Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2009

Open Access 01-02-2009 | Research

Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value

Authors: Jian-guo Sun, Yan Wang, Zheng-tang Chen, Wen-lei Zhuo, Bo Zhu, Rong-xia Liao, Shao-xiang Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2009

Login to get access

Abstract

Background

Our aim was to detect lymphatic endothelial marker podoplanin, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR)-3 and study the prognostic relevance of lymphangiogenesis in non-small cell lung cancer (NSCLC).

Materials

82 paraffin-embedded tissues and 40 fresh frozen tissues from patients with NSCLC were studied. Tumor samples were immunostained for the lymphatic endothelial markers. Lymphangiogenesis was assessed by immunohistochemical double stains for Podoplanin and Ki-67. The prognostic relevance of lymphangiogenesis-related clinicopathological parameters in NSCLC was evaluated.

Results

We found that the number of podoplanin positive vessels was correlated positively with the number of LYVE-1 positive vessels. Most of VEGFR-3 positive, few of LYVE-1 positive and none of podoplanin positive vessels were blood vessels. Peritumoral lymphatic vessel density (ptLVD), pathologic stage, lymph node status, lymphatic vessel invasion (LVI), vascular endothelial growth factor-C (VEGF-C) expression and Ki-67 index of the endothelium cells of the micro lymphatic vessels (Ki67%) were associated significantly with a higher risk of tumor progress. ptLVD, pathologic stage, lymph-node metastasis and Ki67% were independent prognostic parameters for overall survival.

