Researching Progress of The Relationship of VEGF-C and Its Receptor with Lymphatic Metastasis In Gastric Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Shenghua , YU Jiwei , JIANG Bojian .

Department of General Surgery, The Third People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China;

Corresponding author：

Keywords：

Gastric cancer; Vascular endothelial cell growth factor-C; Vascular endothelial growth factor receptor; Lymphatic metastasis; Treatment of gastric cancer

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Objective To investigate the role of vascular endothelial growth factor-C (VEGF-C) and its receptors in the formation of lymphatic vessels and lymphatic metastasis in gastric cancer.
Methods By the domestic and overseas literatures review, the expressions of VEGF-C and its receptors in gastric cancer, their role in tumor lymphatic metastasis and prospect in treatment of gastric cancer were summarized.
Results There was a significant correlation between VEGF-C and its receptors and the formation of lymphatic vessels and lymphatic metastasis in gastric cancer. VEGF-C high expression might be an early event in lymphatic metastasis and could be considered as an independent predictive factor of lymphaticmicrometastasis. By inhibition of gastric cancer cell from secrete VEGF-C or blockage of the interaction of VEGF-C with VEGFR3, it was possible to inhibit tumor angiogenesis and the invasion and distant spread of cancer cells, thereby decreased mortality and improve survival.
ConclusionVEGF-C and its receptors may promote the formation of lymphatic vessels and lymphatic metastasis in gastric cancer. It may be an effective way to gastric cancer for the treatments against VEGF-C and its receptors.

Citation： WU Shenghua,YU Jiwei,JIANG Bojian .. Researching Progress of The Relationship of VEGF-C and Its Receptor with Lymphatic Metastasis In Gastric Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(8): 872-875. doi: Copy

