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DOI: 10.1055/s-0038-1650270
Retinoids Induce t-PA Synthesis by C6 Glioma Cells -Role in Tumoral Haemorrhagic Necrosis
Publikationsverlauf
Received: 26. Juni 1995
Accepted after resubmission04. Oktober 1995
Publikationsdatum:
27. Juli 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199602/lookinside/thumbnails/10-1055-s-0038-1650270-1.jpg)
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.
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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
- 2 Sawaya R, Highsmith R. Plasminogen activator activity and molecular weight patterns in human brain tumors. J Neurosurg 1988; 68: 73-79
- 3 Humphries JE, Vasudevan J, Gonias SL. Fibrinogenolytic and fibrinolytic activity of cell-associated plasmin. Arterioscler Thromb 1993; 13: 48-55
- 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
- 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
- 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
- 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
- 8 Hall SW, Vanderberg SR, Gonias SL. Expression of plasminogen receptors on C6 glioma cells. Brain Res 1989; 495: 373-376
- 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
- 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
- 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
- 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
- 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
- 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
- 15 Benjamin LA, McGarry RC, Hart DA. Effect of retinoic acid on human neuroblastoma. Cancer Chemother Pharmacol 1989; 25: 25-31
- 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
- 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
- 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
- 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
- 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
- 21 Kobayashi NN, Allen N, Clendenon NR, Li Wen K. An improved rat brain tumor model. J Neurosurg 1980; 53: 808-815
- 22 Benda P, Lightbody J, Sato G, Levine L, Sweet W. Differentiated rat glial cell strain in tissue culture. Science 1968; 161: 370-371
- 23 Wohlwend A, Belin D, Vassalli JD. Plasminogen activator-specific inhibitors produced by human monocytes/macrophages. J Exp Med 1987; 165: 320-339
- 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
- 25 Granelli-Pipemo A, Reich E. A study of proteases and protease-inhibitor complexes in biological fluid. J Exp Med 1978; 148: 223-234
- 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
- 27 Vassalli JD, Belin D. Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett 1987; 214: 187-191
- 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
- 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
- 30 Chomczinski P, Sacchi N. Single step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-159
- 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
- 32 Declerck PJ, Juhan-Vague I, Felez J, Wiman B. Pathophysiology of fibrinolysis. J Int Med 1994; 236: 425-432
- 33 Booth NA, Bennett B, Wijngaards G, Grieve JHK. A new lifelong hemorrhagic disorder due to excess plasminogen activator. Blood 1983; 61: 267-275
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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