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Urinary trypsin inhibitor inhibits tumor cell invasion and metastasis
WS2-B2-2-06 TISSUE-TYPE PLASMINOGEN ACTIVATOR AS A FUNCTIONAL MARKER FOR ESTROGEN DEPENDENCE IN HUMAN PANCREATIC CARCINOMA CEl.lS J. Yamashita, M. Ogawa, M. Kuramoto, K. Nomura, T. Saishoji, K. Sakai Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan Estrogen r e c e p t o r (ER) has been described in a variety of h u m a n cancers including pancreatic carcinoma, b u t the potential benefit of endocrine t h e r a p y has never been adequately assessed. We investigated ER status a n d h o r m o n a l regulation of tissue-type plasminogen activator (t-PA) in 9 human pancreatic carcinoma cell lines, AsPC-1, BxPC-3, Capan-1, Capan-2, Hs-7OOT, Hs-766T, MiaPaCa2, PANC-1, a n d SUIT-2. In a 17B-estradiol (E2)-binding assay, 3 of the 9 pancreatic carcinoma cell lines (BxPC-3, Capan-2, a n d MiaPaCa-2) contained measurable levels of estradiol binding sites in vitro, as well as in v/vo using tumors transplanted into nude mice. Although t-PA was present in the culture m e d i u m in 8 of the 9 pancreatic carcinoma cell lines (not in Hs-7OOT), t-PA p r o d u c t i o n was regulated by estrogen via an ER system in vitro only in the Capan-2 cell line. To examine whether e s t r o g e n - d e p e n d e n c y o f t-PA p r o d u c t i o n in p a n c r e a t i c c a r c i n o m a cells c o r r e l a t e d with responsiveness to e n d o c r i n e therapy, we determined the in vivo effects of various endocrine agents, including ER antagonist, luteinizing h o r m o n e - r e l e a s i n g h o r m o n e (LH-RH) analogue, a r o m a t a s e inhibitor, a n d m e d r o x y p r o g e s t e r o n e a c e t a t e (MPA), on the growth of 9 p a n c r e a t i c cell lines t r a n s p l a n t e d into n u d e mice. We r e p o r t here that in vitro estrogen d e p e n d e n c y of t-PA production clearly predicts the responsiveness to endocrine t h e r a p y in h u m a n pancreatic c a r c i n o m a in vivo; this finding m a y aid in planning endocrine t h e r a p y for patients with this lethal cancer.
WS2-B2-2-07
URINARY TRYPSIN INHIBITOR INHIBITS TUMOR CELL INVASION AND METASTASIS H. Kobayashi, J. Gotoh, H. Shinohara, T. Terao Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handacho 3600, Hamamatsu, Shizuoka, 431-31, Japan. We have d e m o n s t r a t e d the presence of the anti-invasive and antimetastatic activity in the acid extract from h u m a n arrmiotic fluid. The p r i m a r y structure of this factor (Mr. 67 kDa) was detected and a computer homology search revealed that this factor is identical to urinary trypsin inhibitor (UTI). UTI is one of the physiological protease inhibitors in h u m a n s e r u m and in urine. A highly purified UTI efficiently inhibits the soluble and the t u m o r cell-surface receptorb o u n d plasrnin. UTI inhibits not only tumor cell invasion in an in vitro Matrigel assay b u t also production of experimental and spontaneous lung metastasis in an in vivo mouse model. Anti-invasive effect is d e p e n d on the anti-plasmin activity of UTI. UTI peptide, which inhibits plasmin activity, synthesized b y an a u t o m a t e d peptide synthesizer showed the Lewis lung carcinoma 3LL cell invasion inhibitory activity. UTI and the effective peptide inhibited the t u m o r cell invasion through Matrigel, but did not inhibit the tumor cell proliferation or the binding of the cells to Matrigel. Some t u m o r ceils and neutrophils express UTI on their cell surface a n d that endogenous UTI m a y play an important role in tumor cell invasion to Matrix in vitro. UTI m a y control proteolysis and contribute to prevent the excessive fibrinolysis on their cell surface in conditions such as t u m o r invasion and metastasis.
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WS2-B2-2-07
URINARY TRYPSIN INHIBITOR INHIBITS TUMOR CELL INVASION AND METASTASIS H. Kobayashi, J. Gotoh, H. Shinohara, T. Terao Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handacho 3600, Hamamatsu, Shizuoka, 431-31, Japan. We have d e m o n s t r a t e d the presence of the anti-invasive and antimetastatic activity in the acid extract from h u m a n arrmiotic fluid. The p r i m a r y structure of this factor (Mr. 67 kDa) was detected and a computer homology search revealed that this factor is identical to urinary trypsin inhibitor (UTI). UTI is one of the physiological protease inhibitors in h u m a n s e r u m and in urine. A highly purified UTI efficiently inhibits the soluble and the t u m o r cell-surface receptorb o u n d plasrnin. UTI inhibits not only tumor cell invasion in an in vitro Matrigel assay b u t also production of experimental and spontaneous lung metastasis in an in vivo mouse model. Anti-invasive effect is d e p e n d on the anti-plasmin activity of UTI. UTI peptide, which inhibits plasmin activity, synthesized b y an a u t o m a t e d peptide synthesizer showed the Lewis lung carcinoma 3LL cell invasion inhibitory activity. UTI and the effective peptide inhibited the t u m o r cell invasion through Matrigel, but did not inhibit the tumor cell proliferation or the binding of the cells to Matrigel. Some t u m o r ceils and neutrophils express UTI on their cell surface a n d that endogenous UTI m a y play an important role in tumor cell invasion to Matrix in vitro. UTI m a y control proteolysis and contribute to prevent the excessive fibrinolysis on their cell surface in conditions such as t u m o r invasion and metastasis.
146