VEGF-C、VEGFR-3在乳腺良恶性肿瘤中的表达及其意义
摘要
目的 乳腺癌是一个世界范围内严重危害女性健康的恶性肿瘤，其发病率呈不断上升趋势，有些地区已跃居女性肿瘤的第一位。乳腺富含淋巴管网，因此乳腺癌早期即可经淋巴道转移，研究证实淋巴结转移与否是乳腺癌重要的临床预后因素。因此，如何早期检测和抑制淋巴结转移，成为乳腺癌诊治过程中的一个重要环节。
血管内皮生长因子-C(vascular endothelial growth factor C，VEGF-C)是VEGF家族中可特异性作用于淋巴管内皮的成员，参与了胚胎发育过程中淋巴管网的形成。其特异受体是血管内皮生长因子受体-3(vascular endothelial growth factorreceptor-3，VEGFR-3)，主要表达于淋巴管内皮细胞上。初步研究发现VEGF-C与VEGFR-3结合后，可诱导VEGFR-3酪氨酸激酶磷酸化，促进淋巴管生成。在许多实体瘤细胞中VEGF-C呈高表达，且与VEGFR-3相互作用，参与肿瘤的淋巴管生成，并与肿瘤的淋巴道转移呈正相关。有关VEGF-C与乳腺癌淋巴道转移的关系国外已有报道，但VEGF-C、VEGFR-3在乳腺良恶性肿瘤中的表达情况及其与乳腺癌淋巴道转移和其它病理学特征的关系国内外尚未见文献报道。本研究通过检测VEGF-C、VEGFR-3在乳腺良恶性肿瘤中的蛋白表达，探讨其在乳腺癌发生发展及转移中的作用，探索乳腺癌淋巴转移的机制，为抗乳腺癌淋巴转移的治疗提供理论依据。
方法 1．采用免疫组织化学sP法，检测18例乳腺良性肿瘤(导管内乳头
Objective Breast cancer is a kind of maligant tumor which affects on women's health all over the world. The disease incidence of breast cancer has a trend of increasing. In some areas,especially in some cities,it has leaped to first place in the maligant tumors of females.Breast has plentiful lymphatic vessel network,thus metastasis of early-stage breast cancer occurs primarily through the lymphatic system. It has been proved wether or not lymphatic metastasis of breast cancer is a major factor to the clinical prognosis.Therefore,in the process of diagnosis and therapy of breast cancer,how to check and control lymphatic metastasis is very important.
VEGF-C(vascurlar endothelial growth factor-C)is one member of the VEGF family.It is a specific regulating factor for lymphatic endothelial cells and attend the lymphangiogenesis during embryonic development.VEGFR-3 is primarily expressed on lymphatic endothelium.
Some researches have found that VEGF-C can bind to VEGFR-3 and accelerates the process of lymph vessel hyperplasia and enlargement,induces the tumor lymphangiogenesis and is highly correlated with lymphatic metastasis.In foreign literature about the correlation between lymphatic metastasis of breast cancer and VEGF-C have been reported,but the expression of VEGF-C、VEGFR-3 in breast neoplasms and its relationship with lymphatic metastasis of breast cancer and clinicopathological
血管内皮生长因子-C(vascular endothelial growth factor C，VEGF-C)是VEGF家族中可特异性作用于淋巴管内皮的成员，参与了胚胎发育过程中淋巴管网的形成。其特异受体是血管内皮生长因子受体-3(vascular endothelial growth factorreceptor-3，VEGFR-3)，主要表达于淋巴管内皮细胞上。初步研究发现VEGF-C与VEGFR-3结合后，可诱导VEGFR-3酪氨酸激酶磷酸化，促进淋巴管生成。在许多实体瘤细胞中VEGF-C呈高表达，且与VEGFR-3相互作用，参与肿瘤的淋巴管生成，并与肿瘤的淋巴道转移呈正相关。有关VEGF-C与乳腺癌淋巴道转移的关系国外已有报道，但VEGF-C、VEGFR-3在乳腺良恶性肿瘤中的表达情况及其与乳腺癌淋巴道转移和其它病理学特征的关系国内外尚未见文献报道。本研究通过检测VEGF-C、VEGFR-3在乳腺良恶性肿瘤中的蛋白表达，探讨其在乳腺癌发生发展及转移中的作用，探索乳腺癌淋巴转移的机制，为抗乳腺癌淋巴转移的治疗提供理论依据。
方法 1．采用免疫组织化学sP法，检测18例乳腺良性肿瘤(导管内乳头
Objective Breast cancer is a kind of maligant tumor which affects on women's health all over the world. The disease incidence of breast cancer has a trend of increasing. In some areas,especially in some cities,it has leaped to first place in the maligant tumors of females.Breast has plentiful lymphatic vessel network,thus metastasis of early-stage breast cancer occurs primarily through the lymphatic system. It has been proved wether or not lymphatic metastasis of breast cancer is a major factor to the clinical prognosis.Therefore,in the process of diagnosis and therapy of breast cancer,how to check and control lymphatic metastasis is very important.
