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Thromb Haemost 1996; 75(02): 332-338
DOI: 10.1055/s-0038-1650270
Original Article
Schattauer GmbH Stuttgart

Retinoids Induce t-PA Synthesis by C6 Glioma Cells -Role in Tumoral Haemorrhagic Necrosis

Gilles Pernod
1   The Laboratoire d’Hematologie, INSERM U 318, CHU de Grenoble, France
2   Laboratoire de Neurobiophysique, INSERM U 318, CHU de Grenoble, France
,
Guy Amalfltano
2   Laboratoire de Neurobiophysique, INSERM U 318, CHU de Grenoble, France
,
Brigitte Le Magueresse
3   Laboratoire de Biochimie, INSERM U 407, Lyon-Sud, France
,
Francois Berger
2   Laboratoire de Neurobiophysique, INSERM U 318, CHU de Grenoble, France
,
Benolt Polack
1   The Laboratoire d’Hematologie, INSERM U 318, CHU de Grenoble, France
,
Lucien Kolodie
1   The Laboratoire d’Hematologie, INSERM U 318, CHU de Grenoble, France
› Author Affiliations
Further Information

Publication History

Received: 26 June 1995

Accepted after resubmission04 October 1995

Publication Date:
27 July 2018 (online)

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Summary

Treatment of rat C6 glioma with high doses of 13 cis-retinoic acid (cRA) was responsible for death related to haemorrhagic necrosis localized to the tumor. Our aim was to explore this adverse effect of retinoid treatment. We show that cRA-treated C6 glioma at 25 mg/kg/day for 18 days exhibits in vivo an increased t-PA activity, which is responsible for a localized tumor fibrinolytic activity. Production of t-PA is supported by specific enhancement of gene expression, as was shown by the increase in t-PA mRNA (X 2.3). This production is a direct effect of cRA when treating the tumor, since tumor cells themself do not produce enough t-PA and treatment of control rats does not increase the t-PA level. t-PA production by rat C6 glioma is in vivo related to the specific synthesis of t-PA by the C6 cell-line. The stimulation of C6 cell-line by cRA in vitro is dose-dependent and reached a maximum for 3 and 30 |iM at the 72nd h. So cRA-treated C6 glioma cells produce t-PA which appears to be the major species associated with the fibrinolytic activity-induced intra-tumoral haemorrhage after exposure to retinoid treatment.

 

