血管内皮生长因子-C在乳腺癌组织中的表达及临床意义
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摘要
目的：1、研究和探讨乳腺癌组织中VEGF-C、MVD的表达水平及与乳腺癌侵袭、转移和预后之间的关系；2、探讨乳腺癌X线表现与VEGF-C、MVD、ER水平之间的关系，为临床选择治疗方法提供参考。
方法：1、50例经乳腺X线照相，手术病理证实乳腺癌标本运用免疫组化方法定性、定量的检测了VEGF-C、MVD的表达情况，分析各检测指标间及与乳腺癌生物学特征的相关意义；2、将X线照相特征与各检测指标进行对比研究。
结果：1、在50例乳腺癌患者中，腋窝淋巴结无转移者共19例，9例VEGF-C呈阳性(47％)；腋窝淋巴结有转移者共31例，24例VEGF-C呈阳性(77％)。腋窝淋巴结转移组的VEGF-C的表达明显高于无淋巴结转移组，统计学上有显著性差异(p＜0.05)；VEGF-C阳性表达组共33例，MVD值为31.67±7.85，VEGF-C阴性表达组共17例，MVD值为26.84±7.03。经统计学分析，两者之间有相关性，差异显著(p＜0.05)；腋窝淋巴结无转移组MVD值为25.56±5.87；腋窝淋巴结有转移者组MVD值为32.76±7.74。腋窝淋巴结转移组的MVD
硕士学位论文
的表达明显高于无淋巴结转移组，统计学上有显著性差异(P<0.05);
VEGF(、MVD与肿瘤的临床分期、肿瘤大小、病理分型等无统计学
意义。
2、在50例乳腺癌患者中，ER染色阳性组共17例，8例VEGF一C
染色呈阳性(47%):ER染色阴性组共33例，25例VEGF一C染色呈阳
，胜(76%)。ER染色阳性组的VEGF一C的阳性表达与ER染色阴性组的
vEGF一C的阳性表达在统计学上有显著性差异(P=0.04);在50例乳
腺癌患者FFDM检查中，有毛刺组共30例，24例ER染色呈阳性(8。%);
无毛刺组共20例，11例ER染色呈阳性(55%)。无毛刺组的ER的阳
性表达率高于有毛刺组的ER的阳性率，经统计学分析有显著性差异
(P<0.05);而vEGF一C与钙化、毛刺均无显著差异。
结论:乳腺癌组织中，VEGF一C、MDv的表达与乳腺癌淋巴结转
移有关，VEGF一C、MVD、ER可以协同判断淋巴结转移、评佑预后;
乳腺癌的X线表现有一定的特征，其与乳腺癌各生物学指标密切相
关，在一定程度上可为临床治疗方法的选择提供参考。
Objectives: 1, To study the expressions of VEGF-C and MVD in breast cancer and their correlation with the invasion,metastasis and prognosis of breast cancer.2, To investigate the mammographic features of the breast cancer and correlation between the mammographic features and the expressions of VEGF-C,MVD,ER,and try to provide clinical criteria for selecting pations for appropriate local treatment.
Methods: 1 , A totle of 50 patients with breast cancer, comfirmed by both mammography and pathology, was rolled in this study. We investigated the expressions of VEGF-C and MVD by immuno-histochemical staining. 2. To analyze the mammographic features and the expressions of VEGF-C,MVD,ER.
Results: 1 , Of 50 cases, lymph node non-metastasis was seen in 19cases, of which VEGF-C positive expre- ssion was seen in 9cases(47%).In 31eases of lymph node metastasis,24 cases were expressed VEGF-C (77%).The VEGF-C expression of group with lymph node metastasis was significantly higher than that of group
without lymph node metastasis( p<0.05 ). The level of MVD in group of VEGF-C-positive expression was 31.67 卤 7.85 , in group of VEGF-C-negative expression was 26.84 卤 7.03.The difference between them was distinct ( p<0.05 ). The level of MVD in group of lymph node non-metastasis was 25.56 卤 5.87, which had distinct difference contrasted with group of lymph node metastasis(p<0.05 ) . There was no statistically significant difference between the expressions of VEGF-C,MVD and clinical stage, tumor size, pathologic features.
