胃癌组织HGF/c-Met的表达与淋巴管生成及转移的关系
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摘要
目的:通过检测胃癌组织中HGF、c-Met的表达和MLD值,探讨HGF、c-Met的表达和MLD值与临床病理因素之间的关系以及三者之间的相互关系,研究胃癌淋巴管转移的可能机制。
     方法:应用免疫组化方法检测52例胃癌病人癌组织中HGF、c-Met的表达,计数单克隆抗体D2-40标记的微淋巴管密度(MLD)。
     结果:
     1、胃癌组织中HGF及c-Met阳性表达均主要位于肿瘤细胞胞浆内,其表达阳性率分别为67.3%和78.8%。
     2、HGF的表达与组织学分级、浸润深度、临床分期、淋巴结转移显著相关(P<0.05),与年龄、肿瘤大小无关(P>0.05)。
     3、c-Met的表达与组织学分级及淋巴管转移密切相关,而与肿瘤大小、年龄、浸润深度、临床分期无关(P>0.05)。
     4、胃癌中MLD值显著高于癌旁正常组织,与肿瘤浸润深度、临床分期无显著性相关(P>0.05),而与组织学分型及淋巴结转移密切相关(P<0.05)。
     5、52例胃癌组织中,HGF和c-Met共阳性表达者占31例,共阴性表达者7例,两者表达呈正相关(r=0.342,P<0.05)。
     6、HGF表达阳性者的MLD值显著高于阴性者(P<0.005)。
     结论:
     1.HGF及c-Met表达于大部分胃癌癌细胞胞浆内。
     2.HGF的高表达与胃癌组织学分级、浸润深度、临床分期及淋巴结转移密切相关;c-Met的高表达与胃癌的组织学分级及淋巴结转移密切相关。
     3.胃癌组织中MLD值显著高于癌旁正常组织,与肿瘤组织学分级及淋巴结转移密切相关。
     4.胃癌组织中MLD与HGF的表达密切相关,而与c-Met的表达无关。
Objective:To detect the expressive levels of hepatocyte growth factor and c-Met and D2-40 in gastric carcinoma;To detect the MLD and its correlation with clinicopathological factors in gastric carcinoma;To investigate the possible mechanism of lymph node metastasis in gastric carcinoma.
     Methods:Immunohistochemistry method was used to detect the expression of HGF and c-Met and D2-40 in gastric cancer tissue and the normal tissues near the tumor borderline,with microlymphatic density (MLD)counted.
     Results
     (1).HGF and c-Met was expressed mainly in cytoplasm of gastric carcinoma cells.The expressive rate of HGF and c-Met in gastric cancer were 67.3%and 78.8%,respectively.
     (2).The expression of HGF had the positive correlation with histologic types,infiltration depth,clinical stage and lymph node metastasis(P<0.05).No correlation was found in age,tumor diameter(P>0.05).
     (3).The expression of c-Met had the positive correlation with histologic types and lymph node metastasis(p<0.05).No correlation was found in age,tumor diameter,infiltration depth and clinical stage(P>0.05).
     (4).The MLD in the gastric cancer was higher than that in the normal tissues near the tumor borderline(P<0.05).The MLD had no correlation with infiltration depth and clinical stage(P>0.05).The positive correlation was found in histologic types and lymph node metastasis(p<0.05)
     (5).In 52 cases of gastric cancer,there were 31 cases where the expression of HGF and c-Met was positive simultaneously.The simultaneously negative was 7 cases.Correlation coefficient showed that HGF had a positive correlation with c-Met in gastric cancer(r=0.342, P<0.05).
     (6).In gastric cancer,The MLD in the HGF-positive group was higher than that in the HGF-negative group(P<0.05)
     Conclusion
     (1).HGF and c-Met are expressed in plasma in most gastric cancer cell.
     (2).The expression of HGF has correlation with histologic types, infiltration depth,clinical stage and lymph node metastasis in the gastric carcinoma.The expression of c-Met has correlation with histologic types and lymph node metastasis in the gastric carcinoma.
     (3).The MLD in the gastric cancer was higher than that in the normal tissues near the tumor borderline.The MLD has the positive correlation with histologic types and lymph node metastasis.
     (4).The MLD in the gastric cancer has correlation with the expression of HGF,but it has no correlation with the expression of c-Met.
引文
[1]倪海滨,张彦亮,黄介飞,等.胃癌多步骤侵袭转移相关研究[J].南通医学院学报,2002,22(2):233-236.
    [2]高玉堂.1992-1994年中国恶性肿瘤三年抽样调查的意义及评价[J].中华肿瘤杂志,2000,3(6):263-264.
    [3]汤钊猷主编.现代肿瘤学[M].第2版.上海:上海医科大学出版社,2000:699.
    [4]潘剑,温玉明.淋巴管生成与肿瘤转移[J].国外医学口腔医学分册,2002,29(3):154-156
    [5]Cotran RS,Kumar V,Tucker C.Robbins Pathologic Basis of Disease.Philadelphia,PA:Saunders,1999,15(5):672-675.
