Thorac Cardiovasc Surg 2011; 59(3): 133-136
DOI: 10.1055/s-0030-1250152
Original Basic Science

© Georg Thieme Verlag KG Stuttgart · New York

Endostar, a Recombined Humanized Endostatin, Inhibits Lymphangiogenesis and Lymphatic Metastasis of Lewis Lung Carcinoma Xenograft in Mice

X. Dong1 , X. Zhao1 , T. Xiao2 , H. Tian3 , C. Yun2
  • 1Department of Thoracic Surgery, Second Hospital of Shandong University, Jinan, China
  • 2Second Hospital of Shandong University, Jinan, China
  • 3Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, China
Further Information

Publication History

received May 2, 2010

Publication Date:
08 April 2011 (online)

Abstract

Objective: The aim of this study was to investigate the effects of Endostar, a recombined humanized endostatin, on lymphatic tumor growth, lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma (LLC) xenograft in mice. Methods: Lewis lung carcinoma xenografts were established in C57BL/6 mice by intravenous injection of 1 × 106 cells. Then the mice were assigned to two groups: the control group received caudal vein injections of 0.2 ml of 0.9 % sodium chloride for 15 days, and the treatment group received 500 µg Endostar daily. Six weeks after LLC cell injection, the mice were sacrificed, and tumor multiplicity and tumor sizes were recorded. The expression of vascular endothelial growth factor C (VEGF‐C) and podoplanin were observed by immunohistochemical staining. Results: Tumor numbers and sizes in the control group were significantly higher than those of the treatment group. The microlymphatic vessel density (MLVD) was 5.67 ± 1.57 in the treatment group, which was markedly lower than in the control mice (7.78 ± 1.56). Two lymph node metastases were observed in the treatment group, and eight in the control group. Lymphatic metastases were more frequent in the control group than in the treatment group. Expression of VEGF‐C in the control group was significantly higher than that in the treatment group. Conclusion: Endostar significantly inhibits the lymphatic tumor growth, lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma xenografts, and its inhibitory effect is due to its ability to partially regulate the tumor expression of VEGF‐C.

References

  • 1 Detmar M, Hirakawa S. The formation of lymphatic vessels and its importance in the setting of malignancy.  J Exp Med. 2002;  196 713-718
  • 2 Stacker S A, Caesar C, Baldwin M E et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics.  Nat Med. 2001;  7 186-191
  • 3 Mattila M M- T, Ruohola J K, Karpanen T et al. VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors.  Int J Cancer. 2002;  98 946-951
  • 4 O'Reilly M S, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.  Cell. 1997;  88 277-285
  • 5 Boehm T, Folkman J, Browder T et al. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.  Nature. 1997;  390 404-407
  • 6 Han Q, Fu Y, Zhou H et al. Contributions of Zn (II)-binding to the structural stability of endostatin.  FEBS Lett. 2007;  581 3027-3032
  • 7 Ling Y, Yang Y, Lu N et al. Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells.  Biochem Biophys Res Commun. 2007;  361 79-84
  • 8 Wen Q L, Meng M B, Yang B et al. Endostar, a recombined humanized endostatin, enhances the radioresponse for human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts in mice.  Cancer Sci. 2009;  100 1510-1519
  • 9 Sun Y, Wang J, Liu Y et al. Results of phase III trial of rh-endostatin (YH-16) in advanced non-small cell lung cancer (NSCLC) patients. Annual ASCO Meeting May 2005 in FL, USA
  • 10 Folkman J. Angiogenesis in cancer therapy – endostatin and its mechanisms of action.  Exp Cell Res. 2006;  312 594-607
  • 11 Nyberg P, Xie L, Kalluri R. Endogenous inhibitors of angiogenesis.  Cancer Res. 2005;  65 3967-3979
  • 12 Sauter B V, Martinet O, Zhang W J et al. Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases.  PNAS. 2000;  97 4802-4807
  • 13 Solaun M S, Mendoza L, Luca M D et al. Endostatin inhibits murine colon carcinoma sinusoidal-type metastases by preferential targeting of hepatic sinusoidal endothelium.  Hepatology. 2002;  35 1104-1116
  • 14 Davidoff A D, Leary M A, Ng C Y C et al. Autocrine expression of both endostatin and green fluorescent protein provides a synergistic antitumor effect in a murine neuroblastoma model.  Cancer Gene Ther. 2001;  8 537-545
  • 15 Yamanaka R, Zullo S A, Ramsey J et al. Induction of therapeutic antitumor antiangiogenesis by intratumoral injection of genetically engineered endostatin-producing Semi Forest virus.  Cancer Gene Ther. 2001;  8 796-802
  • 16 Feldman A, Restifo N P, Alexander H R et al. Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice.  Cancer Res. 2000;  60 1503-1506
  • 17 Shao X J, Xie F M. Influence of angiogenesis inhibitors, endostatin and PF-4, on lymphangiogenesis.  Lymphology. 2005;  38 1-8
  • 18 Fukumoto S, Morifuji M, Katakura Y et al. Endostatin inhibits lymph node metastasis by a down-regulation of the vascular endothelial growth factor C expression in tumor cells.  Clin Exp Metastasis. 2005;  22 31-38
  • 19 Brideau G, Mäkinen M J, Elamaa H et al. Endostatin over expression inhibits lymphangiogenesis and lymph node metastasis in mice.  Cancer Res. 2007;  15 11528-11535
  • 20 Eder Jr J P, Supko J G, Clark J W. Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.  J Clin Oncol. 2002;  20 3772-3784
  • 21 Song H F, Liu X W, Zhang H N, Zhu B Z, Yuan S J, Liu S Y, Tang Z M. Pharmacokinetics of His-tag recombinant human endostatin in rhesus monkeys.  Acta Pharmacol Sin. 2005;  261 124-128
  • 22 Kim Y M, Jang J W, Lee O H et al. Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase 2.  Cancer Res. 2000;  60 5410-5413
  • 23 Na L, Yun L, Ying G et al. Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells.  Exp Biol Med. 2008;  233 1013-1020
  • 24 Nyberg P, Heikkila P, Sorsa T et al. Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13.  J Biol Chem. 2003;  278 22404-22411
  • 25 Yancopoulos G D, Davis S, Gale N W et al. Vascular-specific growth factors and blood vessel formation.  Nature. 2000;  407 (6801) 242-248
  • 26 Skobe M, Hawighorst T, Jackson D G et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.  Nat Med. 2001;  7 192-198
  • 27 Cong B, Dong X P, Peng C L et al. Expression of vascular endothelial growth factors C and D correlates with lymphangiogenesis and lymph node metastasis in lung adenocarcinoma.  Thorac and Cardiov Surg. 2009;  59 291-294
  • 28 Makinen T, Jussila L, Veikkola T et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3.  Nat Med. 2001;  7 199-205
  • 29 Veikkola T, Jussila L, Makinen T et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice.  EMBO J. 2001;  20 (6) 1223-1231
  • 30 Shimizu K, Kubo H, Yamaguchi K et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer.  Cancer Sci. 2004;  95 328-333
  • 31 He Y, Kozaki K, Karpanen T et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling.  J Natl Cancer Inst. 2002;  94 819-825
  • 32 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.  Cancer Res. 2003;  63 713-722

Mr.Xiaogang Zhao

Department of Thoracic Surgery
Second Hospital of Shandong University

Beiyuan Street 247

250033 Jinan

China

Phone: +86 05 38 58 75 55

Fax: +86 05 38 58 75 30

Email: dxp3260@sina.com

    >