1.	Wang TB, Deng MH, Qiu WS, et al. Association of serum vascular endothelial growth factorC and lymphatic vessel density with lymph node metastasis and prognosis of patients with gastric cancer [J]. World J Gastroenterol, 2007; 13(12): 17941798.
2.	Matsumura S, Oue N, Mitani Y, et al. DNA demethylation of vascular endothelial growth factorC is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer [J]. Int J Cancer, 2007; 120(8): 16891695.
3.	Mkinen T, Norrmén C, Petrova TV. Molecular mechanisms of lymphatic vascular development [J]. Cell Mol Life Sci, 2007; 64(15): 19151929.
4.	Albuquerque RJ, Hayashi T, Cho WG, et al. Alternatively spliced vascular endothelial growth factor receptor2 is an essential endogenous inhibitor of lymphatic vessel growth [J]. Nat Med, 2009; 15(9): 10231030.
5.	Morita H, Ishikawa Y, AkishimaFukasawa Y, et al. Histopathological predictor for regional lymph node metastasis in gastric cancer [J]. Virchows Arch, 2009; 454(2): 143151.
6.	Nishi M, Abe Y, Tomii Y, et al. Cell binding isoforms of vascular endothelial growth factorA (VEGF189) contribute to blood flowdistant metastasis of pulmonary adenocarcinoma [J]. Int J Oncol, 2005; 26(6): 15171524.
7.	Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors [J]. Nat Med, 2003; 9(6): 669676.
8.	Siegfried G, Basak A, Cromlish JA, et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGFC to induce tumorigenesis [J]. J Clin Invest, 2003; 111(11): 17231732.
9.	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395.
10.	Favier B, Alam A, Barron P, et al. Neuropilin2 interacts with VEGFR2 and VEGFR3 and promotes human endothelial cell survival and migration [J]. Blood, 2006; 108(4): 12431250.
11.	Kim WH, Lee SH, Jung MH, et al. Neuropilin2 expressed in gastric cancer endothelial cells increases the proliferation and migration of endothelial cells in response to VEGF [J]. Exp Cell Res, 2009; 315(13): 21542164.
12.	Matsumoto T, ClaessonWelsh L. VEGF receptor signal transduction [J]. Sci STKE, 2001; 2001(112): re21.
13.	Li J, Huang S, Armstrong EA, et al. Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor2 (VEGFR2) blockade [J]. Int J Radiat Oncol Biol Phys, 2005; 62(5): 14771485.
14.	Caunt M, Mak J, Liang WC， et al. Blocking neuropilin2 function inhibits tumor cell metastasis [J]. Cancer Cell， 2008; 13(4): 331342.
15.	Yuan L， Moyon D， Pardanaud L， et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice [J]. Development， 2002; 129(20): 47974806.
16.	Su JL， Yang PC， Shih JY， et al. The VEGFC/Flt4 axis promotes invasion and metastasis of cancer cells [J]. Cancer Cell， 2006; 9(3): 209223.
17.	Kodama M， Kitadai Y， Tanaka M， et al. Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms [J]. Clin Cancer Res， 2008; 14(22): 72057214.
18.	Li Q， Dong X， Gu W， et al. Clinical significance of coexpression of VEGFC and VEGFR3 in nonsmall cell lung cancer [J]. Chin Med J (Engl)， 2003; 116(5): 727730.
19.	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1466.
20.	Neuchrist C， Erovic BM， Handisurya A， et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck [J]. Head Neck， 2003; 25(6): 464474.
21.	Kaushal V， Mukunyadzi P， Dennis RA， et al. Stagespecific characterization of the vascular endothelial growth factor axis in prostate cancer: expression of lymphangiogenic markers is associated with advancedstage disease [J]. Clin Cancer Res， 2005; 11(2 Pt 1): 584593.
22.	Weninger W， Partanen TA， BreitenederGeleff S， et al. Expression of vascular endothelial growth factor receptor3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells [J]. Lab Invest， 1999; 79(2): 243251.
23.	Vondenhoff MF， Greuter M， Goverse G， et al. LT R signaling induces cytokine expression and upregulates lymphangiogenic factors in lymph node anlagen [J]. J Immunol， 2009; 182(9): 54395445.
24.	Anisimov A， Alitalo A， Korpisalo P， et al. Activated forms of VEGFC and VEGFD provide improved vascular function in skeletal muscle [J]. Circ Res， 2009; 104(11): 13021312.
25.	Alitalo K， Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease [J]. Cancer Cell， 2002; 1(3): 219227.
26.	Su JL， Chen PS， Chien MH， et al. Further evidence for expression and function of the VEGFC/VEGFR3 axis in cancer cells [J]. Cancer Cell， 2008; 13(6): 557560.
27.	吴立刚，刘奇伦，胡志强. MMP2和VEGFC在甲状腺乳头状癌中的表达及临床意义 [J]. 中国普外基础与临床杂志， 2009; 16(11): 906910.
28.	黄桂林，侯吉学，吴毅平，等. 乳腺癌患者血清VEGFC水平与癌组织CerbB2蛋白的表达及临床意义 [J]. 中国普外基础与临床杂志， 2009; 16(7): 514517.
29.	Da MX， Wu XT， Wang J， et al. Expression of cyclooxygenase2 and vascular endothelial growth factorC correlates with lymphangiogenesis and lymphatic invasion in human gastric cancer [J]. Arch Med Res， 2008; 39(1): 9299.
30.	Gao P， Zhou GY， Zhang QH， et al. Lymphangiogenesis in gastric carcinoma correlates with prognosis [J]. J Pathol， 2009; 218(2): 192200.
31.	Gao Y， Zhong WX， Mu DB， et al. Distributions of angiogenesis and lymphangiogenesis in gastrointestinal intramucosal tumors [J]. Ann Surg Oncol， 2008; 15(4): 11171123.
32.	Arigami T， Natsugoe S， Uenosono Y， et al. Vascular endothelial growth factorC and D expression correlates with lymph node micrometastasis in pN0 early gastric cancer [J]. J Surg Oncol， 2009; 99(3): 148153.
33.	Kabashima A， Maehara Y， Kakeji Y， et al. Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma [J]. Oncology， 2001; 60(2): 146150.
34.	He XW， Liu T， Chen YX， et al. Calcium carbonate nanoparticle delivering vascular endothelial growth factorC siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo [J]. Cancer Gene Ther， 2008; 15(3): 193202.
35.	Iwata C， Kano MR， Komuro A， et al. Inhibition of cyclooxygenase2 suppresses lymph node metastasis via reduction of lymphangiogenesis [J]. Cancer Res， 2007; 67(21): 1018110189.

