Lymphangiogenic Factors and Gastrointestinal Tract Malignant Neoplasmas_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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DA Mingxu , WU Xiaoting , LUO Ting.

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Keywords：

Vascular endothelial growth factor-C Vascular endothelial growth factor-D Lymphangiogenesis Gastrointestinal neoplasmas

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【Abstract】Objective To introduce the current studies of the role of vascular endothelial growth factorC (VEGFC) and VEGFD in lymphangiogenesis and lymph node metastasis of gastrointestinal neoplasma.
Methods The related literatures in recent 5 years were reviewed.
Results The growth factors VEGFC and VEGFD enhance lymphangiogenic metastasis of gastrointestinal neoplasma with the property of angiogenesis and lymphangiogenesis. In gastric adenocarcinoma, VEGFC mRNA and tissue protein expression correlate with lymphatic invasion, lymph node metastasis, venous invasion and reduced 5year survival rates. The role of VEGFC in esophageal squamous cancer and colorectal cancer and VEGFD in colorectal cancer is not certain, with conflicting reports in the published literatures.
Conclusion The VEGFC, VEGFD/VEGFR3 signal pathway may become the ideal target for inhibition of tumor proliferation and metastases, antilymphangiogenesis therapy may be a novel potential strategy in tumor biological therapy.

Citation： DA Mingxu,WU Xiaoting,LUO Ting.. Lymphangiogenic Factors and Gastrointestinal Tract Malignant Neoplasmas. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2005, 12(6): 630-633. doi: Copy

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. 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Lymphangiogenic Factors and Gastrointestinal Tract Malignant Neoplasmas

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