Skip to main content

Advertisement

SpringerLink
Log in

Liposome-mediated gene transfer of K1-5 suppresses tumor development and improves the prognosis of hepatocellular carcinoma in mice

  • SPECIAL REVIEW SERIES: Molecular morphological approach for pathogenesis of hepatogastrointestinal diseases
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

It has been reported that kringle 1-5 (K1-5) has a potent and specific antiangiogenic activity. In the present study, we investigated the antitumor effect of gene transfer of K1-5 for hepatocellular carcinoma in mice. Inhibitory effect by the media of Cos-1 cells containing K1-5 on bovine capillary endothelial (BCE) cell proliferation was evaluated by a tetrazolium-based assay. For tumor growth, intrahepatic metastasis, and survival studies, intravenous injection of liposome–K1-5 cDNA complexes was performed to nude mice implanted with three hepatoma cell lines into the liver. Production of K1-5 was investigated by immunohistochemistry and Western blotting. The number of vessels in the tumor was counted in 0.125 mm2 fields. Expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-1 and -2 in tumors was investigated by Western blotting. Serum ALT levels and body weight of the mice were measured. Proliferation of BCE cells was inhibited by 44% in the media containing K1-5. Gene transfer of K1-5 suppressed tumor growth of the three hepatoma cell lines, respectively. In the K1-5-treated group, survival period was prolonged and the number of intrahepatic metastases was reduced. Expression of K1-5 protein was detected on hepatoma cells and hepatocytes. The number of vessels in tumor tissues was decreased by K1-5 transfection. Expression of angiopoietin-2 in tumor tissues was suppressed by K1-5 transfection. Serum ALT levels and body weight of mice were not influenced by K1-5 transfection. These findings suggest that antiangiogenic gene therapy with K1-5 cDNA will be a safe and effective strategy to suppress the growth of hepatocellular carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. M Kirsch G Schackert PM Black (2004) ArticleTitleMetastasis and angiogenesis Cancer Treat Res 117 285–304 Occurrence Handle15015566 Occurrence Handle1:CAS:528:DC%2BD2cXptFKiu7c%3D

    PubMed  CAS  Google Scholar 

  2. XM Li ZY Tang G Zhou YK Lui SL Ye (1998) ArticleTitleSignificance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma J Exp Clin Cancer Res 17 13–17 Occurrence Handle9646228

    PubMed  Google Scholar 

  3. L Holmgren MS O’Reilly J Folkman (1995) ArticleTitleDormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression Nat Med 1 149–153 Occurrence Handle7585012 Occurrence Handle10.1038/nm0295-149 Occurrence Handle1:CAS:528:DyaK2MXksVeru78%3D

    Article  PubMed  CAS  Google Scholar 

  4. M Miyagami Y Katayama (2005) ArticleTitleAngiogenesis of glioma: evaluation of ultrastructural characteristics of microvessels and tubular bodies (Weibel-Palade) in endothelial cells and immunohistochemical findings with VEGF and p53 protein Med Mol Morphol 38 36–42 Occurrence Handle16158178 Occurrence Handle10.1007/s00795-004-0273-0

    Article  PubMed  Google Scholar 

  5. MS O’Reilly L Holmgren Y Shing C Chen RA Rosenthal M Moses WS Lane Y Cao EH Sage J Folkman (1994) ArticleTitleAngiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma Cell 79 315–328 Occurrence Handle7525077 Occurrence Handle10.1016/0092-8674(94)90200-3 Occurrence Handle1:CAS:528:DyaK2MXhvFWrsbY%3D

    Article  PubMed  CAS  Google Scholar 

  6. MS O’Reilly T Boehm Y Shing N Fukai G Vasios WS Lane E Flynn JR Birkhead BR Olsen J Folkman (1997) ArticleTitleEndostatin: an endogenous inhibitor of angiogenesis and tumor growth Cell 88 277–285 Occurrence Handle9008168 Occurrence Handle10.1016/S0092-8674(00)81848-6 Occurrence Handle1:CAS:528:DyaK2sXpsFSktQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  7. MS O’Reilly S Pirie-Shepherd WS Lane J Folkman (1999) ArticleTitleAntiangiogenic activity of the cleaved conformation of the serpin antithrombin Science 285 1926–1928 Occurrence Handle10489375 Occurrence Handle10.1126/science.285.5435.1926 Occurrence Handle1:CAS:528:DyaK1MXmtVCmsLs%3D

