Kringle 1-5 Reduces Growth of Malignant Gliomas in Rats

  • Ming-Chao HuangEmail author
  • Yi-Lo Lin
Part of the Tumors of the Central Nervous System book series (TCNS, volume 14)


Malignant gliomas is a highly vascularized and invasive tumor. The prognosis is still extremely poor despite advances in the cancer therapy. The growth and spread of gliomas within the host tissue depends upon their ability to stimulate new vessel formation, the angiogenesis, to get nutrients and remove waste products. Therefore, blocking the action of angiogenic factors, or utilizing angiogenic suppressors to inhibit angiogenesis, constitute a new strategy to suppress tumor growth. A representative drug is Avastin (Bevacizumab). It has been proved by FDA to treat patients with recurrent glioblastoma. It is a protein that acts against vessel growth factor. However, there are many vessel growth factors and Avastin only target one of them. Therefore the inhibition effect for vessel growth can be compensated by other angiogenic factors. Other disadvantages such as drug resistance and increased vascular cooption of the host vasculature have been reported. Kringle 1-5 (K1-5), discovered by Cao, is also a protein aimed on the vessels. Compared with Avastin, K1-5 acts directly on endothelial cells and leads endothelial cell death. The tumor inhibition effect of K1-5 was proven in a murine hepatocellular carcinoma model. In this chapter the therapeutic effect of K1-5 in malignant gliomas was discussed. We demonstrated that K1-5 is effective in the treatment of malignant gliomas. It is effective not only in the inhibition of vascular growth but also in limiting tumor invasiveness and improving tumor hypoxia, and then lead to a longer survival.


Vascular Endothelial Growth Factor Malignant Glioma Intensity Modulate Radiation Therapy Tumor Hypoxia Recurrent Glioblastoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Professor Y. Cao for providing K1-5 and his valuable advice; Professor Henrich Cheng and Yang-Hsin Shih for their support during the work.