2 > Of 50 cases,17cases were seen to express ER, in whith VEGF-C positive expression was seen in 9 cases (47%), The VEGF-C expression of group with ER-negative expressions(76%) was significantly higher than that of group with ER-positive expressions (p<0.05).Spicule sign were seen in 30 cases, in which 24 cases were seen to express ER. ER expression of group with Spicule sign was significantly higher than that of group without Spicule sign ( p<0.05 ) .But no significant difference was found between VEGF-C and spicule sige,calcification.
Conclution:There are clinical significance between VEGF-QMVD expressions and lymph-node metastasis in breast cancer. VEGF-C, MVD and ER were of clinical significance in evaluating lymph node metastatic potency and prognosis. The mammographic findings of breast cancer were characteristic.They were closely correlated with the clinicopathologic findings.To some extent, the
choice of treatment could be based on these mammographic findings.
方法：1、50例经乳腺X线照相，手术病理证实乳腺癌标本运用免疫组化方法定性、定量的检测了VEGF-C、MVD的表达情况，分析各检测指标间及与乳腺癌生物学特征的相关意义；2、将X线照相特征与各检测指标进行对比研究。
结果：1、在50例乳腺癌患者中，腋窝淋巴结无转移者共19例，9例VEGF-C呈阳性(47％)；腋窝淋巴结有转移者共31例，24例VEGF-C呈阳性(77％)。腋窝淋巴结转移组的VEGF-C的表达明显高于无淋巴结转移组，统计学上有显著性差异(p＜0.05)；VEGF-C阳性表达组共33例，MVD值为31.67±7.85，VEGF-C阴性表达组共17例，MVD值为26.84±7.03。经统计学分析，两者之间有相关性，差异显著(p＜0.05)；腋窝淋巴结无转移组MVD值为25.56±5.87；腋窝淋巴结有转移者组MVD值为32.76±7.74。腋窝淋巴结转移组的MVD
硕士学位论文
的表达明显高于无淋巴结转移组，统计学上有显著性差异(P<0.05);
VEGF(、MVD与肿瘤的临床分期、肿瘤大小、病理分型等无统计学
意义。
2、在50例乳腺癌患者中，ER染色阳性组共17例，8例VEGF一C
染色呈阳性(47%):ER染色阴性组共33例，25例VEGF一C染色呈阳
，胜(76%)。ER染色阳性组的VEGF一C的阳性表达与ER染色阴性组的
vEGF一C的阳性表达在统计学上有显著性差异(P=0.04);在50例乳
腺癌患者FFDM检查中，有毛刺组共30例，24例ER染色呈阳性(8。%);
无毛刺组共20例，11例ER染色呈阳性(55%)。无毛刺组的ER的阳
性表达率高于有毛刺组的ER的阳性率，经统计学分析有显著性差异
(P<0.05);而vEGF一C与钙化、毛刺均无显著差异。
结论:乳腺癌组织中，VEGF一C、MDv的表达与乳腺癌淋巴结转
移有关，VEGF一C、MVD、ER可以协同判断淋巴结转移、评佑预后;
乳腺癌的X线表现有一定的特征，其与乳腺癌各生物学指标密切相
关，在一定程度上可为临床治疗方法的选择提供参考。
Objectives: 1, To study the expressions of VEGF-C and MVD in breast cancer and their correlation with the invasion,metastasis and prognosis of breast cancer.2, To investigate the mammographic features of the breast cancer and correlation between the mammographic features and the expressions of VEGF-C,MVD,ER,and try to provide clinical criteria for selecting pations for appropriate local treatment.
Methods: 1 , A totle of 50 patients with breast cancer, comfirmed by both mammography and pathology, was rolled in this study. We investigated the expressions of VEGF-C and MVD by immuno-histochemical staining. 2. To analyze the mammographic features and the expressions of VEGF-C,MVD,ER.
Results: 1 , Of 50 cases, lymph node non-metastasis was seen in 19cases, of which VEGF-C positive expre- ssion was seen in 9cases(47%).In 31eases of lymph node metastasis,24 cases were expressed VEGF-C (77%).The VEGF-C expression of group with lymph node metastasis was significantly higher than that of group
without lymph node metastasis( p<0.05 ). The level of MVD in group of VEGF-C-positive expression was 31.67 卤 7.85 , in group of VEGF-C-negative expression was 26.84 卤 7.03.The difference between them was distinct ( p<0.05 ). The level of MVD in group of lymph node non-metastasis was 25.56 卤 5.87, which had distinct difference contrasted with group of lymph node metastasis(p<0.05 ) . There was no statistically significant difference between the expressions of VEGF-C,MVD and clinical stage, tumor size, pathologic features.