    Article  PubMed  CAS  Google Scholar 

  8. K Matsumoto H Ishikawa D Nishimura K Hamasaki K Nakao K Eguchi (2004) ArticleTitleAntiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma Hepatology 40 252–259 Occurrence Handle15239109 Occurrence Handle10.1002/hep.20259 Occurrence Handle1:CAS:528:DC%2BD2cXmtlSgu74%3D

    Article  PubMed  CAS  Google Scholar 

  9. M Elkin A Orgel HK Kleinman (2004) ArticleTitleAn angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1 J Natl Cancer Inst 96 875–878 Occurrence Handle15173272 Occurrence Handle1:CAS:528:DC%2BD2cXkvVSrurg%3D Occurrence Handle10.1093/jnci/djh140

    Article  PubMed  CAS  Google Scholar 

  10. Y Maeshima A Sudhakar JC Lively K Ueki S Kharbanda CR Kahn N Sonenberg RO Hynes R Kalluri (2002) ArticleTitleTumstatin, an endothelial cell-specific inhibitor of protein synthesis Science 295 140–143 Occurrence Handle11778052 Occurrence Handle10.1126/science.1065298 Occurrence Handle1:CAS:528:DC%2BD38XksVCktA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  11. Z Cao BC Baguley LM Ching (2001) ArticleTitleInterferon-inducible protein 10 induction and inhibition of angiogenesis in vivo by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) Cancer Res 61 1517–1521 Occurrence Handle11245459 Occurrence Handle1:CAS:528:DC%2BD3MXhvVeltLc%3D

    PubMed  CAS  Google Scholar 

  12. Y Hayakawa K Takeda H Yagita MJ Smyth L Van Kaer K Okumura I Saiki (2002) ArticleTitleIFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide Blood 100 1728–1733 Occurrence Handle12176894 Occurrence Handle1:CAS:528:DC%2BD38Xmslyht7g%3D

    PubMed  CAS  Google Scholar 

  13. S Indraccolo E Gola A Rosato S Minuzzo W Habeler V Tisato V Roni G Esposito M Morini A Albini DM Noonan M Ferrantini A Amadori L Chieco-Bianchi (2002) ArticleTitleDifferential effects of angiostatin, endostatin and interferon-alpha(1) gene transfer on in vivo growth of human breast cancer cells Gene Ther 9 867–878 Occurrence Handle12080381 Occurrence Handle10.1038/sj.gt.3301703 Occurrence Handle1:CAS:528:DC%2BD38XkslKntrc%3D

    Article  PubMed  CAS  Google Scholar 

  14. Z von Marschall A Scholz T Cramer G Schafer M Schirner K Oberg B Wiedenmann M Hocker S Rosewicz (2003) ArticleTitleEffects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis J Natl Cancer Inst 95 437–448 Occurrence Handle12644537 Occurrence Handle1:CAS:528:DC%2BD3sXisFCrurc%3D

    PubMed  CAS  Google Scholar 

  15. Y Cao L Xue (2004) ArticleTitleAngiostatin Semin Thromb Hemostas 30 83–93 Occurrence Handle10.1055/s-2004-822973 Occurrence Handle1:CAS:528:DC%2BD2MXotFyksg%3D%3D