VEGF-C(vascurlar endothelial growth factor-C)is one member of the VEGF family.It is a specific regulating factor for lymphatic endothelial cells and attend the lymphangiogenesis during embryonic development.VEGFR-3 is primarily expressed on lymphatic endothelium.
Some researches have found that VEGF-C can bind to VEGFR-3 and accelerates the process of lymph vessel hyperplasia and enlargement,induces the tumor lymphangiogenesis and is highly correlated with lymphatic metastasis.In foreign literature about the correlation between lymphatic metastasis of breast cancer and VEGF-C have been reported,but the expression of VEGF-C、VEGFR-3 in breast neoplasms and its relationship with lymphatic metastasis of breast cancer and clinicopathological
引文
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2. Joukov V, Pajusola K, Kaipainen A. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt-4(VEGFR-3) and KDR(VEGFR-2) receptor tyrosine kinases[J]. The EMBO J, 1996, 15(2):290-298
3. Kimura Y, Watanabe M, Ohga T, et al. Vascular endothelial growth factor C expression correlates with lymphatic involvement and poor prognosis in patients with esophageal squamous cell carcinoma[J]. Oncolgy Reports, 2003, 10(6): 1747-1751
1. Onogawa S, Kitadai Y, Tanaka S,et al. Expression of VEGF-C and VEGFR-3 at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma[J]. Cancer Sci, 2004, 95(1):32-39
2. Li R, Younes M, Wheder TM, et al. Expression of vascular endothelial growth factor receptor-3(VEGFR-3) in human prostates[J]. Prostate, 2004, 58(2): 193-199
3. Gombos Z, Xu XW, Chu christina S, et al. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix[J]. Clin cancer Res, 2005, 11(23):8364-8371
4. Tang RF, Itakura J, Aikawa T, et al. Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer[J]. Pancreas, 2001, 22(3):285-292
5. Weidner N. Current Pathologic methods for measuring intratumoral microvessel density with breast carcinoma and other solid tumor[J]. Breadt Cancer Res Treat, 1995;36(2): 169-180
9. Jusila L, Alitalo K. Vascular growth factors and lymphangiogenesis[J]. Physiol Rev, 2002, 82(3):673-70010．李秋梨，陈福进．血管内皮生长因子-C、-D与肿瘤淋巴道转移研究进展[J]．癌症，2002，21(6)：696-700
11．谢永红，杜月光，许敬尧等．VEGF-C在乳腺癌诊断中的意义[J]．诊断病理学杂志，2003，10(4)：252-252
12. Paavonen K, Hrelli-kuitunen N, Chilov D, et al. Novel human vascular endothelial growth factors genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively[J]. Circulation, 1996, 93(6): 1079-1082
13. Joukov V, Kaijainen A, Jeltsch M, et al. Vascular endothelial growth factor VEGF-B and VEGF-C[J]. Jounal of Celular Physiology, 1997, 173(2):211-215
14. Kirkin V, Mazitschek R, Krishnan J, et al. Characterization of indolinones which preferentially inhibit VEGF-C and VEGF-D-induced activation of VEGFR-3 rather than VEGFR-2[J]. Eur J Biochem, 2001,268(21):5530-5540
15. Mandrito AJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-C mediated lymphangiogenesis promotes tumor metastasis[J]. The EMBO J, 2001, 20(14):642-682
16. Mattila MM, Ruohola JK, Karpanen T, et al. VEGF-C induced lymphangiogenesis associated with lymphnode metastasis in orthotopic MCF-7 tumors[J]. Int J Cancer, 2002, 98(6):946-951
17. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis[J]. Nature Medicine, 2001, 7(2): 192-198
18. Stacker SA, Williams RA, Achen MG. Lymphangiogenic growth factors as markers of tumor metastasis[J]. APMIS, 2004, 112(7-8):539-549
19. Kinoshita J, Kitamura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factor-C(VEGF-C) in breast cancer[J]. Breast Cancer Res Treat, 2001, 66(2): 159-164
20. 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):918-92321. Akagi A, Ikeda Y, Miyazaki M, et al. Vascular endothelial tissues[J]. Br J Cancer, 2000, 83(7):887-891
22. Ueda M, Hung YCh, Terai Y, et al. Vascular endothelial growth factor-C expression and invasive phenotype in ovarian carcinomas[J]. Clin Cancer Res, 2005, 11(5):3225-3232
23. Yu XM, Lo CY, Chan WF, et al. Increased expression of vascular endothelial growth factor C in papillary thyroid carcinoma correlates with cervical lymph node metastases [J]. Clin Cancer Res, 2005, 11(22):8063-8069
24. Dias S, Choy M, Alitalo K, et al. Vascular endothelial growth factor(VEGF-C) signaling through FLT-4(VEGFR-3) mediates leukemic cell proliferation、survival and resistance to chemotherapy[J]. Blood, 2002, 99 (6):2179-2184
25. Goydos JS, Gorski DH. Vascular endothelial growth factor C mRNA expression correlates with stage of progression in patients with melanoma[J]. Clin Cancer Res, 2003, 9(16Pt 1):5962-5967
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