    [6]Maruyama K,Gunven P,Okabayashi K,et al.Lymph Node Metastases of Gastric Cancer[J].Ann Surg,1989,210(5):596-602.
    [7]Zeng Q,Chen S,You Z,et al.Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and akt signaling independent of NF-κB[J].J Biol Chem,2002;277(28):25203-25208.
    [8]Herynk MH,Tsan R,Radinsky R.et al.Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated beta-catenin.Clin Exp Metastasis,2003,20(4):291-300.
    [9]Mareel M,Leroy A.Clinical,cellular,and molecular aspects of cancer invasion.Physiol Rev,2003,83(2):337-376.
    [10]Bottaro DP,Rubin JS,Faletto DL,et al.Identification of hepatocyte growth factor receptor as the c-met proto-oncogene product[J].Science,1991;251(2):802.
    [11]Tomita N,Morishita R,Taniyama Y,et al.Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis,ets-1 Circulation,2003,107(10):1411-1417.
    [12]Maulik G,Shrikhande A,Kijima T,et al.Role of the hepatocyte growth factor receptor,c-Met,in oncogenesis and potential for therapeutic inhibition.Cytokine Growth Factor Rev,2002,13(1):41-59.
    [13]Davies G,Mason MD,Martin TA,et al.The HGF/SF antagonist NK4reverses fibroblast and HGF-induced prostate tumor growth and angiogenesis in vivo.Int J Cancer,2003,106(3):348-354.
    [14]Clauss M.Molecular biology of the VEGF and VEGF receptor family.Semin Thromb Hemost,2000,26(6):561-569.
    [15]Banerji S,Ni J,Wang SX,et al.LYVE-1,a new homologue of the CD44glycoprotein,is a lymph-specific receptor for hyaluronan.J Cell Biol,1999,144(8):789-801.
    [16]Breiteneder-Geleff S,Soleiman A,Kowalski H,et al.Angiosarcomas express mixed endothelial phenotype of blood and lymphatic capillaryies:podoplania as a specific marker for lymphatic endothelium.Am J Pathol,1999,154(4):385-394.
    [17]Kato S,Yasunaga A,Uchida Y.Enzyme-histochemical staining for identification of lymphatic capillaryies.Lymphology,1991,24(3):125-129.
    [18]Kahn HJ,Marks A.A new monoclonal antibody,D2-40,for detection of lymphatic invasion in primary tumor.Lab Invest,2002,82(9):1255-1257.
    [19]Franehi A,Gallo O;Massi D,et al.Tumor lymphangiogenesis in head and neck squamous cell carcinoma:a morphometric study with clinical correlations.Cancer,2004,101(5):973-978.
    [20]Kahn HJ,Bailey D,Marks A.Monoclonal antibody D2-40,a new marker of lymphatic endothelium,reats with Kaposi's sarcoma and a subset of angiosarcomas.Mod Pathol,2002,15(4):434-440.
    [21]刘慧冬,赵玲辉,张雅芳,等.胃、结肠癌癌组织周边区淋巴管的形态特征[J].癌症,2005,24(6):699-703.
    [22]Mattila MM,Ruohola JK,Karpanen T,et al.VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7tumor.Int J Cancer,2002,98(10):946-951.
    [23]Beasely NJ,Prevo R,Baneriji S,et al.Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer.Cancer Res,2002,62(4):1315-1320.
    [24]王宗贵,金春顺,李野,等.喉癌中血管内皮生长因子C与淋巴转移的关系.中国免疫学杂志,2007,23(1):82-84.
    [25]牟江洪,阎晓初,肖华亮,等.VEGF-C及其受体VEGFR-3mRNA在大肠癌的表达和意义[J].重庆医学,2006,35(3):215-218.
    [26]Yonemura Y,Fushida S,Bando E,et al.Lymphangiogenesis and the vascular endothelial growth factor receptor(VEGFR-3)in gastric cancer.Eur J Cancer,2001,37(9):918-923.
    [27]Tanaka K,Miki C,Wakuda R,et al.Circulating level of hepatocyte growth factor as a useful tumor marker in patients with early-stage carcinoma[J].Scand J Gastroenterol,2004,39(8):754-760.
    [28]尹芳,乔泰东,时永全,等.紧密连接分子Occludin mRNA在胃癌中的表达和分布.中华肿瘤杂志.2002,24(12):557-560.
    [29]Shijubo N,Uede T,Kon S,et al.Vascular endothelial growth factor and osteopontin in stage I lung adenocarcinoma.Am J Respir Crit Care Med,1999,160(4):1269-1273.
    [30]Ohno Masakazu,Takeshi N,Yukihiro K,et al.Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer.Oncology Reports.2003,10(10):939-943.