    Article  CAS  Google Scholar 

  16. Y Cao RW Ji D Davidson J Schaller D Marti S Sohndel SG McCance MS O’Reilly M Llinas J Folkman (1996) ArticleTitleKringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells J Biol Chem 271 29461–29467 Occurrence Handle8910613 Occurrence Handle10.1074/jbc.271.46.29461 Occurrence Handle1:STN:280:DyaK2s%2Fmslaisw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  17. Y Cao R Cao N Veitonmaki (2002) ArticleTitleKringle structures and antiangiogenesis Curr Med Chem Anti-Cancer Agents 2 667–681 Occurrence Handle10.2174/1568011023353705 Occurrence Handle1:CAS:528:DC%2BD38XnvVGnsb4%3D

    Article  CAS  Google Scholar 

  18. Y Cao A Chen SS An RW Ji D Davidson M Llinas (1997) ArticleTitleKringle 5 of plasminogen is a novel inhibitor of endothelial cell growth J Biol Chem 272 22924–22928 Occurrence Handle9278456 Occurrence Handle10.1074/jbc.272.36.22924 Occurrence Handle1:CAS:528:DyaK2sXlvFGnt7k%3D

    Article  PubMed  CAS  Google Scholar 

  19. R Cao HL Wu N Veitonmaki P Linden J Farnebo GY Shi Y Cao (1999) ArticleTitleSuppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis Proc Natl Acad Sci U S A 96 5728–5733 Occurrence Handle10318952 Occurrence Handle10.1073/pnas.96.10.5728 Occurrence Handle1:CAS:528:DyaK1MXjtFCntbs%3D

    Article  PubMed  CAS  Google Scholar 

  20. QR Chen D Kumar SA Stass AJ Mixson (1999) ArticleTitleLiposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice Cancer Res 59 3308–3312 Occurrence Handle10416583 Occurrence Handle1:CAS:528:DyaK1MXks1Omsr8%3D

    PubMed  CAS  Google Scholar 

  21. BV Sauter O Martinet WJ Zhang J Mandeli SL Woo (2000) ArticleTitleAdenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases Proc Natl Acad Sci U S A 97 4802–4807 Occurrence Handle10758166 Occurrence Handle10.1073/pnas.090065597 Occurrence Handle1:CAS:528:DC%2BD3cXivFKjur8%3D

    Article  PubMed  CAS  Google Scholar 

  22. A Auricchio KC Behling AM Maguire EM O’Connor J Bennett JM Wilson MJ Tolentino (2002) ArticleTitleInhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents Mol Ther 6 490–494 Occurrence Handle12377190 Occurrence Handle10.1006/mthe.2002.0702 Occurrence Handle1:CAS:528:DC%2BD38Xns1Kluro%3D

    Article  PubMed  CAS  Google Scholar 

  23. A Calvo AL Feldman SK Libutti JE Green (2002) ArticleTitleAdenovirus-mediated endostatin delivery results in inhibition of mammary gland tumor growth in C3(1)/SV40 T-antigen transgenic mice Cancer Res 62 3934–3938 Occurrence Handle12124322 Occurrence Handle1:CAS:528:DC%2BD38XlsV2ls70%3D

    PubMed  CAS  Google Scholar 

  24. Y Li Y Jin H Chen G Jie G Tobelem JP Caen ZC Han (2003) ArticleTitleSuppression of tumor growth by viral vector-mediated gene transfer of N-terminal truncated platelet factor 4 Cancer Biother Radiopharm 18 829–840 Occurrence Handle14629831 Occurrence Handle10.1089/108497803770418373 Occurrence Handle1:CAS:528:DC%2BD3sXptFaiurk%3D

    Article  PubMed  CAS  Google Scholar 

  25. T Noro K Miyake N Suzuki-Miyake T Igarashi E Uchida T Misawa Y Yamazaki T Shimada (2004) ArticleTitleAdeno-associated viral vector-mediated expression of endostatin inhibits tumor growth and metastasis in an orthotropic pancreatic cancer model in hamsters Cancer Res 64 7486–7490 Occurrence Handle15492274 Occurrence Handle10.1158/0008-5472.CAN-03-1296 Occurrence Handle1:CAS:528:DC%2BD2cXosFynurs%3D