  • References

  • 1 Amalfitano G, Berger F, Laine M, Nisson MF, Verna JM, Benhabid AL. Retinoic acid therapy in the rat C6 glioma model: induction of in vivo redifferentiation and hemorrhagic intra-tumoral side effects. Submitted 1995
    PubMedGoogle Scholar
  • 2 Sawaya R, Highsmith R. Plasminogen activator activity and molecular weight patterns in human brain tumors. J Neurosurg 1988; 68: 73-79
    CrossrefPubMedGoogle Scholar
  • 3 Humphries JE, Vasudevan J, Gonias SL. Fibrinogenolytic and fibrinolytic activity of cell-associated plasmin. Arterioscler Thromb 1993; 13: 48-55
    CrossrefPubMedGoogle Scholar
  • 4 Humphries JE, De la Cadena RA, Atkins TL, Colman RW, Gonias SL. Interaction of high molecular weight kininogen with plasminogen to cell surfaces. Fibrinolysis 1994; 8: 245-254
    PubMedGoogle Scholar
  • 5 Hall SW, Humphries JE, Gonias SL. Inhibition of cell surface receptor-bound plasmin by a2-antiplasmin and a2-macroglobulin. J Biol Chem 1991; 266: 12329-12336
    PubMedGoogle Scholar
  • 6 Vaithilingam IS, McDonald W, Brown NK, Stroude E, Cook RA, Del Maestro RF. Serum proteolytic activity during the growth of C6 astrocytoma. J Neurosurg 1992; 77: 595-600
    CrossrefPubMedGoogle Scholar
  • 7 Mignatti P, Robbins E, Rifkin DB. Tumor cell invasion through the human amniotic membrane: requirement for a proteinase cascade. Cell 1986; 47: 487-498
    CrossrefPubMedGoogle Scholar
  • 8 Hall SW, Vanderberg SR, Gonias SL. Expression of plasminogen receptors on C6 glioma cells. Brain Res 1989; 495: 373-376
    CrossrefPubMedGoogle Scholar
  • 9 Hall SW, Braud LL, Gonias SL. Binding of bovine, ovine, porcine, canine, and rat plasminogen to rat hepatocytes and rat C6 glioma cells in vitro. Biochem Biophys Res Commun 1989; 164: 1288-1294
    CrossrefPubMedGoogle Scholar
  • 10 Benabid AL, Remy C, Chauvin C. Experimental models of rat brain tumors by stereotaxic injection of C6 glioma and HTC hepatoma cell lines. Biology of Brain Tumor. Walker MD, Thomas DGT, eds. Boston: Martinus Nijhoff Publishers 1986: 221-226
    PubMedGoogle Scholar
  • 11 Bernstein JJ, Goldberg WJ, Laws ER, Conger D, Morreale V, Wood LR. C6 glioma cell invasion and migration of rat brain after neural homografting: Ultrastructure. Neurosurg 1990; 26: 622-628
    CrossrefPubMedGoogle Scholar
  • 12 Pernod G, Amalfitano G, Polack B, Mossuz P, Berger F, Kolodie L. t-PA production by C6 glioma cells and effect of retinoid-induced differentiation. XIIth International Congress of fibrinolysis. Fibrinolysis 1994; 8: 426
    PubMedGoogle Scholar
  • 13 Murphy PG, Hart DA. Regulation of plasminogen activator and plasminogen activator inhibitor expression by cells of neural origin. Sem Thromb Hemost 1991; 17: 268-275
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Seeds NW, Verrall S, Friedman G, Hayden S, Gadotti D, Haffke S, Christensen K, Gardner B, McGuire P, Krystosek A. Plasminogen activators and plasminogen activator inhibitors in neural development. Ann N Y Acad Sci 1992; 667: 32-40
    CrossrefPubMedGoogle Scholar
  • 15 Benjamin LA, McGarry RC, Hart DA. Effect of retinoic acid on human neuroblastoma. Cancer Chemother Pharmacol 1989; 25: 25-31
    CrossrefPubMedGoogle Scholar
  • 16 Thompson EA, Nelles L, Collen D. Effect of retinoic acid on the synthesis of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in human endothelial cells Eur. J Biochem 1991; 201: 627-632
    CrossrefPubMedGoogle Scholar
  • 17 Kooistra T, Opdenberg JP, Toet K, Hendriks HFJ, Van den Hoogen RM, Emeis JJ. Stimulation of tissue-type plasminogen activator synthesis by retinoids in cultured human endothelial cells and rat tissues in vivo. Thromb Haemost 1991; 65: 565-572
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Padro T, Van den Hoogen CM, Emeis JJ. Distribution of tissue-type plasminogen activator (activity and antigen) in rat tissues. Blood Coag Fibrinol 1990; 1: 601-608
    PubMedGoogle Scholar
  • 19 Van Bennekum AM, Emeis JJ, Kooistra T, Hendriks HFJ. Modulation of tissue-type plasminogen activator by retinoids in rat plasma and tissues. Am J Physiol 1993; 264: 931-937
    PubMedGoogle Scholar
  • 20 Van Giezen JJJ, Boon DIA, Jansen JWCM, Bouma BN. Retinoic acid enhances fibrinolytic activity in-vivo by enhancing tissue-type plasminogen activator (t-PA) activity and inhibits venous thrombosis. Thromb Haemost 1993; 69: 381-386
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Kobayashi NN, Allen N, Clendenon NR, Li Wen K. An improved rat brain tumor model. J Neurosurg 1980; 53: 808-815
    CrossrefPubMedGoogle Scholar
  • 22 Benda P, Lightbody J, Sato G, Levine L, Sweet W. Differentiated rat glial cell strain in tissue culture. Science 1968; 161: 370-371
