Skip to main content
Top
Published in: World Journal of Surgical Oncology 1/2012

Open Access 01-12-2012 | Research

u-PA inhibitor amiloride suppresses peritoneal metastasis in gastric cancer

Authors: Youcheng Ding, Hui Zhang, Zhuqing Zhou, Mingan Zhong, Qiliang Chen, Xujing Wang, Zhenggang Zhu

Published in: World Journal of Surgical Oncology | Issue 1/2012

Login to get access

Abstract

Background

Peritoneal metastasis in gastric cancer represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. Although previous research suggested that u-PA was involved in some tumor metastasis such as lung-specific metastasis, the role of u-PA for peritoneal metastasis in gastric cancer is still unclear. The aim of this study was to explore whether selective pharmacological blockade of u-PA is able to affect the peritoneal metastasis of gastric cancer both in vivo and in vitro.

Methods

In the present study, we evaluated the effects and explored the anti-tumor mechanisms of amiloride, a selective u-PA inhibitor, on a panel of gastric cancer cell lines and in a murine model of human gastric cancer MKN45.

Results

The study showed that amiloride significantly inhibited the tumor growth and prolonged the survival of the tumor-bearing mice. In vitro, compared with controls, amiloride could not only significantly down-regulate the mRNA expression and protein level of u-PA from MKN45 cells with dose dependence but also inhibit the adhesion of HMrSV5 cells, migration and invasion of MKN45 cells.