    Article  PubMed  CAS  Google Scholar 

  26. V Schmitz L Wang M Barajas C Gomar J Prieto C Qian (2004) ArticleTitleTreatment of colorectal and hepatocellular carcinomas by adenoviral mediated gene transfer of endostatin and angiostatin-like molecule in mice Gut 53 561–567 Occurrence Handle15016752 Occurrence Handle10.1136/gut.2003.019307 Occurrence Handle1:CAS:528:DC%2BD2cXjsVWgu78%3D

    Article  PubMed  CAS  Google Scholar 

  27. AM Di Bisceglie VK Rustgi JH Hoofnagle GM Dusheiko MT Lotze (1988) ArticleTitleNIH conference. Hepatocellular carcinoma Ann Intern Med 108 390–401 Occurrence Handle2449110 Occurrence Handle1:STN:280:DyaL1c7jt1Wksw%3D%3D

    PubMed  CAS  Google Scholar 

  28. H Honda T Tajima K Kajiyama T Kuroiwa K Yoshimitsu H Irie H Aibe M Shimada K Masuda (1999) ArticleTitleVascular changes in hepatocellular carcinoma: correlation of radiologic and pathologic findings AJR Am J Roentgenol 173 1213–1217 Occurrence Handle10541091 Occurrence Handle1:STN:280:DC%2BD3c%2FgslWjtg%3D%3D

    PubMed  CAS  Google Scholar 

  29. O Matsui M Kadoya T Kameyama J Yoshikawa T Takashima Y Nakanuma M Unoura K Kobayashi R Izumi M Ida (1991) ArticleTitleBenign and malignant nodules in cirrhotic livers: distinction based on blood supply Radiology 178 493–497 Occurrence Handle1846240 Occurrence Handle1:STN:280:DyaK3M7gt1amtA%3D%3D

    PubMed  CAS  Google Scholar 

  30. D Semela JF Dufour (2004) ArticleTitleAngiogenesis and hepatocellular carcinoma J Hepatol 41 864–880 Occurrence Handle15519663 Occurrence Handle10.1016/j.jhep.2004.09.006

    Article  PubMed  Google Scholar 

  31. H Toyoda Y Fukuda T Hayakawa T Kumada S Nakano (1997) ArticleTitleChanges in blood supply in small hepatocellular carcinoma: correlation of angiographic images and immunohistochemical findings J Hepatol 27 654–660 Occurrence Handle9365041 Occurrence Handle10.1016/S0168-8278(97)80082-7 Occurrence Handle1:STN:280:DyaK1c%2FjtVehsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  32. N Veitonmaki R Cao LH Wu TL Moser B Li SV Pizzo B Zhivotovsky Y Cao (2004) ArticleTitleEndothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for k1-5-induced antiangiogenesis Cancer Res 64 3679–3686 Occurrence Handle15150128 Occurrence Handle10.1158/0008-5472.CAN-03-1754

    Article  PubMed  Google Scholar 

  33. NS Templeton DD Lasic PM Frederik HH Strey DD Roberts GN Pavlakis (1997) ArticleTitleImproved DNA: liposome complexes for increased systemic delivery and gene expression Nat Biotechnol 15 647–652 Occurrence Handle9219267 Occurrence Handle10.1038/nbt0797-647 Occurrence Handle1:CAS:528:DyaK2sXktlOgsL0%3D

    Article  PubMed  CAS  Google Scholar 

  34. MS O’Reilly L Holmgren C Chen J Folkman (1996) ArticleTitleAngiostatin induces and sustains dormancy of human primary tumors in mice Nat Med 2 689–692 Occurrence Handle8640562 Occurrence Handle10.1038/nm0696-689 Occurrence Handle1:CAS:528:DyaK28XjsVSjtbc%3D

    Article  PubMed  CAS  Google Scholar 

  35. LA Liotta (1986) ArticleTitleTumor invasion and metastases – role of the extracellular matrix: Rhoads Memorial Award lecture Cancer Res 46 1–7 Occurrence Handle2998604 Occurrence Handle1:CAS:528:DyaL28Xjt1Ckug%3D%3D Occurrence Handle10.1016/S0065-230X(08)60034-2

