The Expression of VEGF-C and It’s Receptor VEGFR-3 Correlates with Lymph Node Metastasis in Gastric Cancer

Abstract

Background: Regional lymph node invasion and metastasis may happen early during the progres-sion of gastric cancer. The lymphadenectomy is still the key method to treat lymph nodemetastasis. In the recent years, scientists have found some growth factors and receptors that can promote angiogenesis which also play an important role in adjusting the formation of the new lymph vessel, and lymphangiogenesis may play a key role in the process of lymph node metastasis. Objectives: This study aims to explore the correlation between the expression of vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor receptor 3 (VEGFR-3) and lymph node me-tastasis (LNM), and its impact on prognosis of patients with gastric cancer. Methods: The samples were collected from gastric cancer database of Sichuan Provincial People’s Hospital from 2005 to 2007, which were registered and followed up. The samples were divided into two groups according to situation whether there is lymph node metastasis, which is lymph node metastasis N(+) and without lymph node metastasis N(﹣). The expression of VEGF-C, VEGFR-3 and CD34 were measured by immuno histochemistry staining with monoclonal antibody (anti-VEGF-C, anti-VEGFR-3, and anti-CD34). Kaplan-meier, logistic and Cox regression was performed to explore their impact on the prognosis of patients with gastric cancer. Results: In total 186 cases were collected, 96 cases in N(+) group and 90 cases in N(﹣) group. The percentage of VEGF-C expression is 54.83% (102/186) in all groups, 73.9% (71/96) in N(+) group, and 34.44% (31/90) in N(﹣) group (p = 0.001). The percentage of VEGFR-3 expression is 33.33% (62/186) in all groups, 44.78% (43/96) in N(+) group, and 21.11% (19/90) in N(﹣) group (p = 0.001). There are no statistical differences in microvessel density (MVD) between N(﹣) and N(+) group. The average lymphatic vessel density (LVD) was significant different between N(+) and N(﹣) group (26.23 ± 8.2 and 18.46 ± 7.4, t = ﹣2.427, p = 0.016). The five-year overall survival rate of N(+) group is 31% and the N(﹣) group is 66%; there are statistical differences between the two groups (Log rank = 27.15, p = 0.001). The five-year overall survival rates of VEGF-C positive group and VEGF-C negative group are 36% and 59%, with the statistical differences (Log rank = 27.15, p = 0.001). And the five-year overall survival rates of VEGFR-3 positive group and VEGFR-3 negative group are 31% and 43%, also with the statistical differences (Log rank = 5.241, p = 0.041). Conclusions: The expressions of VEGF-C, VEGFR-3 in cell plasma of gastric cancer tissue not only correlate with lymphatic vessel density and lymph node metastasis (LNM), but also are important factors which impact prognosis of gastric cancer patients.

Share and Cite:

Yang, C. and Zhang, Z. (2014) The Expression of VEGF-C and It’s Receptor VEGFR-3 Correlates with Lymph Node Metastasis in Gastric Cancer. Open Journal of Gastroenterology, 4, 357-377. doi: 10.4236/ojgas.2014.412050.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. and Forman, D. (2011) Global Cancer Statistics. CA: A Cancer Journal for Clinicians, 61, 69-90.
http://dx.doi.org/10.3322/caac.20107
[2] Ferlay, J., Soerjomataram, I.I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D.D. and Bray, F. (2014) Cancer Incidence and Mortality Worldwide: Sources, Methods and Major Patterns in GLOBOCAN 2012. International Journal of Cancer, Published Online.
http://dx.doi.org/10.1002/ijc.29210
[3] Chen, W., Zheng, R., Zhang, S., Zhao, P., Li, G., Wu, L. and He, J. (2013) The Incidences and Mortalities of Major Cancers in China, 2009. Chinese Journal of Cancer Research, 32, 106-112.
http://dx.doi.org/10.5732/cjc.013.10018
[4] Akagi, K., Ikeda, Y., Miyazaki, T., et al. (2000) Vascular Endothelial Growth Factor-C Expression in Human Colorectal Cancer Tissues. British Journal of Cancer, 83, 887-891.
http://dx.doi.org/10.1054/bjoc.2000.1396
[5] Shayan, R., Achen, M.G. and Stacker, S.A. (2006) Lymphatic Vessels in Cancer Metastasis: Bridging the Gaps. Carcinogenesis, 27, 1729-1738.
http://dx.doi.org/10.1093/carcin/bgl031
[6] Mumprecht, V. and Detmar, M. (2009) Lymphangiogenesis and Cancer Metastasis. Journal of Cellular and Molecular Medicine, 13, 1405-1416.
http://dx.doi.org/10.1111/j.1582-4934.2009.00834.x
[7] Ferrara, N. (2001) Role of Vascular Endothelial Growth Factor in Regulation of Physiological Angiogenesis. American Journal of Physiology—Cell Physiology, 280, C1358-C1366.