Conclusions

The findings in our current report provide evidence that selective u-PA inhibitor amiloride has potent effects against peritoneal metastasis in gastric cancer, suggesting its possible therapeutic value for the treatment of gastric cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Tanaka T, Kumagai K, Shimizu K, Masuo K, Yamagata K: Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; extranodal invasion is a significant risk factor for peritoneal metastasis. J Surg Oncol. 2000, 75: 165-171. 10.1002/1096-9098(200011)75:3<165::AID-JSO3>3.0.CO;2-5.CrossRefPubMed Tanaka T, Kumagai K, Shimizu K, Masuo K, Yamagata K: Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; extranodal invasion is a significant risk factor for peritoneal metastasis. J Surg Oncol. 2000, 75: 165-171. 10.1002/1096-9098(200011)75:3<165::AID-JSO3>3.0.CO;2-5.CrossRefPubMed
2.
go back to reference Boku T, Nakane Y, Minoura T, Takada H, Yamamura M, Hioki K, Yamamoto M: Prognostic significance of serosal invasion and free intraperitoneal cancer cells in gastric cancer. Br J Surg. 1990, 77: 436-439. 10.1002/bjs.1800770425.CrossRefPubMed Boku T, Nakane Y, Minoura T, Takada H, Yamamura M, Hioki K, Yamamoto M: Prognostic significance of serosal invasion and free intraperitoneal cancer cells in gastric cancer. Br J Surg. 1990, 77: 436-439. 10.1002/bjs.1800770425.CrossRefPubMed
3.
go back to reference Hippo Y, Yashiro M, Ishii M, Taniguchi H, Tsutsumi S, Hirakawa K, Kodama T, Aburatani H: Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes. Cancer Res. 2001, 61: 889-895.PubMed Hippo Y, Yashiro M, Ishii M, Taniguchi H, Tsutsumi S, Hirakawa K, Kodama T, Aburatani H: Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes. Cancer Res. 2001, 61: 889-895.PubMed
4.
go back to reference Yoo CH, Noh SH, Shin DW, Choi SH, Min JS: Recurrence following curative resection for gastric carcinoma. Br J Surg. 2000, 87: 236-242. 10.1046/j.1365-2168.2000.01360.x.CrossRefPubMed Yoo CH, Noh SH, Shin DW, Choi SH, Min JS: Recurrence following curative resection for gastric carcinoma. Br J Surg. 2000, 87: 236-242. 10.1046/j.1365-2168.2000.01360.x.CrossRefPubMed
5.
go back to reference Crosby J, Catton C, Davis A, Couture J, O’Sullivan B, Kandel R, Swallow C: Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol. 2001, 8: 50-59. 10.1007/s10434-001-0050-4.CrossRefPubMed Crosby J, Catton C, Davis A, Couture J, O’Sullivan B, Kandel R, Swallow C: Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol. 2001, 8: 50-59. 10.1007/s10434-001-0050-4.CrossRefPubMed
6.
go back to reference Poste G, Fidler IJ: The pathogenesis of cancer metastasis. Nature. 1980, 283: 139-146. 10.1038/283139a0.CrossRefPubMed Poste G, Fidler IJ: The pathogenesis of cancer metastasis. Nature. 1980, 283: 139-146. 10.1038/283139a0.CrossRefPubMed
7.
go back to reference Steven DS: Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr Opin Cell Biol. 1998, 10: 602-608. 10.1016/S0955-0674(98)80035-5.CrossRef Steven DS: Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr Opin Cell Biol. 1998, 10: 602-608. 10.1016/S0955-0674(98)80035-5.CrossRef
8.
go back to reference Stetler-Stevenson W, Liotta L, Kleiner D: Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J. 1993, 7: 1434-1441.PubMed Stetler-Stevenson W, Liotta L, Kleiner D: Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J. 1993, 7: 1434-1441.PubMed
9.
go back to reference Wilhelm O, Schmitt M, Höhl S, Senekowitsch R, Graeff H: Antisense inhibition of urokinase reduces spread of human ovarian cancer in mice. Clin Exp Metastasis. 1995, 13: 296-302. 10.1007/BF00133485.CrossRefPubMed Wilhelm O, Schmitt M, Höhl S, Senekowitsch R, Graeff H: Antisense inhibition of urokinase reduces spread of human ovarian cancer in mice. Clin Exp Metastasis. 1995, 13: 296-302. 10.1007/BF00133485.CrossRefPubMed
10.
go back to reference Chantret I, Barbat A, Dussaulx E, Brattain MG, Zweibaum A: Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines. Cancer Res. 1988, 48: 1936-1942.PubMed Chantret I, Barbat A, Dussaulx E, Brattain MG, Zweibaum A: Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines. Cancer Res. 1988, 48: 1936-1942.PubMed
11.
go back to reference Zhang Z, Li M, Wang H, Agrawal S, Zhang R: Antisense therapy targeting MDM2 oncogene in prostate cancer: effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci. 2003, 100: 11636-11641. 10.1073/pnas.1934692100.PubMedCentralCrossRefPubMed Zhang Z, Li M, Wang H, Agrawal S, Zhang R: Antisense therapy targeting MDM2 oncogene in prostate cancer: effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci. 2003, 100: 11636-11641. 10.1073/pnas.1934692100.PubMedCentralCrossRefPubMed
12.