1. Wang TB, Deng MH, Qiu WS, et al. Association of serum vascular endothelial growth factorC and lymphatic vessel density with lymph node metastasis and prognosis of patients with gastric cancer [J]. World J Gastroenterol, 2007; 13(12): 17941798.
2. Matsumura S, Oue N, Mitani Y, et al. DNA demethylation of vascular endothelial growth factorC is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer [J]. Int J Cancer, 2007; 120(8): 16891695.
3. Mkinen T, Norrmén C, Petrova TV. Molecular mechanisms of lymphatic vascular development [J]. Cell Mol Life Sci, 2007; 64(15): 19151929.
4. Albuquerque RJ, Hayashi T, Cho WG, et al. Alternatively spliced vascular endothelial growth factor receptor2 is an essential endogenous inhibitor of lymphatic vessel growth [J]. Nat Med, 2009; 15(9): 10231030.
5. Morita H, Ishikawa Y, AkishimaFukasawa Y, et al. Histopathological predictor for regional lymph node metastasis in gastric cancer [J]. Virchows Arch, 2009; 454(2): 143151.
6. Nishi M, Abe Y, Tomii Y, et al. Cell binding isoforms of vascular endothelial growth factorA (VEGF189) contribute to blood flowdistant metastasis of pulmonary adenocarcinoma [J]. Int J Oncol, 2005; 26(6): 15171524.
7. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors [J]. Nat Med, 2003; 9(6): 669676.
8. Siegfried G, Basak A, Cromlish JA, et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGFC to induce tumorigenesis [J]. J Clin Invest, 2003; 111(11): 17231732.
9. 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395.
10. Favier B, Alam A, Barron P, et al. Neuropilin2 interacts with VEGFR2 and VEGFR3 and promotes human endothelial cell survival and migration [J]. Blood, 2006; 108(4): 12431250.
11. Kim WH, Lee SH, Jung MH, et al. Neuropilin2 expressed in gastric cancer endothelial cells increases the proliferation and migration of endothelial cells in response to VEGF [J]. Exp Cell Res, 2009; 315(13): 21542164.
12. Matsumoto T, ClaessonWelsh L. VEGF receptor signal transduction [J]. Sci STKE, 2001; 2001(112): re21.
13. Li J, Huang S, Armstrong EA, et al. Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor2 (VEGFR2) blockade [J]. Int J Radiat Oncol Biol Phys, 2005; 62(5): 14771485.
14. Caunt M, Mak J, Liang WC， et al. Blocking neuropilin2 function inhibits tumor cell metastasis [J]. Cancer Cell， 2008; 13(4): 331342.
15. Yuan L， Moyon D， Pardanaud L， et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice [J]. Development， 2002; 129(20): 47974806.
16. Su JL， Yang PC， Shih JY， et al. The VEGFC/Flt4 axis promotes invasion and metastasis of cancer cells [J]. Cancer Cell， 2006; 9(3): 209223.
17. Kodama M， Kitadai Y， Tanaka M， et al. Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms [J]. Clin Cancer Res， 2008; 14(22): 72057214.
18. Li Q， Dong X， Gu W， et al. Clinical significance of coexpression of VEGFC and VEGFR3 in nonsmall cell lung cancer [J]. Chin Med J (Engl)， 2003; 116(5): 727730.
19. 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1466.
20. Neuchrist C， Erovic BM， Handisurya A， et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck [J]. Head Neck， 2003; 25(6): 464474.
21. Kaushal V， Mukunyadzi P， Dennis RA， et al. Stagespecific characterization of the vascular endothelial growth factor axis in prostate cancer: expression of lymphangiogenic markers is associated with advancedstage disease [J]. Clin Cancer Res， 2005; 11(2 Pt 1): 584593.
22. Weninger W， Partanen TA， BreitenederGeleff S， et al. Expression of vascular endothelial growth factor receptor3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells [J]. Lab Invest， 1999; 79(2): 243251.
23. Vondenhoff MF， Greuter M， Goverse G， et al. LT R signaling induces cytokine expression and upregulates lymphangiogenic factors in lymph node anlagen [J]. J Immunol， 2009; 182(9): 54395445.
24. Anisimov A， Alitalo A， Korpisalo P， et al. Activated forms of VEGFC and VEGFD provide improved vascular function in skeletal muscle [J]. Circ Res， 2009; 104(11): 13021312.
25. Alitalo K， Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease [J]. Cancer Cell， 2002; 1(3): 219227.
26. Su JL， Chen PS， Chien MH， et al. Further evidence for expression and function of the VEGFC/VEGFR3 axis in cancer cells [J]. Cancer Cell， 2008; 13(6): 557560.
27. 吴立刚，刘奇伦，胡志强. MMP2和VEGFC在甲状腺乳头状癌中的表达及临床意义 [J]. 中国普外基础与临床杂志， 2009; 16(11): 906910.
28. 黄桂林，侯吉学，吴毅平，等. 乳腺癌患者血清VEGFC水平与癌组织CerbB2蛋白的表达及临床意义 [J]. 中国普外基础与临床杂志， 2009; 16(7): 514517.
29. Da MX， Wu XT， Wang J， et al. Expression of cyclooxygenase2 and vascular endothelial growth factorC correlates with lymphangiogenesis and lymphatic invasion in human gastric cancer [J]. Arch Med Res， 2008; 39(1): 9299.
30. Gao P， Zhou GY， Zhang QH， et al. Lymphangiogenesis in gastric carcinoma correlates with prognosis [J]. J Pathol， 2009; 218(2): 192200.
31. Gao Y， Zhong WX， Mu DB， et al. Distributions of angiogenesis and lymphangiogenesis in gastrointestinal intramucosal tumors [J]. Ann Surg Oncol， 2008; 15(4): 11171123.
32. Arigami T， Natsugoe S， Uenosono Y， et al. Vascular endothelial growth factorC and D expression correlates with lymph node micrometastasis in pN0 early gastric cancer [J]. J Surg Oncol， 2009; 99(3): 148153.
33. Kabashima A， Maehara Y， Kakeji Y， et al. Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma [J]. Oncology， 2001; 60(2): 146150.
34. He XW， Liu T， Chen YX， et al. Calcium carbonate nanoparticle delivering vascular endothelial growth factorC siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo [J]. Cancer Gene Ther， 2008; 15(3): 193202.
35. Iwata C， Kano MR， Komuro A， et al. Inhibition of cyclooxygenase2 suppresses lymph node metastasis via reduction of lymphangiogenesis [J]. Cancer Res， 2007; 67(21): 1018110189.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Researching Progress of The Relationship of VEGF-C and Its Receptor with Lymphatic Metastasis In Gastric Cancer

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