2 > Of 50 cases,17cases were seen to express ER, in whith VEGF-C positive expression was seen in 9 cases (47%), The VEGF-C expression of group with ER-negative expressions(76%) was significantly higher than that of group with ER-positive expressions (p<0.05).Spicule sign were seen in 30 cases, in which 24 cases were seen to express ER. ER expression of group with Spicule sign was significantly higher than that of group without Spicule sign ( p<0.05 ) .But no significant difference was found between VEGF-C and spicule sige,calcification.
Conclution:There are clinical significance between VEGF-QMVD expressions and lymph-node metastasis in breast cancer. VEGF-C, MVD and ER were of clinical significance in evaluating lymph node metastatic potency and prognosis. The mammographic findings of breast cancer were characteristic.They were closely correlated with the clinicopathologic findings.To some extent, the
choice of treatment could be based on these mammographic findings.
引文
[1] Spigel DR,Burstein HJ.HER2 overexpressing metas- tatic breast cancer. Curr Treat Options Oncol, 2002, 3:163.
[2] Camp RL, Rimm EB,Rimm DL.Met expression is associated with poor outcome in patient with axillary lymph node negative breast carcinoma. Cancer, 1999,86:2259.
[3] 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．癌症，2002，21：696．
[4] 谢永红，杜月光，许敬尧等．VEGF-C在乳腺癌诊断中的意义．诊断病理学杂志，2003，10(4)：251-252．
[5] 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]. E MB O J, 1996, 15: 290-298.
[6] Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C trans- genic mice. Science, 1997; 276 (5317): 1423-1425.
[7] Mandriota S J, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-C-mediated lymphangio- genesis promotes tumor metastasis. EMBO J, 2001; 20(4): 672-682.
[8] Fellmer PT, Saca K, Tanaka R, et al. Vascular endo- thelial growth factor-C gene expression in papillary and follicular thyroid
carcinomas [J]. Surgery, 1999, 92:3566.
[9] Tsurusaki T, Kanda S, Sakai H ,et al. Vascular endothelial growth factor-C expression in human prostaic carcinoma and its relationship to lymph node metastasis[J]. Br J Cancer, 1999,80(1-2): 309 -313.
[10] K kagi,Y lkeda,M Mlyazaki, et al. Vascular endoth- elial growth factor-C(VEGF-C) expression in human colorectal cancer tissues[J]. Br J Cancer, 2000, 83 (7):887.
[11] 刘刚，沈镇宙，邵志敏．肿瘤新生淋巴管调控机制与淋巴道转移研究进展，临床肿瘤学杂志，2003，8(3)：226-228．
[12] Skobe M, Hawighorst T, Jackson DG.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis[J]. Nat Med, 2001,7(2) :151-152.
[13] Karpanen T, Egeblad M, Karkkainen MJ. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth[J]. Cancer Res, 2001, 61(5): 1786-1790.
[14] 刘刚，张杰，陆劲松，等．乳腺癌组织淋巴管内皮细胞生长因子表达及其意义．肿瘤防治杂志，2003，10(7)：680-683．
[15] Kinoshita J, Kitamura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factoe-C (VEGF-C) in breast cancer. Breast Cancer Res Treat, 2001, 66(2): 159-164.
[16] 高杰，刘执玉，毕玉顺，等．血管内皮生长因子C mRNA在乳腺癌细胞株中的表达．山东大学学报(医学版)，2002，21(3)：
219-229.
[17] Nathanson SD, Zarbo RJ, Wachna DL, et al. Microvessels that predict axillary lymph node metastases in patients with breast cancer. Arch Surg, 2000, 135(5):586-593.
[18] Niki T, Iba S, Tokunou M, et al. Expression of vascular endothelial growth factors A, B, C, D and their relationships to lymph node status in lung adenocarcinoma[J]. Clin Cancer Res, 2000, 6(6):2431-2439.
[19] O charoenrat P, Rhysevans P, Eccles SA, et al. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma collation with lymph node mestastasis[J]. Cancer, 2001, 92(8):556-558.
[20] 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): 1669-1675.