    [31]Ma PC,Maulik G,Christensen J,et al.c-Met:structure,functions and potential for therapeutic inhibition.Cancer Metastasis Rev,2003,22(4):309-325.
    [32]李智,林素暇,梁惠珍,等.肝细胞生长因子/c-Met系统在鼻咽癌中的表达及意义,中华病理学杂志,2005,34(2):75-79.
    [33]Fluge O,Haugen DR,Lillehaug JR,et al.Difference in patterns of Met expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue.World J Surg,2001,25(5):623-631.
    [34]Horiguchi N,Takayama H,Toyoda M,et al.Hepatocyte growth factor promotes hepatica rcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.Oncogene,2002,21(12):1791-1799.
    [35]Rasola A,Anguissola S,Ferrero N,et al.Hepatocyte growth factor sensitizes human ovarian carcinoma cell lines to paclitaxel and ciplatin.Cancer Res,2004,64(5):1744-1750.
    [36]Tang z,Zhao M,Ji J,et al.Overexpression of gastric and c-met protein involved in human gastric carcinomas and intestinal metaplasia.Oncol Rep,2004,11(2):333-339.
    [37]He Y,Karpanen T,Alitalo K.Role of lymphangiogenic factors in tumor metastasis.Biochim Biophys Acta.2004,1654(1):3-12.
    [38]Michalopoulos GK,Zamegar R.Hepatocyte growth factor[J].Hepatolegy,1992;15(1):149-155.
    [39]Cooper CS,Park M,Blair DG,et al.Molecular cloning of a new transforming gene from a chemically transformed human cell line.Nature,1984;311(5981):29-33.
    [40]To CT,Tsao MS.The roles of hepatocyte growth factor/scatter factor and met receptor in human cancers.Oncol Rep,1998;5(5):1013-1024.
    [41]彭挺生,李智,邱锯世,等.细胞因子HGF体外增强骨肉瘤细胞株的增殖和黏附性.中山大学学报(医学科学版),2006,27(5):529-532.
    [42]赵仲升,茹国庆,马杰.IGF-Ⅱ和HGFmRNA表达与胃癌微血管密度的关系[J].中华肿瘤杂志,2004,26(11):673-677.
    [43]江晨,崔琳,纪萍,等.胃癌组织中HGF/c-Met的组织芯片检测及其与肿瘤血管生成关系[J].齐鲁医学杂志,2005,20(3):211-213.
    [44]Moriyama T,Kataoka H,Koono M,et al.Expression of hepatocyte growth factor/scatter factor and its receptor c-met in brain tumors:evidence for a role in progression of astrocytic tumors.Int J Mol Med,1999,3(5):531-536.
    [45]Rosenthal EL,Johnson TM,Allen ED,et al.Role of the plasminogen activator matrix metalloproteinase systems in epidermal growth factor and scatter factor stimulated invasion of carcinoma cells[J].Cancer Res,1998,85(22):5221-5230.
    [46]Dong G,Chen Z,Li ZY,et al.Hepatocyte growth factor/scatter factor induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squarnous cell carcinoma[J].Cancer Res,2001,61(11):5911-5918.
    [47]Edakuni G,Sasatomi E,Satoh T,et al.Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma[J].Pathol Int,2001,51(3):172-178.
    [48]杨进强,李勇,范立侨,等.VEGF-C及其受体VEGFR-3在胃癌淋巴转移中的作用[J].第二军医大学学报,2005,26(11):1256-1259.
    [49]Padera TP,Kadambi A,di Tomaso E,et al.Lymphatic metastasis in the absence of functional intratumor lymphatics.Science,2002,296(7):1883-1886.
    [50]Wong SY,Haack H,Crowley D,et al.Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis,but lymphangiogenesisis unnecessary for lymph node metastasis.Cancer Res,2005,65(21):9789-9798.
    [51]Guo XJ,Chen L,Long RG,et al.Invasive micropapillary carcinoma of the breast association of pathologic features with lymph node metastasis.Am J Clin Pathol,2006,126(5):740-746.
    [52]Atsuo shida MD,Shuichi fujioka MD.Prognostic Significance of Vascular Endothelial Growth Factor D in Gastric carcinoma World J Surg,2005,29 (5):1600-1607.
    [53]Trovato M,Villari D,Bartolone L,et al.Expression of the hepatocyte growth factor and c-met in normal thyroid,non-neoplastic,and neoplastic nodules Thyroid,1998;8(2):125-131.
    [1]Parkin M,Pisani P,Ferlay J.Global Cancer Statistics.CA Cancer J Clin 1999;49(1):33-64.
    [2]Castells A,Anil K.Principles of Oncogenesis.2002,Chapter 5:Tumor Invasion and Metastasis pp:1-12.
