EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3 IN HUMAN BREAST CANCER AND ITS SIGNIFICANCE_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WU Jianzhong ¹ , CHEN Lin ¹ , ZHOU Wenbin ¹ , LIU Xiaoan ¹ , CHEN Xin ¹ , MIAO Dengshun ²

1Department of General Surgery, the First Affiliated Hospital to Nanjing Medical University, Nanjing Jiangsu, 210029, P.R.China;;
2College of Basic Medicine, Nanjing Medical University. Corresponding author: CHEN Lin, E-mail: hxchenlin@aliyun.com;

Corresponding author：

Keywords：

Breast cancer; Vascular endothelial growth factor receptor 3; Lymph node metastasis

DOI：

10.7507/1002-1892.20130327

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Objective To investigate the expression and prognostic value of vascular endothelial growth factor receptor 3 (VEGFR-3) in human breast cancer. Methods A tissue microarray containing cores was constructed from 173 female patients with primary breast cancers (experimental group) and 19 female patients with benign breast lesions (control group) between March 2004 and June 2007. HE staining was performed to determine the quality of tissue microarray and immunohistochemistry staining was used to detect VEGFR-3 expression in the tissue microarray. Statistical analysis was performed to show the association between VEGFR-3 expression and clinicopathologic parameters. Results Histological examination showed that the tissue microarray had good quality, which could represent the histological characteristics of breast cancer and benign breast lesions. VEGFR-3 was expressed in 55.5% (96/173) breast cancer patients of experimental group, while the expression was negative in lesions of control group. VEGFR-3 expression rate had no significant relation with age, estrogen receptor, and progesterone receptor (P gt; 0.05). VEGFR-3 expression rate correlated positively with tumor size and pathological staging compared to VEGFR-3 negative tumors (P lt; 0.05). The positive expression rate of VEGFR-3 in breast cancer with lymph node metastasis was significantly higher than that without lymph node metastasis (P lt; 0.05). Furthermore, VEGFR-3 positive staining correlated with human EGF receptor 2 expression (P lt; 0.05). Conclusion The expressions of VEGFR-3 in human breast cancer have close relations with lymph node metastasis. Thus, VEGFR-3 may be a potential prognostic indicator and a new anti-cancer target for breast cancer.

Citation： WU Jianzhong,CHEN Lin,ZHOU Wenbin,LIU Xiaoan,CHEN Xin,MIAO Dengshun. EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3 IN HUMAN BREAST CANCER AND ITS SIGNIFICANCE. Chinese Journal of Reparative and Reconstructive Surgery, 2013, 27(12): 1487-1491. doi: 10.7507/1002-1892.20130327 Copy

1.	Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90.
2.	Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in regulation of angiogenesis and lymphangiogenesis. Oncogene, 2000, 19(49): 5598-5605．.
3.	Laakkonen P, Waltari M, Holopainen T, et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res, 2007, 67(2): 593-599.
4.	Achen MG, Mann GB, Stacker SA. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer, 2006, 94(10): 1355-1360.
5.	Petrova TV, Bono P, Holnthoner W, et al. VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell, 2008, 13(6): 554-556.
6.	Sauter G, Simon R, Hillan K. Tissue microarrays in drug discovery. Nat Rev Drug Discov, 2003, 2(12): 962-972.
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8.	Nocito A, Bubendorf L, Tinner EM, et al. Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol, 2001, 194(3): 349-357.
9.	Moch H, Schraml P, Bubendorf L, et al. High-throughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal cell carcinoma. Am J Pathol, 1999, 154(4): 981-986.
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13.	Kriehuber E, Breiteneder-Geleff S, Groeger M, et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med, 2001, 194(6): 797-808.
14.	Oliver G. Lymphatic vasculature development. Nat Rev Immunol, 2004, 4(1): 35-45.
15.	White JD, Hewett PW, Kosuge D, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res, 2002, 62(6): 1669-1675.
16.	Valtola R, Salven P, Heikkilä P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol, 1999, 154(5): 1381-1390.
17.	Kojima H, Shijubo N, Yamada G, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer, 2005, 104(8): 1668-1677.
18.	Mylona E, Alexandrou P, Mpakali A, et al. Clinicopathological and prognostic significance of vascular endothelial growth factors (VEGF)- C and -D and VEGF receptor 3 in invasive breast carcinoma. Eur J Surg Oncol, 2007, 33(3): 294-300.
19.	Arinaga M, Noguchi T, Takeno S, et al. Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer, 2003, 97(2): 457-464.
20.	Saintigny P, Kambouchner M, Ly M, et al. Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumorand metastatic lymph node. Lung Cancer, 2007, 58(2): 205-213.
21.	Kurenova EV, Hunt DL, He D, et al. Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo. Cell Cycle, 2009, 8(14): 2266-2280.
22.	Kodera Y, Katanasaka Y, Kitamura Y, et al. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. Breast Cancer Res, 2011, 13(3): R66.
23.	Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res, 2008, 14(17): 5459-5465.