go back to reference Akedo H, Shinkai K, Mukai M, Mori Y, Tateishi R, Tanaka K, Yamamoto R, Morishita T: Interaction of Rat ascites hepatoma cells with cultured mesothelial cell layers: a model for tumor invasion. Cancer Res. 1986, 46: 2416-2422.PubMed Akedo H, Shinkai K, Mukai M, Mori Y, Tateishi R, Tanaka K, Yamamoto R, Morishita T: Interaction of Rat ascites hepatoma cells with cultured mesothelial cell layers: a model for tumor invasion. Cancer Res. 1986, 46: 2416-2422.PubMed
13.
go back to reference Li Y-H, Zhu C: A modified Boyden chamber assay for tumor cell transendothelial migration in vitro. Clin Exp Metastasis. 1999, 17: 423-429. 10.1023/A:1006614232388.CrossRefPubMed Li Y-H, Zhu C: A modified Boyden chamber assay for tumor cell transendothelial migration in vitro. Clin Exp Metastasis. 1999, 17: 423-429. 10.1023/A:1006614232388.CrossRefPubMed
14.
go back to reference Mason DP, Kenagy RD, Hasenstab D, Bowen-Pope DF, Seifert RA, Coats S, Hawkins SM, Clowes AW: Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res. 1999, 85: 1179-1185. 10.1161/01.RES.85.12.1179.CrossRefPubMed Mason DP, Kenagy RD, Hasenstab D, Bowen-Pope DF, Seifert RA, Coats S, Hawkins SM, Clowes AW: Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res. 1999, 85: 1179-1185. 10.1161/01.RES.85.12.1179.CrossRefPubMed
15.
go back to reference Ishikawa M, Kitayama J, Yamauchi T, Kadowaki T, Maki T, Miyato H, Yamashita H, Nagawa H: Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2. Cancer Sci. 2007, 98: 1120-1127. 10.1111/j.1349-7006.2007.00486.x.CrossRefPubMed Ishikawa M, Kitayama J, Yamauchi T, Kadowaki T, Maki T, Miyato H, Yamashita H, Nagawa H: Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2. Cancer Sci. 2007, 98: 1120-1127. 10.1111/j.1349-7006.2007.00486.x.CrossRefPubMed
16.
go back to reference Kaneko T, Konno H, Baba M, Tanaka T, Nakamura S: Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci. 2003, 94: 43-49. 10.1111/j.1349-7006.2003.tb01350.x.CrossRefPubMed Kaneko T, Konno H, Baba M, Tanaka T, Nakamura S: Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci. 2003, 94: 43-49. 10.1111/j.1349-7006.2003.tb01350.x.CrossRefPubMed
17.
go back to reference Shin VY, Wu WKK, Chu K-M, Wong HPS, Lam EKY, Tai EKK, Koo MWL, Cho C-H: Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol Cancer Res. 2005, 3: 607-615. 10.1158/1541-7786.MCR-05-0106.CrossRefPubMed Shin VY, Wu WKK, Chu K-M, Wong HPS, Lam EKY, Tai EKK, Koo MWL, Cho C-H: Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol Cancer Res. 2005, 3: 607-615. 10.1158/1541-7786.MCR-05-0106.CrossRefPubMed
18.
go back to reference Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006, 103: 2257-2261. 10.1073/pnas.0510565103.PubMedCentralCrossRefPubMed Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006, 103: 2257-2261. 10.1073/pnas.0510565103.PubMedCentralCrossRefPubMed
19.
go back to reference Takei Y, Takigahira M, Mihara K, Tarumi Y, Yanagihara K: The metastasis-associated microRNA miR-516a-3p Is a novel therapeutic target for inhibiting peritoneal dissemination of human scirrhous gastric cancer. Cancer Res. 2011, 71: 1442-1453. 10.1158/0008-5472.CAN-10-2530.CrossRefPubMed Takei Y, Takigahira M, Mihara K, Tarumi Y, Yanagihara K: The metastasis-associated microRNA miR-516a-3p Is a novel therapeutic target for inhibiting peritoneal dissemination of human scirrhous gastric cancer. Cancer Res. 2011, 71: 1442-1453. 10.1158/0008-5472.CAN-10-2530.CrossRefPubMed
20.
go back to reference Christiansen JJ, Rajasekaran AK: Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006, 66: 8319-8326. 10.1158/0008-5472.CAN-06-0410.CrossRefPubMed Christiansen JJ, Rajasekaran AK: Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006, 66: 8319-8326. 10.1158/0008-5472.CAN-06-0410.CrossRefPubMed
21.
go back to reference Drabsch Y, ten Dijke P: TGF-β signaling in breast cancer cell invasion and bone metastasis. J Mammary Gland Biol Neoplasia. 2011, 16: 97-108. 10.1007/s10911-011-9217-1.PubMedCentralCrossRefPubMed Drabsch Y, ten Dijke P: TGF-β signaling in breast cancer cell invasion and bone metastasis. J Mammary Gland Biol Neoplasia. 2011, 16: 97-108. 10.1007/s10911-011-9217-1.PubMedCentralCrossRefPubMed
22.
go back to reference Abstracts of papers presented at a meeting of the British society for haemostasis and thrombosis, Sheffield, 21–22 September 1989. Br J Haematol. 1989, 73: 436-454. Abstracts of papers presented at a meeting of the British society for haemostasis and thrombosis, Sheffield, 21–22 September 1989. Br J Haematol. 1989, 73: 436-454.
23.