    [3]OH SJ,Jeltsch MM,Birkenhager R,et al.VEGF and VEGF-C:specific induction if angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane.Dev Biol.1997.188(1):96-109.
    [4]Michalopoulos GK,Zamegar R.Hepatocyte growth factor[J].Hepatolegy,1992;15(1):149-155.
    [5]Zeng Q,Chen S,You Z,et al.Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and akt signaling independent of NF-κ B[J].J Biol Chem,2002,277(28):25203-25208.
    [6]Kim CH,Moon SK,Bae JU,et al.Expression of hepatocyte growth factor and c-Met in hypoparyngeal squamous cell carcinoma.Acta Otoaryngol,2006,126(1):88-94.
    [7]Ueoka Y,Kato K,Wake N.Hepatocyte growth factor modulates motility and invasiveness of ovarian carcinomas via ras mediated pathway.Mol Cell Endocrinol,2003,202(1-2):81-88.
    [8]Gual P,Giordano S,Anguissola S,et al.Differential requirement of the last C-terminal tail of Met receptor for cell transformation and invasiveness.Oncogene,2001;20(39):5493-5502.
    [9]Kermorgant S,Cadiot G,Lewin MJ,et al.Expression of hepatocyte growth factor and its receptor,c-Met in human digestive tissues and different gastric and colonic cancer cell lines[J].Gastroenterol Clin Biol,1996,20(5):438-445.
    [10]Tomita N,Morishita R,Taniyama Y,et al.Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis,ets-1 Circulation,2003,107(10):1411-1417.
    [11]To CT,Tsao MS.The roles of hepatocyte growth factor/scatter factor and met receptor in human cancers.Oncol Rep,1998;5(5):1013-1024.
    [12]Vattimo Mde F,Santos OF.Functional interface between cathepsins and growth factors in the kidney development.Ren Fail,2005,27(5):615-622.
    [13]Nagayama T,Nagayama m,Kohara S,et al.Post-ischemic delayed expression of hepatocyte growth factor and c-Met in mouse brain following focal cerebral ischemia.Brain Res,2004,999(2):155-166.
    [14]Kaido T,Imamura M.Hepatocyte growth factor:clinical implications in hepatobiliary pancreatic surgery.J Hepatobiliary Pancreat Surg,2001,8(1):65-75.
    [15]Maulik G,Shrikhande A,Kijima T,et al.Role of the hepatocyte growth factor receptor,c-Met,in oncogenesis and potential for therapeutic inhibition.Cytokine Growth Factor Rev,2002,13(1):41-59.
    [16]Horiguchi N,Takayama H,Toyoda M,et al.Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.Oncogene,2002,21(12):1791-1799.
    [17]Nicola MH,Bizon R,Machado JJ,et al.Breast cancer micrometastases:different interactions of carcinoma cells with normal and cancer patients' bone marrow stromatal[J].Clin Exp Metastasis,2003,20(5):471-479.
    [18]Trovato M,Villari D,Bartolone L,et al.Expression of the hepatocyte growth factor and c-met in normal thyroid,non-neoplastic,and neoplastic nodules Thyroid,1998;8(2):125-131.
    [19]Rao UN,Sonmez-Alpan E,Michalopoulos GK.Hepatocyte growth factor and c-Met in benign and malignant peripheral nerve sheath tumors Hum Pathol,1997,28(9):1066-1070.
    [20]Nakajima M,Sawada H,Yamada Y,et al.The prognostic significance of amplification and overexpression of c-met and c-erbB-2 in human gastric carcinomas [J].Cancer,1999,85(9):1894-1902.
    [21]赵仲升,茹国庆,马杰.IGF-Ⅱ和HGFmRNA表达与胃癌微血管密度的关系[J].中华肿瘤杂志,2004,26(11):673-677.
    [22]江晨,崔琳,纪萍,等.胃癌组织中HGF/c-Met的组织芯片检测及其与肿瘤血管生成关系[J].齐鲁医学杂志,2005,20(3):211-213.
    [23]Nagy J,Curry GW,Hillan KJ,et al.Hepatocyte growth factor/scatter factor expression and c-met in primary breast cancer.Surg Oncol,1996,5(1):15-21.
    [24]Tanaka K,Miki C,Wakuda R,et al.Circulating level of hepatocyte growth factor as a useful tumor marker in patients with early-stage carcinoma[J].Scand J Gastroenterol,2004,39(8):754-760.
    [25] Herynk MH, Tsan R, Radinsky R. et al. Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated beta-catenin. Clin Exp Metastasis, 2003,20(4): 291-300.
    