  1. Birlik B, Canda S, Ozer E (2006) Tumour vascularity is of prognostic significance in adult, but not paediatric astrocytomas. Neuropathol Appl Neurobiol 32:532–538CrossRefPubMedGoogle Scholar
  2. Cao Y (2011) Antiangiogenic cancer therapy: why do mouse and human patients respond in a different way to the same drug? Int J Dev Biol 55:557–562CrossRefPubMedGoogle Scholar
  3. Cao Y, Ji RW, Davidson D, Schaller J, Marti D, Sohndel S, McCance SG, O’Reilly MS, Llinas M, Folkman J (1996) Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells. J Biol Chem 271:29461–29467CrossRefPubMedGoogle Scholar
  4. Cao R, Wu HL, Veitonmaki N, Linden P, Farnebo J, Shi GY, Cao Y (1999) Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis. Proc Natl Acad Sci U S A 96:5728–5733PubMedCentralCrossRefPubMedGoogle Scholar
  5. Chaudhry IH, O’Donovan DG, Brenchley PE, Reid H, Roberts IS (2001) Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology 39:409–415CrossRefPubMedGoogle Scholar
  6. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, Parada LF (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526PubMedCentralCrossRefPubMedGoogle Scholar
  7. de Groot J, Milano V (2009) Improving the prognosis for patients with glioblastoma: the rationale for targeting Src. J Neurooncol 95:151–163CrossRefPubMedGoogle Scholar
  8. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220PubMedCentralCrossRefPubMedGoogle Scholar
  9. Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins K, Magarelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ (2004) Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 10:8177–8184CrossRefPubMedGoogle Scholar
  10. Farin A, Suzuki SO, Weiker M, Goldman JE, Bruce JN, Canoll P (2006) Transplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia 53:799–808CrossRefPubMedGoogle Scholar
  11. Galaup A, Magnon C, Rouffiac V, Opolon P, Opolon D, Lassau N, Tursz T, Perricaudet M, Griscelli F (2005) Full kringles of plasminogen (aa 1-566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice. Gene Ther 12:831–842CrossRefPubMedGoogle Scholar
  12. Gessler F, Voss V, Dutzmann S, Seifert V, Gerlach R, Kogel D (2010) Inhibition of tissue factor/protease-activated receptor-2 signaling limits proliferation, migration and invasion of malignant glioma cells. Neuroscience 165:1312–1322CrossRefPubMedGoogle Scholar
  13. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47CrossRefPubMedGoogle Scholar
  14. Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN (2009) The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8:3274–3284PubMedCentralCrossRefPubMedGoogle Scholar
  15. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622CrossRefPubMedGoogle Scholar
  16. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A 108:3749–3754PubMedCentralCrossRefPubMedGoogle Scholar
  17. Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58:4654–4659PubMedGoogle Scholar
  18. Lamszus K, Brockmann MA, Eckerich C, Bohlen P, May C, Mangold U, Fillbrandt R, Westphal M (2005) Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin. Clin Cancer Res 11:4934–4940CrossRefPubMedGoogle Scholar
  19. Lin YL, Tsai MJ, Lo MJ, Chang SE, Shih YH, Lee MJ, Kuo HS, Kuo WC, Huang WC, Cheng H, Huang MC (2012) Evaluation of the antiangiogenic effect of Kringle 1-5 in a rat glioma model. Neurosurgery 70:479–489; discussion 489–490CrossRefPubMedGoogle Scholar
  20. Lucio-Eterovic AK, Piao Y, de Groot JF (2009) Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res 15:4589–4599CrossRefPubMedGoogle Scholar
  21. Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, Kuwano M (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5:1107–1113PubMedGoogle Scholar
  22. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328CrossRefPubMedGoogle Scholar
  23. Perri SR, Nalbantoglu J, Annabi B, Koty Z, Lejeune L, Francois M, Di Falco MR, Beliveau R, Galipeau J (2005) Plasminogen kringle 5-engineered glioma cells block migration of tumor-associated macrophages and suppress tumor vascularization and progression. Cancer Res 65:8359–8365CrossRefPubMedGoogle Scholar
  24. Perri SR, Annabi B, Galipeau J (2007a) Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton. Faseb J 21:3928–3936CrossRefPubMedGoogle Scholar
  25. Perri SR, Martineau D, Francois M, Lejeune L, Bisson L, Durocher Y, Galipeau J (2007b) Plasminogen Kringle 5 blocks tumor progression by antiangiogenic and proinflammatory pathways. Mol Cancer Ther 6:441–449CrossRefPubMedGoogle Scholar
  26. Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF (2006) MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66:1258–1260CrossRefPubMedGoogle Scholar
  27. Reynolds TY, Rockwell S, Glazer PM (1996) Genetic instability induced by the tumor microenvironment. Cancer Res 56:5754–5757PubMedGoogle Scholar
  28. Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828CrossRefPubMedGoogle Scholar
  29. Schmitz V, Raskopf E, Gonzalez-Carmona MA, Vogt A, Rabe C, Leifeld L, Kornek M, Sauerbruch T, Caselmann WH (2007) Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model. Gut 56:271–278PubMedCentralCrossRefPubMedGoogle Scholar
  30. Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, Wang M, Wen PY, Ivy P, Batchelor TT, Jain RK (2012) Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 72:402–407PubMedCentralCrossRefPubMedGoogle Scholar
  31. Stupp R, Hegi ME, van den Bent MJ, Mason WP, Weller M, Mirimanoff RO, Cairncross JG (2006) Changing paradigms–an update on the multidisciplinary management of malignant glioma. Oncologist 11:165–180CrossRefPubMedGoogle Scholar
  32. Veitonmaki N, Cao R, Wu LH, Moser TL, Li B, Pizzo SV, Zhivotovsky B, Cao Y (2004) Endothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for k1-5-induced antiangiogenesis. Cancer Res 64:3679–3686CrossRefPubMedGoogle Scholar
  33. von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, Herms J, Winkler F (2011) Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res 17:6192–6205CrossRefGoogle Scholar
  34. Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–833CrossRefPubMedGoogle Scholar
  35. Zhang W, Fulci G, Buhrman JS, Stemmer-Rachamimov AO, Chen JW, Wojtkiewicz GR, Weissleder R, Rabkin SD, Martuza RL (2012) Bevacizumab with angiostatin-armed oHSV increases antiangiogenesis and decreases bevacizumab-induced invasion in U87 glioma. Mol Ther 20:37–45PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Department of NeurosurgeryNeurological Institute, Taipei Veterans General HospitalTaipeiTaiwan
  2. 2.School of MedicineTaipei Medical UniversityTaipeiTaiwan
  3. 3.School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  4. 4.Graduate Institute of Veterinary Pathobiology, College of Veterinary MedicineNational Chung Hsing UniversityTaichungTaiwan

Personalised recommendations