Conclusion

Podoplanin positive ptLVD might play important roles in the lymphangiogenesis and progression of NSCLC. Patients with high podoplanin+ ptLVD have a poor prognosis.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ogawa E, Takenaka K, Yanagihara K, Kurozumi M, Manabe T, Wada H, Tanaka F: Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer. 2004, 91 (3): 498-503. 10.1038/sj.bjc.6601992.CrossRef Ogawa E, Takenaka K, Yanagihara K, Kurozumi M, Manabe T, Wada H, Tanaka F: Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer. 2004, 91 (3): 498-503. 10.1038/sj.bjc.6601992.CrossRef
2.
go back to reference Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG: Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005, 25 (6): 2441-2449. 10.1128/MCB.25.6.2441-2449.2005.CrossRef Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG: Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005, 25 (6): 2441-2449. 10.1128/MCB.25.6.2441-2449.2005.CrossRef
3.
go back to reference Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y: Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with non small cell lung carcinoma. Cancer. 2003, 97 (2): 457-464. 10.1002/cncr.11073.CrossRef Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y: Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with non small cell lung carcinoma. Cancer. 2003, 97 (2): 457-464. 10.1002/cncr.11073.CrossRef
4.
go back to reference Saintigny P, Kambouchner M, Ly M, Gomes N, Sainte-Catherine O, Vassy R, Czernichow S, Letoumelin P, Breau JL, Bernaudin JF, Kraemer M: Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumour and metastatic lymph node. Lung Cancer. 2007, 58 (2): 205-213. 10.1016/j.lungcan.2007.06.021.CrossRef Saintigny P, Kambouchner M, Ly M, Gomes N, Sainte-Catherine O, Vassy R, Czernichow S, Letoumelin P, Breau JL, Bernaudin JF, Kraemer M: Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumour and metastatic lymph node. Lung Cancer. 2007, 58 (2): 205-213. 10.1016/j.lungcan.2007.06.021.CrossRef
5.
go back to reference Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, Sato N: 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. 10.1002/cncr.21366.CrossRef Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, Sato N: 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. 10.1002/cncr.21366.CrossRef
6.
go back to reference Berghmans T, Meert AP, Martin B, Ninane V, Sculier JP: Prognostic role of epidermal growth factor receptor in stage III nonsmall cell lung cancer. Eur Respir J. 2005, 25 (2): 329-335. 10.1183/09031936.05.00060804.CrossRef Berghmans T, Meert AP, Martin B, Ninane V, Sculier JP: Prognostic role of epidermal growth factor receptor in stage III nonsmall cell lung cancer. Eur Respir J. 2005, 25 (2): 329-335. 10.1183/09031936.05.00060804.CrossRef
7.
go back to reference Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG: LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999, 144 (4): 789-801. 10.1083/jcb.144.4.789.CrossRef Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG: LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999, 144 (4): 789-801. 10.1083/jcb.144.4.789.CrossRef
8.
go back to reference Breiteneder-Geleff S, Soleiman A, Horvat R, Amann G, Kowalski H, Kerjaschki D: Podoplanin a specific marker for lymphaticendothelium expressed in angiosarcoma. Verh Dtsch Ges Pathol. 1999, 83: 270-275. Breiteneder-Geleff S, Soleiman A, Horvat R, Amann G, Kowalski H, Kerjaschki D: Podoplanin a specific marker for lymphaticendothelium expressed in angiosarcoma. Verh Dtsch Ges Pathol. 1999, 83: 270-275.
9.
go back to reference Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S: Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res. 2001, 21 (4A): 2351-2355. Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S: Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res. 2001, 21 (4A): 2351-2355.
10.
go back to reference Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, Kenessey I, Ostoros G, Agocs L, Soltesz I, Dome B: Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res. 2005, 11 (20): 7344-7353. 10.1158/1078-0432.CCR-05-1077.CrossRef Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, Kenessey I, Ostoros G, Agocs L, Soltesz I, Dome B: Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res. 2005, 11 (20): 7344-7353. 10.1158/1078-0432.CCR-05-1077.CrossRef
11.
go back to reference Partanen TA, Alitalo K, Miettinen M: Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer. 1999, 86 (11): 2406-2412. 10.1002/(SICI)1097-0142(19991201)86:11<2406::AID-CNCR31>3.0.CO;2-E.CrossRef Partanen TA, Alitalo K, Miettinen M: Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer. 1999, 86 (11): 2406-2412. 10.1002/(SICI)1097-0142(19991201)86:11<2406::AID-CNCR31>3.0.CO;2-E.CrossRef