[8] Karkkainen, M.J. and Petrova, T.V. (2000) Vascular Endothelial Growth Factor Receptors in the Regulation of Angiogenesis and Lymphangiogenesis. Oncogene, 19, 5598-5605.
http://dx.doi.org/10.1038/sj.onc.1203855
[9] Yonemura, Y., Endo, Y., Fujita, H., Fushida, S., Ninomiya, I., Bandou, E., Taniguchi, K., Miwa, K., Ohoyama, S., Sugiyama, K. and Sasaki, T. (1999) Role of Vascular Endothelial Growth Factor C Expression in the Development of Lymph Node Metastasis in Gastric Cancer. Clinical Cancer Research, 5, 1823-1829.
[10] Yonemura, Y., Fushida, S., Bando, E., Kinoshita, K., Miwa, K., Endo, Y., Sugiyama, K., Partanen, T., Yamamoto, H. and Sasaki, T. (2001) Lymphangiogenesis and the Vascular Endothelial Growth Factor Receptor (VEGFR)-3 in Gastric Cancer. European Journal of Cancer, 37, 918-923.
http://dx.doi.org/10.1016/S0959-8049(01)00015-6
[11] Karkkainen, M.J. and Alitalo, K. (2002) Lymphatic Endothelial Regulation, Lymphoedema, and Lymph Node Metastasis. Seminars in Cell & Developmental Biology, 13, 9-18.
http://dx.doi.org/10.1006/scdb.2001.0286
[12] De Asellius, G. (2008) Lacteibussivelacteisvenis Quarto Vasorum Mesaroicumgenere novo invente Gasp. Asellii Cremonensis Antomici Ticiensis Qua Sententiae Anatomicaemultae, nelperperamreceptaeillustrantur. Mediolani, Milan, 1627.
[13] David-Nathanson, S. (2003) Insights into the Mechanisms of Lymph Node Metastasis. Cancer, 98, 413-423.
http://dx.doi.org/10.1002/cncr.11464
[14] Nobutsugu, A., Takashi, W., Kazufumi, S., et al. (2002) Risk Factors Predictive of Lymph Node Metastasis in Depressed Early Gastric Cancer. The American Journal of Surgery, 183, 168-172.
http://dx.doi.org/10.1016/S0002-9610(01)00860-1
[15] Senger, D.R., Galli, S.J., Dvorak, A.M., et al. (1983) Tumor Cells Secrete a Vascular Permeability Factor That Promotes Accumulation of Ascites Fluid. Science, 219, 983-985.
http://dx.doi.org/10.1126/science.6823562
[16] Ferrara, N. and Henzel, W.J. (1989) Pituitary Follicular Cells Secrete a Novel Heparin-Binding Growth Factor Specific for Vascular Endothelial Cells. Biochemical and Biophysical Research Communications, 161, 851-858.
http://dx.doi.org/10.1016/0006-291X(89)92678-8
[17] Gospodarowicz, D. and Lau, K. (1989) Pituitary Follicular Cells Secrete both Vascular Endothelial Growth Factor and Follistatin. Biochemical and Biophysical Research Communications, 165, 292-298.
http://dx.doi.org/10.1016/0006-291X(89)91068-1
[18] Ferrara, N., Gerber, H.-P. and LeCouter, J. (2003) The Biology of VEGF and Its Receptors. Nature Medicine, 9, 669-676.
http://dx.doi.org/10.1038/nm0603-669
[19] Lazar, D., Taban, S., Ardeleanu, C., Simionescu, C., Sporea, I., Cornianu, M. and Vernic, C. (2008) Immunohistochemical Expression of the Cyclooxygenase-2 (COX-2) in Gastric Cancer. The Correlations with the Tumor Angiogenesis and Patients Survival. Romanian Journal of Morphology and Embryology, 49, 371-379.
[20] Joukov, V., Pajusola, K., Kaipainen, A., Chilov, D., Lahtinen, I., Kukk, E., et al. (1996) A Novel Vascular Endothelial Growth Factor, VEGF-C, Is a Ligand for the Flt-4(VEGFR-3) and KDR(VEGFR-2) Receptor Tyrosine Kinases. The EMBO Journal, 15, 290-298.
[21] Lee, J., Gray, A., Yuan, J., et al. (1996) Vascular Endothelial Growth Factor-Related Protein: A Ligand and Specific Activator of the Tyrosine Kinase Receptor Flt4. Proceedings of the National Academy of Sciences of the United States of America, 93, 1988-1992.
[22] Siegfried, G., Basak, A., Cromlish, J.A., et al. (2003) The Secretory Proprotein Convertases Furin, PC5, and PC7 Activate VEGF-C to Induce Tumorigenesis. Journal of Clinical Investigation, 111, 1723-1732.
http://dx.doi.org/10.1172/JCI200317220
[23] Saharinen, P., Tammela, T., Karkkainen, M.J., et al. (2004) Lymphatic Vasculature: Development, Molecular Regulation and Role in Tumor Metastasis and Inflammation. Trends in Immunology, 25, 387-395.
http://dx.doi.org/10.1016/j.it.2004.05.003
[24] Tang, R.F., Wang, S.X., Zhang, F.R., Peng, L., Wang, S.X., Xiao, Y. and Zhang, M. (2005) Interleukin1alpha, 6 Regulate the Secretion of Vascular Endothelial Growth Factor A, C in Pancreatic Cancer. Hepatobiliary & Pancreatic Diseases International, 4, 460-463.
[25] Pajusola, K., Aprelikova, O., Armstrong, E., Morris, S. and Alitalo, K. (1993) Two Human FLT4 Receptor Tyrosine Kinase Isoforms with Distinct Carboxy Terminal Tails Are Produced by Alternative Processing of Primary Transcripts. Oncogene, 8, 2931-2937.
[26] Lymboussaki, A., Partanen, T.A., Olofsson, B., et al. (1998) Expression of the Vascular Endothelial Growth Factor C Receptor VEGFR-3 in Lymphatic Endothelium of the Skin and in Vascular Tumors. The American Journal of Pathology, 153, 395-403.
http://dx.doi.org/10.1016/S0002-9440(10)65583-6
[27] Clauss, M. (2000) Molecular Biology of the VEGF and the VEGF Receptor Family. Seminars in Thrombosis and Hemostasis, 26, 561-569.
http://dx.doi.org/10.1055/s-2000-13213
[28] Reis-Filho, J.S. and Schmitt, F.C. (2003) Lymphangiogenesis in Tumors: What Do We Know? Microscopy Research and Technique, 60, 171-180.
http://dx.doi.org/10.1002/jemt.10255
[29] Schmid-Schonbein, G.W. (1990) Microlymphatics and Lymph Flow. Physiological Reviews, 70, 987-1028.
[30] Alitalo, K. and Carmeliet, P. (2002) Molecular Mechanisms of Lymphangiogenesis in Health and Disease. Cancer Cell, 1, 219-227.
http://dx.doi.org/10.1016/S1535-6108(02)00051-X
[31] Wigle, J.T. and Oliver, C. (1999) PROX-1 Function Is Required for the Development of the Murine Lymphatic System. Cell, 98, 769-778.
http://dx.doi.org/10.1016/S0092-8674(00)81511-1
[32] Witte, M.H., Way, D.L., Witte, C.L., et al. (1997) Lymphangiogenesis: Mechanisms, Significance and Clinical Implications. Experientia Supplementum, 79, 65-112.
http://dx.doi.org/10.1007/978-3-0348-9006-9_5
[33] Chang, L., Kaipainen, A. and Folkman, J. (2002) Lymphangiogenesis: New Mechanisms. Annals of the New York Academy of Sciences, 979, 111-119.
http://dx.doi.org/10.1111/j.1749-6632.2002.tb04872.x
[34] Van-Netten, J.P., Cann, S.A. and vander-Westhuizen, N.G. (1996) Angiogenesis and Tumor Growth. The New England Journal of Medicine, 334, 920-921.
http://dx.doi.org/10.1056/NEJM199604043341413
[35] Marl, Y.H., Witte, M.J., Bernas, C.P., et al. (2001) Lymph Angiogenesis and Lymph Angiodysplasia: From Molecular to Clinical Lymphology. Microscopy Research and Technique, 55, 122-145.
http://dx.doi.org/10.1002/jemt.1163
[36] de Waal, R.M., van Altena, M.C., Erhard, H., et al. (1997) Lack of Lymphangiogenesis in Human Primary Cutaneous Melanoma. Consequences for the Mechanism of Lymphatic Dissemination. The American Journal of Pathology, 150, 1951-1957.
[37] Kaipainen, A., Korhonen, J., Mustonen, T., van Hinsbergh, V.W., Fang, G.H., Dumont, D., et al. (1995) Expression of the Fms-Like Tyrosine Kinase 4 Gene Becomes Restricted to Lymphatic Endothelium during Development. Proceedings of the National Academy of Sciences of the United States of America, 92, 3566-3570.