    Article  PubMed  CAS  Google Scholar 

  36. Y Cao MS O’Reilly B Marshall E Flynn RW Ji J Folkman (1998) ArticleTitleExpression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases J Clin Invest 101 1055–1063 Occurrence Handle9486976 Occurrence Handle1:CAS:528:DyaK1cXhs1yqsLo%3D

    PubMed  CAS  Google Scholar 

  37. J Holash PC Maisonpierre D Compton P Boland CR Alexander D Zagzag GD Yancopoulos SJ Wiegand (1999) ArticleTitleVessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF Science 284 1994–1998 Occurrence Handle10373119 Occurrence Handle10.1126/science.284.5422.1994 Occurrence Handle1:CAS:528:DyaK1MXktVWntrY%3D

    Article  PubMed  CAS  Google Scholar 

  38. MS O’Reilly (2002) ArticleTitleVessel maneuvers: vaccine targets tumor vasculature Nat Med 8 1352–1353 Occurrence Handle12457172 Occurrence Handle10.1038/nm1202-1352 Occurrence Handle1:CAS:528:DC%2BD38XptVSgsL8%3D

    Article  PubMed  CAS  Google Scholar 

  39. PF Sumariwalla Y Cao HL Wu M Feldmann EM Paleolog (2003) ArticleTitleThe angiogenesis inhibitor protease-activated kringles 1–5 reduces the severity of murine collagen-induced arthritis Arthritis Res Ther 5 R32–R39 Occurrence Handle12716451 Occurrence Handle10.1186/ar608 Occurrence Handle1:CAS:528:DC%2BD38XpsFWltb0%3D

    Article  PubMed  CAS  Google Scholar 

  40. M Kin T Torimura T Ueno T Nakamura R Ogata M Sakamoto S Tamaki M Sata (2000) ArticleTitleAngiogenesis inhibitor TNP-470 suppresses the progression of experimentally-induced hepatocellular carcinoma in rats Int J Oncol 16 375–382 Occurrence Handle10639583 Occurrence Handle1:CAS:528:DC%2BD3cXnvF2ltw%3D%3D

    PubMed  CAS  Google Scholar 

  41. KR Kim HE Moon KW Kim (2002) ArticleTitleHypoxia-induced angiogenesis in human hepatocellular carcinoma J Mol Med 80 703–714 Occurrence Handle12436347 Occurrence Handle10.1007/s00109-002-0380-0 Occurrence Handle1:CAS:528:DC%2BD38XoslOrsrg%3D

    Article  PubMed  CAS  Google Scholar 

  42. H Yoshiji S Kuriyama J Yoshii M Yamazaki M Kikukawa H Tsujinoue T Nakatani H Fukui (1998) ArticleTitleVascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells Hepatology 28 1489–1496 Occurrence Handle9828211 Occurrence Handle10.1002/hep.510280607 Occurrence Handle1:CAS:528:DyaK1cXotFSgsbk%3D

    Article  PubMed  CAS  Google Scholar 

  43. H Yoshiji S Kuriyama DJ Hicklin J Huber J Yoshii Y Miyamoto M Kawata Y Ikenaka T Nakatani H Tsujinoue H Fukui (1999) ArticleTitleKDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells Hepatology 30 1179–1186 Occurrence Handle10534339 Occurrence Handle10.1002/hep.510300509 Occurrence Handle1:CAS:528:DyaK1MXnsFSlsLY%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Second Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan

    Takuji Torimura, Takato Ueno & Michio Sata

Authors
  1. Takuji Torimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takato Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michio Sata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takuji Torimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Torimura, T., Ueno, T. & Sata, M. Liposome-mediated gene transfer of K1-5 suppresses tumor development and improves the prognosis of hepatocellular carcinoma in mice. Med Mol Morphol 39, 72–78 (2006). https://doi.org/10.1007/s00795-006-0319-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-006-0319-6

Key words

Search

Navigation