12.
go back to reference Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Gatter KC, Harris AL, Jackson DG: LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer. J Clin Pathol. 2005, 58 (2): 202-206. 10.1136/jcp.2004.019174.CrossRef Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Gatter KC, Harris AL, Jackson DG: LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer. J Clin Pathol. 2005, 58 (2): 202-206. 10.1136/jcp.2004.019174.CrossRef
13.
go back to reference Mouta Carreira C, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK: LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 2001, 61 (22): 8079-8084. Mouta Carreira C, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK: LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 2001, 61 (22): 8079-8084.
14.
go back to reference Jackson DG: Biology of the lymphatic marker LYVE-1 andapplications in research into lymphatic trafficking and lymphangiogenesis. APMIS. 2004, 112 (7–8): 526-538. 10.1111/j.1600-0463.2004.apm11207-0811.x.CrossRef Jackson DG: Biology of the lymphatic marker LYVE-1 andapplications in research into lymphatic trafficking and lymphangiogenesis. APMIS. 2004, 112 (7–8): 526-538. 10.1111/j.1600-0463.2004.apm11207-0811.x.CrossRef
15.
go back to reference Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M: Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol. 2005, 166 (3): 913-921.CrossRef Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M: Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol. 2005, 166 (3): 913-921.CrossRef
16.
go back to reference Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK: Lymphatic metastasis in the absence of functional intratumor lymphatics. Science. 2002, 296 (5574): 1883-1886. 10.1126/science.1071420.CrossRef Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK: Lymphatic metastasis in the absence of functional intratumor lymphatics. Science. 2002, 296 (5574): 1883-1886. 10.1126/science.1071420.CrossRef
17.
go back to reference Auwera Van der I, Cao Y, Tille JC, Pepper MS, Jackson DG, Fox SB, Harris AL, Dirix LY, Vermeulen PB: First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer. 2006, 95 (12): 1611-1625. 10.1038/sj.bjc.6603445.CrossRef Auwera Van der I, Cao Y, Tille JC, Pepper MS, Jackson DG, Fox SB, Harris AL, Dirix LY, Vermeulen PB: First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer. 2006, 95 (12): 1611-1625. 10.1038/sj.bjc.6603445.CrossRef
18.
go back to reference Weidner N: Tumor angiogenesis: review of currentapplications in tumor prognostication. Semin Diagn Pathol. 1993, 10 (2): 302-313. Weidner N: Tumor angiogenesis: review of currentapplications in tumor prognostication. Semin Diagn Pathol. 1993, 10 (2): 302-313.
19.
go back to reference Heimburg S, Oehler MK, Papadopoulos T, Caffier H, Kristen P, Dietl J: Prognostic relevance of the endothelial marker CD 34 in ovarian cancer. Anticancer Res. 1999, 19 (4A): 2527-2529. Heimburg S, Oehler MK, Papadopoulos T, Caffier H, Kristen P, Dietl J: Prognostic relevance of the endothelial marker CD 34 in ovarian cancer. Anticancer Res. 1999, 19 (4A): 2527-2529.
20.
go back to reference Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M: Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005, 18 (9): 1232-1242. 10.1038/modpathol.3800410.CrossRef Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M: Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005, 18 (9): 1232-1242. 10.1038/modpathol.3800410.CrossRef
21.
go back to reference Eynden Van den GG, Vandenberghe MK, van Dam PJ, Colpaert CG, vanDam P, Dirix LY, Vermeulen PB, Van Marck EA: Increasedsentinel lymph node lymphangiogenesis is associated with nonsentinelaxillary lymph node involvement in breast cancer patients with apositive sentinel node. Clin Cancer Res. 2007, 13 (18 Pt 1): 5391-5397. 10.1158/1078-0432.CCR-07-1230.CrossRef Eynden Van den GG, Vandenberghe MK, van Dam PJ, Colpaert CG, vanDam P, Dirix LY, Vermeulen PB, Van Marck EA: Increasedsentinel lymph node lymphangiogenesis is associated with nonsentinelaxillary lymph node involvement in breast cancer patients with apositive sentinel node. Clin Cancer Res. 2007, 13 (18 Pt 1): 5391-5397. 10.1158/1078-0432.CCR-07-1230.CrossRef
22.
go back to reference Wulff C, Dickson SE, Duncan WC, Fraser HM: Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Hum Reprod. 2001, 16 (12): 2515-2524. 10.1093/humrep/16.12.2515.CrossRef Wulff C, Dickson SE, Duncan WC, Fraser HM: Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Hum Reprod. 2001, 16 (12): 2515-2524. 10.1093/humrep/16.12.2515.CrossRef