[38] Karkkainen, M.J., Ferrel, R.E., Lawrence, E.C., et al. (2000) Missense Mutations Interfere with VEGFR-3 Signalling in Primary Lymphoedema. Nature Genet, 25, 153-159.
http://dx.doi.org/10.1038/75997
[39] Jeltsch, M., Kaipainen, A., Joukov, V., et al. (1997) Hyperplasia of Lymphatic Vessels in VEGF-C Transgenic Mice. Science, 276, 1423-1425.
http://dx.doi.org/10.1126/science.276.5317.1423
[40] Salven, P., Lymboussaki, A., Heikkila, P., et al. (1998) Vascular Endothelial Growth Factors VEGF-B and VEGF-C Are Expressed in Human Tumors. The American Journal of Pathology, 153, 103-108.
http://dx.doi.org/10.1016/S0002-9440(10)65550-2
[41] Fielder, W., Graeven, U., Ergun, S., et al. (1997) Expression of FLT4 and Its Ligand VEGF-C in Acute Myeloid Leukemia. Leukemia, 11, 1234-1237.
http://dx.doi.org/10.1038/sj.leu.2400722
[42] Fellmer, P.T., Sato, K., Tanaka, R., et al. (1999) Vascular Endothelial Growth Factor-C Gene Expression in Papillary and Follicular Thyroid Carcinomas. Surgery, 126, 1056-1061.
http://dx.doi.org/10.1067/msy.2099.101432
[43] Tsurusaki, T., Kanda, S., Sakai, H., et al. (1999) Vascular Endothelial Growth Factor-C Expression in Human Prostatic Carcinoma and Its Relationship to Lymph Node Metastasis. British Journal of Cancer, 80, 309-313.
http://dx.doi.org/10.1038/sj.bjc.6690356
[44] Andre, T., Kotelevets, L., Vaillant, J.C., et al. (2000) Vegf, Vegf-B, Vegf-C and Their Receptors KDR, FLT-1 and FLT-4 during the Neoplastic Progression of Human Colonic Mucosa. International Journal of Cancer, 86, 174-181.
http://dx.doi.org/10.1002/(SICI)1097-0215(20000415)86:2<174::AID-IJC5>3.0.CO;2-E
[45] Achen, M.G., Jeltsch, M., Kukk, E., et al. (1998) Vascular Endothelial Growth Factor D (VEGF-D) Is a Ligand for the Tyrosine Kinases VEGF Receptor 2 (Flk1) and VEGF Receptor 3 (Flt4). Proceedings of the National Academy of Sciences of the United States of America, 95, 548-553.
http://dx.doi.org/10.1073/pnas.95.2.548
[46] Stacker, S., Caesar, C., Baldwin, M.E., et al. (2001) VEGF-D Promotes the Metastatic Spread of Tumor Cells via the Lymphatics. Nature Medicine, 7, 186-191.
http://dx.doi.org/10.1038/84635
[47] Yokoyama, Y., Charnock-Jones, D.S., Licence, D., et al. (2003) Expression of Vascular Endothelial Growth Factor (VEGF)-D and Its Receptor, VEGF Receptor 3, as a Prognostic Factor in Endometrial Carcinoma. Clinical Cancer Research, 9, 1361-1369.
[48] Skobe, M., Hawighorst, T., Jackson, D.G., et al. (2001) Induction of Tumor Lymphangiogenesis by VEGF-C Promotes Breast Cancer Metastasis. Nature Medicine, 7, 192-198.
http://dx.doi.org/10.1038/84643
[49] Kajita, T., Ohta, Y., Kimura, K., et al. (2001) The Expression of Vascular Endothelial Growth Factor C and Its Receptor in Non Small Cell Lung Cancer. British Journal of Cancer, 85, 255-260.
http://dx.doi.org/10.1054/bjoc.2001.1882
[50] Saharinen, P., Tammela, T., Karkkainen, M.J., et al. (2004) Lymphatic Vasculature: Development, Molecular Regulation and Role in Tumor Metastasis and Inflammation. Trends in Immunology, 25, 387-395.
http://dx.doi.org/10.1016/j.it.2004.05.003
[51] Bierer, S., Herrmann, E., Kêpke, T., et al. (2008) Lymph Angiogenesis in Kidney Cancer: Expression of VEGF-C, VEGF-D and VEGFR-3 in Clear Cell and Papillary Renal Cell Carcinoma. Oncology Reports, 20, 721-725.