[21] Beasley NJ, Prevo R, Banerji S, et al .I ntratu moral lymphangiogenesis and lymph node metastasis in head and neck cancer [J]. Cancer Res, 2002, 62(5): 1315-1320.
[22] 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—166.
[23] Tsurusaki T, Kanda S, Sakai H ,et al. Vascular endothelial growth factor-C expression in human prostaic carcinoma and its relationship to lymph node metastasis[J]. Br J Cancer, 1999,80(1-2): 309-313.
[24] Kajita T, Ohta Y, Kimura K, et al . The expression of vascular endothelial growth factor-C and its receptors in non-small cell lung cancer[J]. Br J cancer ,2001, 85(2) :255-260.
[25] Hashimoto I, Kodama J, Seki N, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer[J]. Br J Cancer, 2001, 85(1) :93-97.
[26] Weidner N,Semple JP, Wel CH,et al.Tumor angiogenesis and metastasia correlation in invasive breast carcinoma.N Engl J Med,1999;324:1.
[27] Balsari A, Maier JA, Colnaghi MI.Correlation between tumor vascularity, vascular endothelial groeth factor production by tumor cells,serum vascular endothelial groeth factor levels,and serum angiogenic activity in patienta with breast carcinoma.Lab Invest, 1999; 79(7):897.
[28] Liotta LA, Stracke ML, Tumor invasion and metastasis: Biochemical mechanisms.In:Lippman ME, Dickson RB, eds. Bresst cancer: celluler and Molecular Biology. Boston: LKluwer Academic Publishers, 1998, 223-238.
[29] 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 Oncologi, 2002,62:157-166
[30] Ghta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angioge- nesis and lymphangiogenesis in human malignant Mesothelioma tumours Br J Cancer, 1999, 81:54-61.
[31] 董昕，邱雪杉，王恩华等．血管内皮生长因子C及其受体3在非小细胞肺癌组织中的表达及意义．中华病理学杂志，2003，32(2)：128-132．
[32] Ghta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angio- genesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer, 1999,81: 54-61.
[33] Karkkainen MJ, Makinen T, Alitalo K. Lymphatic endothelium:a new frontier of metastasis research. Nat Cell Biol, 2002,4 : E2-5.
[34] Eggert A, Ikegaki N, Kwiatkowski J, et al. High- level expression of angiogenic factors is associated with advanced tumor stage in human neuroblasto- mas. Clin Cancer Res, 2000,6:1900-1908
[35] Ueda M, Terai Y, Yamashita Y, et al. Correlation between vascular endothelial growth factor C expression and invasion phenotype in cervical carcinomas. Int J Cancer, 2002, 98: 335-343.
[36] Kinoshita J, Kiramura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factor C(VEGF C) inbreast cancer. Breast Cancer Res Treat, 2001,66:159-164.
[2] Camp RL, Rimm EB,Rimm DL.Met expression is associated with poor outcome in patient with axillary lymph node negative breast carcinoma. Cancer, 1999,86:2259.
[3] 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．癌症，2002，21：696．
[4] 谢永红，杜月光，许敬尧等．VEGF-C在乳腺癌诊断中的意义．诊断病理学杂志，2003，10(4)：251-252．
[5] 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]. E MB O J, 1996, 15: 290-298.
[6] Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C trans- genic mice. Science, 1997; 276 (5317): 1423-1425.
[7] Mandriota S J, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-C-mediated lymphangio- genesis promotes tumor metastasis. EMBO J, 2001; 20(4): 672-682.
[8] Fellmer PT, Saca K, Tanaka R, et al. Vascular endo- thelial growth factor-C gene expression in papillary and follicular thyroid
carcinomas [J]. Surgery, 1999, 92:3566.
[9] Tsurusaki T, Kanda S, Sakai H ,et al. Vascular endothelial growth factor-C expression in human prostaic carcinoma and its relationship to lymph node metastasis[J]. Br J Cancer, 1999,80(1-2): 309 -313.
[10] K kagi,Y lkeda,M Mlyazaki, et al. Vascular endoth- elial growth factor-C(VEGF-C) expression in human colorectal cancer tissues[J]. Br J Cancer, 2000, 83 (7):887.