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90.
2. Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in regulation of angiogenesis and lymphangiogenesis. Oncogene, 2000, 19(49): 5598-5605．.
3. Laakkonen P, Waltari M, Holopainen T, et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res, 2007, 67(2): 593-599.
4. Achen MG, Mann GB, Stacker SA. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer, 2006, 94(10): 1355-1360.
5. Petrova TV, Bono P, Holnthoner W, et al. VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell, 2008, 13(6): 554-556.
6. Sauter G, Simon R, Hillan K. Tissue microarrays in drug discovery. Nat Rev Drug Discov, 2003, 2(12): 962-972.
7. Torhorst J, Bucher C, Kononen J, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol, 2001, 159(6): 2249-2256.
8. Nocito A, Bubendorf L, Tinner EM, et al. Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol, 2001, 194(3): 349-357.
9. Moch H, Schraml P, Bubendorf L, et al. High-throughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal cell carcinoma. Am J Pathol, 1999, 154(4): 981-986.
10. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 1998, 4(7): 844-847.
11. Hirakawa S, Brown LF, Kodama S, et al. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood, 2007, 109(3): 1010-1017.
12. Tobler NE, Detmar M. Tumor and lymph node lymphangiogenesis—impact on cancer metastasis. J Leukoc Biol, 2006, 80(4): 691-696.
13. Kriehuber E, Breiteneder-Geleff S, Groeger M, et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med, 2001, 194(6): 797-808.
14. Oliver G. Lymphatic vasculature development. Nat Rev Immunol, 2004, 4(1): 35-45.
15. White JD, Hewett PW, Kosuge D, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res, 2002, 62(6): 1669-1675.
16. Valtola R, Salven P, Heikkilä P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol, 1999, 154(5): 1381-1390.
17. Kojima H, Shijubo N, Yamada G, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer, 2005, 104(8): 1668-1677.
18. Mylona E, Alexandrou P, Mpakali A, et al. Clinicopathological and prognostic significance of vascular endothelial growth factors (VEGF)- C and -D and VEGF receptor 3 in invasive breast carcinoma. Eur J Surg Oncol, 2007, 33(3): 294-300.
19. Arinaga M, Noguchi T, Takeno S, et al. Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer, 2003, 97(2): 457-464.
20. Saintigny P, Kambouchner M, Ly M, et al. Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumorand metastatic lymph node. Lung Cancer, 2007, 58(2): 205-213.
21. Kurenova EV, Hunt DL, He D, et al. Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo. Cell Cycle, 2009, 8(14): 2266-2280.
22. Kodera Y, Katanasaka Y, Kitamura Y, et al. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. Breast Cancer Res, 2011, 13(3): R66.
23. Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res, 2008, 14(17): 5459-5465.

Chinese Journal of Reparative and Reconstructive Surgery

EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3 IN HUMAN BREAST CANCER AND ITS SIGNIFICANCE

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