    CrossrefPubMedGoogle Scholar
  • 23 Wohlwend A, Belin D, Vassalli JD. Plasminogen activator-specific inhibitors produced by human monocytes/macrophages. J Exp Med 1987; 165: 320-339
    CrossrefPubMedGoogle Scholar
  • 24 Kolodie L, Rachail M. Different molecular weight forms of tissue-type plasminogen activator in ascitic fluid from patients with liver cirrhosis. Fibrinolysis 1988; 2: 245-249
    PubMedGoogle Scholar
  • 25 Granelli-Pipemo A, Reich E. A study of proteases and protease-inhibitor complexes in biological fluid. J Exp Med 1978; 148: 223-234
    CrossrefPubMedGoogle Scholar
  • 26 Kolokis N, Rekkas C, Tsandarliotou M, Smokovitis A. Circadian variations of plasminogen activator activity, tissue-type plasminogen activator antigen, plasminogen activator inhibition and plasmin inhibition in rat aorta, heart and brain are influenced by endotoxin or aspirin or endotoxin plus aspirin. Haemost 1995; 25: 106-113
    CrossrefPubMedGoogle Scholar
  • 27 Vassalli JD, Belin D. Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett 1987; 214: 187-191
    CrossrefPubMedGoogle Scholar
  • 28 Sappino AP, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, Vassalli JD. Extracellular proteolysis in the adult murine brain. J Clin Invest 1993; 92: 679-685
    CrossrefPubMedGoogle Scholar
  • 29 Sappino AP, Huarte J, Vassalli JD, Belin D. Sites of synthesis of urokinase and tissue-factor plasminogen activators in the murine kidney. J Clin Invest 1991; 87: 962-970
    CrossrefPubMedGoogle Scholar
  • 30 Chomczinski P, Sacchi N. Single step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-159
    PubMedGoogle Scholar
  • 31 Le Magueresse-Battistoni B, Wolff J, Morera AM, Benhamed M. Fibroblast growth-factor receptor type-1 expression during rat testicular development and its regulation in cultured Sertoli cells. Endocrinol 1994; 135: 2404-2411
    CrossrefPubMedGoogle Scholar
  • 32 Declerck PJ, Juhan-Vague I, Felez J, Wiman B. Pathophysiology of fibrinolysis. J Int Med 1994; 236: 425-432
    CrossrefPubMedGoogle Scholar
  • 33 Booth NA, Bennett B, Wijngaards G, Grieve JHK. A new lifelong hemorrhagic disorder due to excess plasminogen activator. Blood 1983; 61: 267-275
    PubMedGoogle Scholar
  • 34 Aznar J, Estelles A, Vilar V, Reganon E, Espana F, Villa P. Inherited fibrinolytic disorder due to an enhanced plasminogen activator level. Thromb Haemost 1984; 52: 196-200
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Stump DC, Taylor FB, Nesheim ME, Giles AR, Dzik WH, Bovill EG. Pathologic fibrinolysis as a cause of clinical bleedig. Sem Thromb Hemost 1990; 16: 260-273
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Markus G, Kohger S, Camiolo SM, Modeja J, Ambrus JL, Karakousis K. Plasminogen activator activity in human malignant melanomas. J Natl Cancer Inst 1984; 72: 1213-1222
    PubMedGoogle Scholar
  • 37 Cajot JF, Kruithof EKO, Schleuning WD, Sordat B, Bachmann F. Plasminogen activators, plasminogen activator inhibitor and procoagulant analyzed in twenty human tumor cell lines. Int J Cancer 1986; 38: 719-727
    CrossrefPubMedGoogle Scholar
  • 38 Grondahl-Hansen J, Ralfkiaer E, Kirkeby L, Kristensen P, Lund LR, Dano K. Localisation of urokinase-type plasminogen activator in stroma cells in adenocarcinomas of the colon in humans. Am J Pathol 1991; 138: 111-117
    PubMedGoogle Scholar
  • 39 Dano K, Andreasen PA, Grondhal-Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 1985; 44: 139-266
    PubMedGoogle Scholar
  • 40 Pyke C, Kristensen P, Ralfkiaer E, Grondahl-Hansen J, Eriksen J, Blasi F, Dano K. Urokinase-type plasminogen activator is expressed in stroma cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 1991; 138: 1059-1067
    PubMedGoogle Scholar
  • 41 Sumi Y, Dent MAR, Owen DE, Seeley PJ, Morris RJ. The expression of tissue and urokinase-type plasminogen activators in neural development suggests different modes of proteolytic involvement in neuronal growth. Development 1992; 116: 625-637
    PubMedGoogle Scholar
  • 42 Rickies RJ, Darrow AL, Strickland S. Differentiation-responsive elements in the 5 region of the mouse tissue plasminogen activator gene confer two-stage regulation by retinoic acid and cyclic AMP in teratocarcinoma cells. Mol Cell Biol 1989; 9: 1691-1704
    CrossrefPubMedGoogle Scholar
  • 43 Bulens F, Ibanez-Tallon I, Van Acker P, De Vriese A, Nelles L, Belayew A, Collen D. Retinoic acid induction of human tissue-type plasminogen activator gene expression via a direct repeat element (DR5) located at -7 kilo-bases. J Biol Chem 1995; 270: 7167-7175
    CrossrefPubMedGoogle Scholar