[52] Papontai, M., Sleeman, J.P. and Wilting, J. (2001) Interaction of Rat Tumor Cells with Blood Vessels and Lymphatics of the Avian Chorioallantoic Membrane. Microscopy Research and Technique, 55, 100-107.
[53] Padera, T.P., Kakambi, A., di Tomaso, E., et al. (2002) Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics. Science, 296, 1883-1886.
http://dx.doi.org/10.1126/science.1071420
[54] Ueda, M., Terai, Y., Yamashita, Y., et al. (2002) Correlation between Vascular Endothelial Growth Factor C Expression and Invasion Phenotype in Cervical Carcinomas. International Journal of Cancer, 98, 335-343.
http://dx.doi.org/10.1002/ijc.10193
[55] Maeda, K., Yashiro, M., Nishihara, T., et al. (2003) Correlation between Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis in Tl Carcinoma of the Colon and Rectum. Surgery Today, 33, 736-739.
http://dx.doi.org/10.1007/s00595-003-2592-5
[56] Li, R., Younes, M., Wheeler, T.M., et al. (2004) Expression of Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) in Human Prostate. Prostate, 58, 193-199.
http://dx.doi.org/10.1002/pros.10321
[57] Nathanson, S.D., Zarbo, R.J., Wachna, D.L., et al. (2000) Microvessels That Predict Axillary Lymph Node Metastases in Breast Cancer. Archives of Surgery, 135, 586-594.
http://dx.doi.org/10.1001/archsurg.135.5.586
[58] Vatanabe, M., Ohga, T., et al. (2003) Vascular Endothelial Growth Factor C Expression Correlates with Lymphatic Involvement and Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma. Oncology Reports, 10, 1747-1751.
[59] Yonemura, Y., Fushida, S., Bando, E., Kinoshita, K., Miwa, K., Endo, Y., et al. (2001) Lymph Angiogenesis and the Vascular Endothelial Growth Factor Receptor (VEGFR)-3 in Gastric Cancer. European Journal of Cancer, 37, 918-923.
[60] Duff, S.E., Li, C., Renehan, A.O., et al. (2003) Immunodetection and Molecular Forms of Plasma Vascular Endothelial Growth Factor-C. International Journal of Oncology, 22, 339-343.
[61] Da, M.X., Wu, X.T., Wan, G.J., et al. (2008) Expression of Cyclooxygenase-2 and Vascular Endothelial Growth Factor-C Correlates with Lymph Angiogenesis and Lymphatic Invasion in Human Gastric Cancer. Archives of Medical Research, 39, 92-99.
http://dx.doi.org/10.1016/j.arcmed.2007.06.021
[62] Kazama, S., Kitayama, J., Watanabe, T. and Nagawa, H. (2004) Expression Pattern of Vascular Endothelial Growth Factor-C in Human Colorectal Normal Mucosa and Neoplastic Mucosa. Hepatogastroenterology, 51, 391-395.
[63] Parr, C. and Jiang, W.G. (2003) Quantitative Analysis of Lymphangiogenic Markers in Human Colorectal Cancer. International Journal of Oncology, 23, 533-539.
[64] Holmqvist, A., Gao, J., Adell, G., et al. (2010) The Location of Lymphangi-Ogenesis Is an Independent Prognostic Factor in Rectal Cancers with or without Preoperative Radiotherapy. Annals of Oncology, 21, 512-517.
http://dx.doi.org/10.1093/annonc/mdp486
[65] Miyazaki, T., Okada, N., Ishibashi, K., et al. (2008) Clinical Significance of Plasma Level of Vascular Endothelial Growth Factor C in Patients with Colorectal Cancer. Japanese Journal of Clinical Oncology, 38, 839-843.
http://dx.doi.org/10.1093/jjco/hyn106
[66] Nakao, K., Nakamura, M., Mori, I. and Kakudo, K. (2003) Clinicopathological Significance of Vascular Endothelial Growth Factor-C in Breast Carcinoma with Long-Term Follow-Up. Modern Pathology, 16, 309-314.
http://dx.doi.org/10.1097/01.MP.0000062858.98295.9F
[67] Nakashima, T., Kondoh, S., Kitoh, H., et al. (2003) Vascular Endothelial Growth Factor-C Expression in Human Gallbladder Cancer and Its Relationship to Lymph Node Metastasis. International Journal of Molecular Medicine, 11, 33-39.
[68] Hashimoto, L., Kodama, J., Seki, N., et al. (2001) Vascular Endothelial Growth Factor-C Expression and Its Relationship to Pelvic Lymph Node Status in Invasive Cervical Cancer. British Journal of Cancer, 85, 93-97.
http://dx.doi.org/10.1054/bjoc.2001.1846

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.