    [26] Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev, 2003, 83(2): 337-376.
    
    [27] Rosenthal EL, Johnson TM, Allen ED, et al . Role of the plasminogen activator matrix metalloproteinase systems in epidermal growth factor and scatter factor stimulated invasion of carcinoma cells [J]. Cancer Res, 1998, 85(22): 5221-5230.
    
    [28] [28] Edakuni G, Sasatomi E, Satoh T, et al. Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma [J]. Pathol Int, 2001,51(3): 172-178.
    
    [29] Davies G, Mason MD, Martin TA, et al. The HGF/SF antagonist NK4 reverses fibroblast and HGF-induced prostate tumor growth and angiogenesis in vivo. Int J Cancer, 2003,106(3): 348-354.
    
    [30] Coltella N, Rasols A, Nano E, et al. P38MAPK turns hepatocyte growth factor to a death signal that commits ovarian concer cells to chemot herapy-induced apoptosis. Int J Cancer, 2006,118(12): 2981-2990.
    
    [31] Qian LW, Mizumoto K, Inadome N, et al. Radiation stimulates HGF receptor/c-Met expression that leads to amplifying cellular response to HGF stimulation via upreglulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells. Int J Cancer, 2003,104(5): 542-549.
    
    [32] 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]. EMBO J, 1996; 15(7): 1751.
    
    [33] Achen MG , Jeltsch M , Kukk E , et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Fltl) and VEGF receptor 3 (Flt4) [J]. Proc Natl Acad Sci USA, 1998; 95(2): 548.
    
    [34] Kukk E , Lymboussaki A ,Taria S , et al. VEGF-C receptor hinding and pattern of expression with VEGF-3 suggest sarolein lymphatic vascular development. Development 1996; 122(16): 3829.
    
    [35] Jeltsch M , Kaipainen A , Joukov V , et al. Hyper plasia of lymphatic vesselsin vegfctrans genicmice. Science 1997; 276(6): 1423-1424.
    
    [36] He Y, Karpanen T, Alitalo, et al. Role of lymphangiogenic factors in tumor metastasis[J].Biochimica Biophysica Acta,2004,1654(1):3.
    [37]Zachary I,Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor.Am J Physiol cell Physiol,2001,280(9):C1375-C1386.
    [38]Mandriota SJ,Jussila L,Jeitsch M,et al.Vascular endothelial growth factor-C mediated lymphangiogenesis promotes tumour metastasis.EMBO 2001;20(4):672-674.
    [39]Fellmer PT,Sato K,Tanaka R,et al.Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas.Surgery 1999;126(5):1056-1058.
    [40]Skobe M,Hawighorst T,Jackson DG,et al.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis[J].Nat Med,2001;7(2):192-194.
    [41]汪蕊,陈睿,杨婉华,等.VEGF-C和VEGF-R3在乳腺癌中的表达及与淋巴结转移的关系[J].肿瘤防治研究,2006,33(6):385-387.
    [42]Krishnan J,Kirkin V,Steffen A,et al.Differential in vivo and in vitro expression of vascular endothelial growth factor(VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats[J].Cancer Res,2003;63(3):713-715.
    [43]Skobe M,Hamberg L,Hawighorst T,et al.Concurrent induction of lymphangiogenesis,angiogenesis,and macrophage recruitment by vascular endothelial growth factor-C in melanoma.Am J Pathol,2004,159:893-903.
    [44]Yonemura Y,Endo Y,Fujita H,et al.Role of vascular endothelial growth factor C expression in the development of lymphnode metastasis in gastric cancer [J].Clin Cancer Res,1999;5(7):1823-1826.
    [45]Karpanen T,Egeblad M,Karkkainen MJ,et al.Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth.Cancer Res.2001,61(7):1786-1790.
    [46]Witzenbichler B,Asahara T,Murohara T,et al.Vascular endothelial growth factor-C(VEGF-C/VEGF-2)promotes angiogenesis in the setting of tissue ischemia.Am J Pathol.1998,153(4):381-394.
    [47]Cao Y,Linden P,Farnebo J,et al.Vascular endothelial growth factor C induces angiogenesis in vivo.Proc Natl Acad Sci USA 1998,95(18):14389-14392.
    [48]Joukov V,Sorsa T,Kumar V,et al.A recombinant mutant vascular endothelial growth factor C that has lost endothelial growth factor receptor-2 binding,activation,and vascular permeability activities.J Biol Chem,1998,273(12):6599-6602.
    [49]Veikkola T,Jussila L,Makinen T,et al.Signaling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in tmnsgenic mice.EMBO J.2001,6(5):1223-1231.
    [50]Skobe M,Hawighorst T,Jackson D,et al.Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.Nature Med.2001,7(2):192-198.
    [51]杨进强,李勇,范立侨,等.VEGF-C及其受体VEGFR-3在胃癌淋巴转移中的作用[J].第二军医大学学报,2005,26(11):1256-1259.
    [52]Strauss L,Volland D,Kunkel M,et al.Dual role of VEGF family members in the pathogenesis of head and neck cancer(HNSCC):possible link between angiogenesis and immune tolerance[J].Med Sci M onit,2005,11(8):280-292.
    [53]Gerber HP,Mcmurtrey A,Kowalski J,et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3kinase/Akt signal transduction pathway.Requirement for Flk-1/KDR activation.J Biol Chem.1998,273(20):30336-30343.
    [54]Amioka T,Kitadai Y,Tanaka S,et al.Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa.Eur-J-Cancer.2002,38(10):1413-1419.
    [55]Ishikawa M,Kitayama J,Kazama S,et al.Expression of vascular endothelial growth factor C and D(VEGF-C and -D)is an important risk factor for lymphatic metastasis in undifferentiated early gastric carcinoma.Jpn-J-Clin-Oncol.2003,33(1):21-27.
    [56]Maeda K,Yashiiro M,Nishihara T.Correlation between Vascular endothelial growth factor-C expression and lymph node metastasis in T1 carcinoma of the colon and rectum.Surg Today,2003,33(10):736-739.
    [57]Junko K,Kaoru K,Akira K,et al.Clinical significance of vascular endothelial growth factor-C(VEGF-C)in breast cancer.Breast Cancer Research and Treatment.2001,66(2):159-164.
    [58]Tanja V,Lotta J,Taija M,et al.Signaling via vascular endothelial growth factor-3 is sufficient for lymphangiogenesis in transgenic mice.The EMBO Journal.2001,20(6):1223-1231.
    [59] 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): 918-920.
    
    [60] Takahashi A, Kono K , Itakura J , et al. Correlation of vascular endothelial growth factor-C expression with tumor infiltrating dendritic cells in gastric cancer[J]. Oncology, 2002; 62(2): 121.