions [J]. Chin Med J (Engl), 2000; 113(11)∶1031.
22.	Kubo H, Cao R, Brakenhielm E, et al. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea [J]. Proc Natl Acad Sci USA, 2002; 99(13)∶8868.
23.	王天宝，董文广，韩方海，等. 血管内皮生长因子受体-3与胃癌临床病理因素的关系 [J]. 中国普外基础与临床杂志， 2004； 11（4）∶341.
24.	Saharinen P, Tammela T, Karkkainen MJ, et al. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation [J]. Trends Immunol, 2004; 25(7)∶387.
25.	Nathanson SD. Insights into the mechanisms of lymph node metastasis [J]. Cancer, 2003; 98(2)∶413.
26.	McCarthy DM, Hruban RH, Argani P, et al. Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: analysis of 140 cases [J]. Mod Pathol, 2003; 16(3)∶272.
27.	Kaliski A, Maggiorella L, Cengel KA, et al. Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion [J]. Mol Cancer Ther, 2005; 4(11)∶1717.
28.	Onogawa S, Kitadai Y, Tanaka S, et al. Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma [J]. Cancer Sci, 2004; 95(1)∶32.
29.	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.
30.	Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis [J]. Cancer Cell, 2005; 7(2)∶121.
31.	Matsumoto K, Konno H, Tanaka T, et al. Combination therapy with vascular endothelial growth factor neutralizing antibody and mitomycin C on human gastric cancer xenograft [J]. Jpn J Cancer Res, 2000; 91(7)∶748.
32.	Wroel T, Mazur G, Dziegiel P, et al. Density of intranodal lymphatics and VEGF-C expression in B-cell lymphoma and reactive lymph nodes [J]. Folia Histochem Cytobiol, 2006; 44(1)∶43.
33.	He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels [J]. Cancer Res, 2005; 65(11)∶4739.

1. Pepper MS, Tille JC, Nisato R, et al. Lymphangiogenesis and tumor metastasis [J]. Cell Tissue Res, 2003; 314(1)∶167.
2. Folkman J, Kaipainen A. Genes tell lymphatics to sprout or not [J]. Nat Immunol, 2004; 5(1)∶11.
3. Schneider M, Büchler P, Giese N, et al. Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread [J]. Int J Oncol, 2006; 28(4)∶883.
4. Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics [J]. Science, 2002; 296(5574)∶1883.
5. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice [J]. Science, 1997; 276(5317)∶1423.
6. Jones A, Fujiyama C, Turner K, et al. Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis [J]. BJU Int, 2000; 86(1)∶80.
7. 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.
8. Valtola R, Salven P, Heikkila P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer [J]. Am J Pathol, 1999; 154(5)∶1381.
9. 敬静，李宏江，朱炜炜，等. 乳腺疾病中血管内皮生长因子的表达及其意义[J]. 中国普外基础与临床杂志， 2001； 8（5）∶322.
10. Liersch R, Nay F, Lu L, et al. Induction of lymphatic endothelial cell differentiation in embryoid bodies [J]. Blood, 2006; 107(3)∶1214.
11. Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype [J]. EMBO J, 2002; 21(7)∶1505.
12. Witmer AN, van Blijswijk BC, Dai J, et al. VEGFR-3 in adult angiogenesis [J]. J Pathol, 2001; 195(4)∶490.
13. Ny A, Koch M, Schneider M, et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis [J]. Nat Med, 2005; 11(9)∶998.
14. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation [J]. Nature, 2000; 407(6801)∶242.
15. Makinen T, Veikkola T, Mustjoki S, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3 [J]. EMBO J, 2001; 20(17)∶4762.
16. Stacker SA, Stenvers K, Caesar C, et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers [J]. J Biol Chem, 1999; 274(45)∶32127.
17. Tsai PW, Shiah SG, Lin MT, et al. Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway [J]. J Biol Chem, 2003; 278(8)∶5750.
18. Su JL, Shih JY, Yen ML, et al. Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma [J]. Cancer Res, 2004; 64(2)∶554.
19. Tang RF, Wang SX, Zhang FR, et al. Interleukin-1alpha, 6 regulate the secretion of vascular endothelial growth factor A, C in pancreatic cancer [J].Hepatobiliary Pancreat Dis Int, 2005; 4(3)∶460.
20. Jenny B, Harrison JA, Baetens D, et al. Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas [J]. J Pathol, 2006; 209(1)∶34.
21. Liao X, Tang W, Cai Q, et al. Lymphangiogenesis in tumor tissues and 5’-nase, Flt-4, Flk-1 expressions [J]. Chin Med J (Engl), 2000; 113(11)∶1031.
22. Kubo H, Cao R, Brakenhielm E, et al. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea [J]. Proc Natl Acad Sci USA, 2002; 99(13)∶8868.
23. 王天宝，董文广，韩方海，等. 血管内皮生长因子受体-3与胃癌临床病理因素的关系 [J]. 中国普外基础与临床杂志， 2004； 11（4）∶341.
24. Saharinen P, Tammela T, Karkkainen MJ, et al. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation [J]. Trends Immunol, 2004; 25(7)∶387.
25. Nathanson SD. Insights into the mechanisms of lymph node metastasis [J]. Cancer, 2003; 98(2)∶413.
26. McCarthy DM, Hruban RH, Argani P, et al. Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: analysis of 140 cases [J]. Mod Pathol, 2003; 16(3)∶272.
27. Kaliski A, Maggiorella L, Cengel KA, et al. Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion [J]. Mol Cancer Ther, 2005; 4(11)∶1717.
28. Onogawa S, Kitadai Y, Tanaka S, et al. Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma [J]. Cancer Sci, 2004; 95(1)∶32.
29. 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.
30. Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis [J]. Cancer Cell, 2005; 7(2)∶121.
31. Matsumoto K, Konno H, Tanaka T, et al. Combination therapy with vascular endothelial growth factor neutralizing antibody and mitomycin C on human gastric cancer xenograft [J]. Jpn J Cancer Res, 2000; 91(7)∶748.
32. Wroel T, Mazur G, Dziegiel P, et al. Density of intranodal lymphatics and VEGF-C expression in B-cell lymphoma and reactive lymph nodes [J]. Folia Histochem Cytobiol, 2006; 44(1)∶43.
33. He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels [J]. Cancer Res, 2005; 65(11)∶4739.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Researching Progress of Tumor Lymphangiogenesis and Lymphatic Metastasis

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