[11] 刘刚，沈镇宙，邵志敏．肿瘤新生淋巴管调控机制与淋巴道转移研究进展，临床肿瘤学杂志，2003，8(3)：226-228．
[12] Skobe M, Hawighorst T, Jackson DG.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis[J]. Nat Med, 2001,7(2) :151-152.
[13] Karpanen T, Egeblad M, Karkkainen MJ. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth[J]. Cancer Res, 2001, 61(5): 1786-1790.
[14] 刘刚，张杰，陆劲松，等．乳腺癌组织淋巴管内皮细胞生长因子表达及其意义．肿瘤防治杂志，2003，10(7)：680-683．
[15] Kinoshita J, Kitamura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factoe-C (VEGF-C) in breast cancer. Breast Cancer Res Treat, 2001, 66(2): 159-164.
[16] 高杰，刘执玉，毕玉顺，等．血管内皮生长因子C mRNA在乳腺癌细胞株中的表达．山东大学学报(医学版)，2002，21(3)：
219-229.
[17] Nathanson SD, Zarbo RJ, Wachna DL, et al. Microvessels that predict axillary lymph node metastases in patients with breast cancer. Arch Surg, 2000, 135(5):586-593.
[18] Niki T, Iba S, Tokunou M, et al. Expression of vascular endothelial growth factors A, B, C, D and their relationships to lymph node status in lung adenocarcinoma[J]. Clin Cancer Res, 2000, 6(6):2431-2439.
[19] O charoenrat P, Rhysevans P, Eccles SA, et al. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma collation with lymph node mestastasis[J]. Cancer, 2001, 92(8):556-558.
[20] 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): 1669-1675.
[21] Beasley NJ, Prevo R, Banerji S, et al .I ntratu moral lymphangiogenesis and lymph node metastasis in head and neck cancer [J]. Cancer Res, 2002, 62(5): 1315-1320.
[22] 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—166.
[23] Tsurusaki T, Kanda S, Sakai H ,et al. Vascular endothelial growth factor-C expression in human prostaic carcinoma and its relationship to lymph node metastasis[J]. Br J Cancer, 1999,80(1-2): 309-313.
[24] Kajita T, Ohta Y, Kimura K, et al . The expression of vascular endothelial growth factor-C and its receptors in non-small cell lung cancer[J]. Br J cancer ,2001, 85(2) :255-260.
[25] Hashimoto I, Kodama J, Seki N, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer[J]. Br J Cancer, 2001, 85(1) :93-97.
[26] Weidner N,Semple JP, Wel CH,et al.Tumor angiogenesis and metastasia correlation in invasive breast carcinoma.N Engl J Med,1999;324:1.
[27] Balsari A, Maier JA, Colnaghi MI.Correlation between tumor vascularity, vascular endothelial groeth factor production by tumor cells,serum vascular endothelial groeth factor levels,and serum angiogenic activity in patienta with breast carcinoma.Lab Invest, 1999; 79(7):897.
[28] Liotta LA, Stracke ML, Tumor invasion and metastasis: Biochemical mechanisms.In:Lippman ME, Dickson RB, eds. Bresst cancer: celluler and Molecular Biology. Boston: LKluwer Academic Publishers, 1998, 223-238.
[29] 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 Oncologi, 2002,62:157-166
[30] Ghta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angioge- nesis and lymphangiogenesis in human malignant Mesothelioma tumours Br J Cancer, 1999, 81:54-61.
[31] 董昕，邱雪杉，王恩华等．血管内皮生长因子C及其受体3在非小细胞肺癌组织中的表达及意义．中华病理学杂志，2003，32(2)：128-132．
[32] Ghta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angio- genesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer, 1999,81: 54-61.
[33] Karkkainen MJ, Makinen T, Alitalo K. Lymphatic endothelium:a new frontier of metastasis research. Nat Cell Biol, 2002,4 : E2-5.
[34] Eggert A, Ikegaki N, Kwiatkowski J, et al. High- level expression of angiogenic factors is associated with advanced tumor stage in human neuroblasto- mas. Clin Cancer Res, 2000,6:1900-1908
[35] Ueda M, Terai Y, Yamashita Y, et al. Correlation between vascular endothelial growth factor C expression and invasion phenotype in cervical carcinomas. Int J Cancer, 2002, 98: 335-343.
[36] Kinoshita J, Kiramura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factor C(VEGF C) inbreast cancer. Breast Cancer Res Treat, 2001,66:159-164.