23.
go back to reference Dango S, Sienel W, Schreiber M, Stremmel C, Kirschbaum A, Pantel K, Passlick B: Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer. Lung Cancer. 2008, 60 (3): 426-433. 10.1016/j.lungcan.2007.11.015.CrossRef Dango S, Sienel W, Schreiber M, Stremmel C, Kirschbaum A, Pantel K, Passlick B: Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer. Lung Cancer. 2008, 60 (3): 426-433. 10.1016/j.lungcan.2007.11.015.CrossRef
24.
go back to reference Mineo TC, Ambrogi V, Baldi A, Rabitti C, Bollero P, Vincenzi B, Tonini G: Prognostic impact of VEGF, CD31, CD34, and CD105 expression and tumour vessel invasion after radical surgery for IB-IIA non-small cell lung cancer. J Clin Pathol. 2004, 57 (6): 591-597. 10.1136/jcp.2003.013508.CrossRef Mineo TC, Ambrogi V, Baldi A, Rabitti C, Bollero P, Vincenzi B, Tonini G: Prognostic impact of VEGF, CD31, CD34, and CD105 expression and tumour vessel invasion after radical surgery for IB-IIA non-small cell lung cancer. J Clin Pathol. 2004, 57 (6): 591-597. 10.1136/jcp.2003.013508.CrossRef
25.
go back to reference Kawai H, Minamiya Y, Ito M, Saito H, Ogawa J: VEGF121 promotes lymphangiogenesis in the sentinel lymph nodes of non-small cell lung carcinoma patients. Lung Cancer. 2008, 59 (1): 41-47. 10.1016/j.lungcan.2007.08.001.CrossRef Kawai H, Minamiya Y, Ito M, Saito H, Ogawa J: VEGF121 promotes lymphangiogenesis in the sentinel lymph nodes of non-small cell lung carcinoma patients. Lung Cancer. 2008, 59 (1): 41-47. 10.1016/j.lungcan.2007.08.001.CrossRef
26.
go back to reference Kadota K, Huang CL, Liu D, Ueno M, Kushida Y, Haba R, Yokomise H: The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur J Cancer. 2008, 44 (7): 1057-1067. 10.1016/j.ejca.2008.03.012.CrossRef Kadota K, Huang CL, Liu D, Ueno M, Kushida Y, Haba R, Yokomise H: The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur J Cancer. 2008, 44 (7): 1057-1067. 10.1016/j.ejca.2008.03.012.CrossRef
27.
go back to reference Trivella M, Pezzella F, Pastorino U, Harris AL, Altman DG, Prognosis In Lung Cancer (PILC) Collaborative Study Group: Microvessel density as a prognostic factor in non-small-cell lung carcinoma: a meta-analysis of individual patient data. Lancet Oncol. 2007, 8 (6): 488-499. 10.1016/S1470-2045(07)70145-6.CrossRef Trivella M, Pezzella F, Pastorino U, Harris AL, Altman DG, Prognosis In Lung Cancer (PILC) Collaborative Study Group: Microvessel density as a prognostic factor in non-small-cell lung carcinoma: a meta-analysis of individual patient data. Lancet Oncol. 2007, 8 (6): 488-499. 10.1016/S1470-2045(07)70145-6.CrossRef
28.
go back to reference Bono P, Wasenius VM, Heikkilä P, Lundin J, Jackson DG, Joensuu H: High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin Cancer Res. 2004, 10 (21): 7144-7149. 10.1158/1078-0432.CCR-03-0826.CrossRef Bono P, Wasenius VM, Heikkilä P, Lundin J, Jackson DG, Joensuu H: High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin Cancer Res. 2004, 10 (21): 7144-7149. 10.1158/1078-0432.CCR-03-0826.CrossRef
29.
go back to reference Vleugel MM, Bos R, Groep van der P, Greijer AE, Shvarts A, Stel HV, Wall van der E, van Diest PJ: Lack of lymphangiogenesis during breast carcinogenesis. J Clin Pathol. 2004, 57 (7): 746-751. 10.1136/jcp.2003.014480.CrossRef Vleugel MM, Bos R, Groep van der P, Greijer AE, Shvarts A, Stel HV, Wall van der E, van Diest PJ: Lack of lymphangiogenesis during breast carcinogenesis. J Clin Pathol. 2004, 57 (7): 746-751. 10.1136/jcp.2003.014480.CrossRef
30.
go back to reference Saijo T, Ishii G, Ochiai A, Hasebe T, Yoshida J, Nishimura M, Nagai K: Evaluation of extratumoral lymphatic permeation in non-small cell lung cancer as a means of predicting outcome. Lung Cancer. 2007, 55 (1): 61-66. 10.1016/j.lungcan.2006.09.027.CrossRef Saijo T, Ishii G, Ochiai A, Hasebe T, Yoshida J, Nishimura M, Nagai K: Evaluation of extratumoral lymphatic permeation in non-small cell lung cancer as a means of predicting outcome. Lung Cancer. 2007, 55 (1): 61-66. 10.1016/j.lungcan.2006.09.027.CrossRef
Metadata
Title
Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value
Authors
Jian-guo Sun
Yan Wang
Zheng-tang Chen
Wen-lei Zhuo
Bo Zhu
Rong-xia Liao
Shao-xiang Zhang
Publication date
01-02-2009
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2009
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-28-21

Other articles of this Issue 1/2009

Journal of Experimental & Clinical Cancer Research 1/2009 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine