Purpose
Several lines of experimental evidence indicated that over-expression of vascular endothelial growth factor-C and cyclooxygenase-2 genes promotes angiogenesis and lymphangiogenesis, both of which are essential for the growth and spreading of tumor cells. This study was designed to evaluate the coexpression of vascular endothelial growth factor-C and cyclooxygenase-2 in human colorectal carcinoma to determine their relationships and correlations with lymph node metastasis and prognosis.
Methods
Tissue samples of primary tumors and metastatic lymph nodes from 150 patients undergoing intentionally curative surgical resections for colorectal adenocarcinoma were immunohistochemically examined for vascular endothelial growth factor-C, cyclooxygenase-2, and CD34 expressions. Then, we analyzed their relationships and correlations with clinicopathologic findings and patients' survival time.
Results
The positivity rate of vascular endothelial growth factor-C and cyclooxygenase-2 in the primary tumor was 68 and 72.7 percent, respectively, and in the metastatic lymph nodes was 93.3 and 80 percent, respectively. A significant correlation was found between the expression scores of vascular endothelial growth factor-C and cyclooxygenase-2 (P < 0.0001), and both also were correlated to microvessels density and several clinicopathologic parameters, including primary tumor size, lymph node metastasis, lymphatic invasion, and TNM stage. Patients with vascular endothelial growth factor-C-positive and/or cyclooxygenase-2-positive tumors had a significant shorter survival time than those with negative tumors did. However, in a multivariate analysis, only cyclooxygenase-2 expression was recognized as an independent prognostic factor (P = 0.0412; relative risk ratio, 3.067; 95 percent confidence interval, 1.046–8.994).
Conclusions
These data show that in human colorectal carcinoma, vascular endothelial growth factor-C and cyclooxygenase-2 are coexpressed and significantly associated with lymph node metastasis and prognosis.
Similar content being viewed by others
References
ET Hawk A Umar JL Viner (2004) ArticleTitleColorectal cancer chemoprevention: an overview of the science Gastroenterology 126 1423–1447 Occurrence Handle10.1053/j.gastro.2004.03.002 Occurrence Handle15131803
J Krishnan V Kirkin A Steffen et al. (2003) ArticleTitleDifferential 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 Cancer Res 63 713–722 Occurrence Handle1:CAS:528:DC%2BD3sXosVyhsQ%3D%3D Occurrence Handle12566318
TE Voyer ParticleLe ER Sigurdson AL Hanlon et al. (2003) ArticleTitleColon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089 J Clin Oncol 21 2912–2919 Occurrence Handle12885809
SD Nathanson (2003) ArticleTitleInsights into the mechanisms of lymph node metastasis Cancer 98 413–423 Occurrence Handle10.1002/cncr.11464 Occurrence Handle12872364
JL Su JY Shih ML Yen et al. (2004) ArticleTitleCyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma Cancer Res 64 554–564 Occurrence Handle1:CAS:528:DC%2BD2cXmsVWqtw%3D%3D Occurrence Handle14744769
M Skobe T Hawighorst DG Jackson et al. (2001) ArticleTitleInduction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis Nat Med 7 192–198 Occurrence Handle10.1038/84643 Occurrence Handle1:CAS:528:DC%2BD3MXhtVylu7s%3D Occurrence Handle11175850
SA Stacker C Caesar ME Baldwin et al. (2001) ArticleTitleVEGF-D promotes the metastatic spread of tumor cells via the lymphatics Nat Med 7 186–191 Occurrence Handle10.1038/84635 Occurrence Handle1:CAS:528:DC%2BD3MXhtVylu74%3D Occurrence Handle11175849
Y Cao P Linden J Farnebo et al. (1998) ArticleTitleVascular endothelial growth factor-C induces angiogenesis in vivo Proc Natl Acad Sci USA 95 14389–14394 Occurrence Handle1:CAS:528:DyaK1cXns1GlsL4%3D Occurrence Handle9826710
Y Yonemura Y Endo H Fujita et al. (1999) ArticleTitleRole of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer Clin Cancer Res 5 1823–1829 Occurrence Handle1:CAS:528:DyaK1MXltVCqt7o%3D Occurrence Handle10430087
T Tsurusaki S Kanda H Sakai et al. (1999) ArticleTitleVascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis Br J Cancer 80 309–313 Occurrence Handle10.1038/sj.bjc.6690356 Occurrence Handle1:STN:280:DyaK1Mzhs12jsw%3D%3D Occurrence Handle10390013
K Akagi Y Ikeda M Miyazaki et al. (2000) ArticleTitleVascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues Br J Cancer 83 887–891 Occurrence Handle10.1054/bjoc.2000.1396 Occurrence Handle1:CAS:528:DC%2BD3cXntFGjtLc%3D Occurrence Handle10970690
I Hashimoto J Kodama N Seki et al. (2001) ArticleTitleVascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer Br J Cancer 85 93–97 Occurrence Handle10.1054/bjoc.2001.1846 Occurrence Handle1:STN:280:DC%2BD3MzosVCisA%3D%3D Occurrence Handle11437408
R Masunaga H Kohno DK Dhar et al. (2000) ArticleTitleCyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients Clin Cancer Res 6 4064–4068 Occurrence Handle1:CAS:528:DC%2BD3cXotVyku7w%3D Occurrence Handle11051257
F Cianchi C Cortesini P Bechi et al. (2001) ArticleTitleUp-regulation of cyclooxygenase-2 gene expression correlates with tumor angiogenesis in human colorectal cancer Gastroenterology 121 1339–1347 Occurrence Handle10.1053/gast.2001.29691 Occurrence Handle1:CAS:528:DC%2BD38Xhs12htw%3D%3D Occurrence Handle11729113
Y Miyata S Koga S Kanda M Nishikido T Hayashi H Kanetake (2003) ArticleTitleExpression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival Clin Cancer Res 9 1741–1749 Occurrence Handle1:CAS:528:DC%2BD3sXjsFeit7w%3D Occurrence Handle12738729
LT Soumaoro H Uetake T Higuchi Y Takagi M Enomoto K Sugihara (2004) ArticleTitleCyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer Clin Cancer Res 10 8465–8471 Occurrence Handle10.1158/1078-0432.CCR-04-0653 Occurrence Handle1:CAS:528:DC%2BD2cXhtFGjs7rF Occurrence Handle15623626
M Oshima JE Dinchuk SL Kargman et al. (1996) ArticleTitleSuppression of intestinal polyposis in \({\text{APC}}^{{\Delta 716}} \) knockout mice by inhibition of cyclooxygenase-2 (Cox-2) Cell 87 803–809 Occurrence Handle10.1016/S0092-8674(00)81988-1 Occurrence Handle8945508
T Kawamori CV Rao K Seibert BS Reddy (1998) ArticleTitleChemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis Cancer Res 58 409–412 Occurrence Handle1:CAS:528:DyaK1cXnsFejtw%3D%3D Occurrence Handle9458081
T Yamauchi M Watanabe T Kubota et al. (2002) ArticleTitleCyclooxygenase-2 expression as a new marker for patients with colorectal cancer Dis Colon Rectum 45 98–103 Occurrence Handle10.1007/s10350-004-6120-5 Occurrence Handle11786771
M Arinaga T Noguchi S Takeno M Chujo T Miura Y Uchida (2003) ArticleTitleClinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma Cancer 97 457–464 Occurrence Handle10.1002/cncr.11073 Occurrence Handle1:CAS:528:DC%2BD3sXhtFGltL0%3D Occurrence Handle12518370
C Denkert KJ Winzer BM Muller et al. (2003) ArticleTitleElevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma Cancer 97 2978–2987 Occurrence Handle10.1002/cncr.11437 Occurrence Handle1:CAS:528:DC%2BD3sXlt1Shtbo%3D Occurrence Handle12784332
JS Byeon HY Jung YJ Lee et al. (2004) ArticleTitleClinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma J Gastroenterol Hepatol 19 648–654 Occurrence Handle10.1111/j.1440-1746.2004.03348.x Occurrence Handle1:CAS:528:DC%2BD2cXlvFOlsb4%3D Occurrence Handle15151619
H Seno M Oshima T Ishikawa et al. (2002) ArticleTitleCyclooxygenase-2 and prostaglandin E2 receptor EP2-dependent angiogenesis in \({\text{APC}}^{{\Delta 716}} \) mouse intestinal polyps Cancer Res 62 506–511 Occurrence Handle1:CAS:528:DC%2BD38XhtVyht7k%3D Occurrence Handle11809702
PA Kyzas D Stefanou NJ Agnantis (2005) ArticleTitleCox-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma Mod Pathol 18 153–160 Occurrence Handle1:CAS:528:DC%2BD2MXisl2l Occurrence Handle15272284
SJ Mandriota L Jussila M Jeltsch et al. (2001) ArticleTitleVascular endothelial growth factor-C- mediated lymphangiogenesis promotes tumour metastasis EMBO J 20 672–682 Occurrence Handle10.1093/emboj/20.4.672 Occurrence Handle1:CAS:528:DC%2BD3MXhsVyhtrw%3D Occurrence Handle11179212
M Tsujii S Kawano RN DuBois (1997) ArticleTitleCyclooxygenase-2 expression in human colon cancer cells increases metastatic potential Proc Natl Acad Sci USA 94 3336–3340 Occurrence Handle10.1073/pnas.94.7.3336 Occurrence Handle1:CAS:528:DyaK2sXisVKnsr8%3D Occurrence Handle9096394
M Tsujii S Kawano S Tsuji H Sawaoka M Hori RN DuBois (1998) ArticleTitleCyclooxygenase regulates angiogenesis induced by colon cancer cells Cell 93 705–716 Occurrence Handle10.1016/S0092-8674(00)81433-6 Occurrence Handle1:CAS:528:DyaK1cXjsl2ksbw%3D Occurrence Handle9630216
JL Masferrer KM Leahy AT Koki et al. (2000) ArticleTitleAntiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors Cancer Res 60 1306–1311 Occurrence Handle1:CAS:528:DC%2BD3cXhvFWrt74%3D Occurrence Handle10728691
K Shimizu H Kubo K Yamaguchi et al. (2004) ArticleTitleSuppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer Cancer Sci 95 328–333 Occurrence Handle10.1111/j.1349-7006.2004.tb03211.x Occurrence Handle1:CAS:528:DC%2BD2cXks1yksrc%3D Occurrence Handle15072591
E Ogawa K Takenaka K Yanagihara et al. (2004) ArticleTitleClinical significance of VEGF-C status in tumor cells and stromal macrophages in non-small cell lung cancer patients Br J Cancer 91 498–503 Occurrence Handle10.1038/sj.bjc.6601992 Occurrence Handle1:CAS:528:DC%2BD2cXlvF2lsbk%3D Occurrence Handle15226767
S Tomozawa NH Tsuno E Sunami et al. (2000) ArticleTitleCyclooxygenase-2 overexpression correlates with tumor recurrence, especially haematogenous metastasis of colorectal cancer Br J Cancer 83 324–328 Occurrence Handle10.1054/bjoc.2000.1270 Occurrence Handle1:CAS:528:DC%2BD3cXlslens74%3D Occurrence Handle10917546
F Vita ParticleDe M Orditura E Lieto et al. (2004) ArticleTitleElevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma Cancer 100 270–278 Occurrence Handle14716760
A Mitsuhashi K Suzuka K Yamazawa H Matsui K Seki S Sekiya (2005) ArticleTitleSerum vascular endothelial growth factor (VEGF) and VEGF-C levels as tumor markers in patients with cervical carcinoma Cancer 103 724–730 Occurrence Handle10.1002/cncr.20819 Occurrence Handle1:CAS:528:DC%2BD2MXit1Ggsrw%3D Occurrence Handle15637689
RM Roumen GD Slooter FA Croiset van Uchelen L Vader Huib (2005) ArticleTitlePreoperative serum vascular endothelial growth factor is not a marker for subsequent recurrence during long-term follow-up of colorectal cancer patients Dis Colon Rectum 48 1070–1075 Occurrence Handle10.1007/s10350-004-0870-y Occurrence Handle15785896
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.
About this article
Cite this article
Soumaoro, L.T., Uetake, H., Takagi, Y. et al. Coexpression of VEGF-C and Cox-2 in Human Colorectal Cancer and its Association With Lymph Node Metastasis. Dis Colon Rectum 49, 392–398 (2006). https://doi.org/10.1007/s10350-005-0247-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10350-005-0247-x