go back to reference Odekon LE, Sato Y, Rifkin DB: Urokinase-type plasminogen activator mediates basic fibroblast growth factor-induced bovine endothelial cell migration independent of its proteolytic activity. J Cell Physiol. 1992, 150: 258-263. 10.1002/jcp.1041500206.CrossRefPubMed Odekon LE, Sato Y, Rifkin DB: Urokinase-type plasminogen activator mediates basic fibroblast growth factor-induced bovine endothelial cell migration independent of its proteolytic activity. J Cell Physiol. 1992, 150: 258-263. 10.1002/jcp.1041500206.CrossRefPubMed
24.
go back to reference Andreasen PA, Kjøller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997, 72: 1-22. 10.1002/(SICI)1097-0215(19970703)72:1<1::AID-IJC1>3.0.CO;2-Z.CrossRefPubMed Andreasen PA, Kjøller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997, 72: 1-22. 10.1002/(SICI)1097-0215(19970703)72:1<1::AID-IJC1>3.0.CO;2-Z.CrossRefPubMed
25.
go back to reference Lokman NA, Ween MP, Oehler MK, Ricciardelli C: The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenvironment. 2011, 4: 199-208. 10.1007/s12307-011-0064-9.PubMedCentralCrossRefPubMed Lokman NA, Ween MP, Oehler MK, Ricciardelli C: The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenvironment. 2011, 4: 199-208. 10.1007/s12307-011-0064-9.PubMedCentralCrossRefPubMed
26.
go back to reference Jankun J, Keck RW, Skrzypczak-Jankun E, Swiercz R: Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combined immunodeficient mice. Cancer Res. 1997, 57: 559-563.PubMed Jankun J, Keck RW, Skrzypczak-Jankun E, Swiercz R: Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combined immunodeficient mice. Cancer Res. 1997, 57: 559-563.PubMed
27.
go back to reference Wang Y, Dang J, Liang X, Doe WF: Amiloride modulates urokinase gene expression at both transcription and post-transcription levels in human colon cancer cells. Clin Exp Metastasis. 1995, 13: 196-202. 10.1007/BF00132208.CrossRefPubMed Wang Y, Dang J, Liang X, Doe WF: Amiloride modulates urokinase gene expression at both transcription and post-transcription levels in human colon cancer cells. Clin Exp Metastasis. 1995, 13: 196-202. 10.1007/BF00132208.CrossRefPubMed
28.
go back to reference Ogura N, Nagura H, Abiko Y: Increase of urokinase-type plasminogen activator receptor expression in human gingival fibroblasts by porphyromonas gingivalis lipopolysaccharide. J Periodontol. 1999, 70: 402-408. 10.1902/jop.1999.70.4.402.CrossRefPubMed Ogura N, Nagura H, Abiko Y: Increase of urokinase-type plasminogen activator receptor expression in human gingival fibroblasts by porphyromonas gingivalis lipopolysaccharide. J Periodontol. 1999, 70: 402-408. 10.1902/jop.1999.70.4.402.CrossRefPubMed
29.
go back to reference Vairo G, Cocks B, Jr Cragoe E, Hamilton Jl: Selective suppression of growth factor-induced cell cycle gene expression by Na+/H+ antiport inhibitors. J Biol Chem. 1992, 267: 19043-19046.PubMed Vairo G, Cocks B, Jr Cragoe E, Hamilton Jl: Selective suppression of growth factor-induced cell cycle gene expression by Na+/H+ antiport inhibitors. J Biol Chem. 1992, 267: 19043-19046.PubMed
30.
go back to reference Provost J, Rastedt D, Canine J, Ngyuen T, Haak A, Kutz C, Berthelsen N, Slusser A, Anderson K, Dorsam G: Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity. Cell Oncol. 2012, 35: 95-110.CrossRef Provost J, Rastedt D, Canine J, Ngyuen T, Haak A, Kutz C, Berthelsen N, Slusser A, Anderson K, Dorsam G: Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity. Cell Oncol. 2012, 35: 95-110.CrossRef
31.
go back to reference Kinsella J, Aronson P: Amiloride inhibition of the Na+−H+ exchanger in renal microvillus membrane vesicles. Am J Physiol Renal Physiol. 1981, 241: F374-F379. Kinsella J, Aronson P: Amiloride inhibition of the Na+−H+ exchanger in renal microvillus membrane vesicles. Am J Physiol Renal Physiol. 1981, 241: F374-F379.
32.
go back to reference Cardone RA, Casavola V, Reshkin SJ: The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer. 2005, 5: 786-795. 10.1038/nrc1713.CrossRefPubMed Cardone RA, Casavola V, Reshkin SJ: The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer. 2005, 5: 786-795. 10.1038/nrc1713.CrossRefPubMed
33.
go back to reference Yang X, Wang D, Dong W, Song Z, Dou K: Suppression of Na+/H+ exchanger 1 by RNA interference or amiloride inhibits human hepatoma cell line SMMC-7721 cell invasion. Medical Oncology. 2011, 28: 385-390. 10.1007/s12032-010-9447-x.CrossRefPubMed Yang X, Wang D, Dong W, Song Z, Dou K: Suppression of Na+/H+ exchanger 1 by RNA interference or amiloride inhibits human hepatoma cell line SMMC-7721 cell invasion. Medical Oncology. 2011, 28: 385-390. 10.1007/s12032-010-9447-x.CrossRefPubMed
34.
go back to reference Tuck A, Hota C, Chambers A: Osteopontin(OPN)-induced increase in human mammary epithelial cell invasiveness is urokinase (uPA)-dependent. Breast Cancer Res Treat. 2001, 70: 197-204. 10.1023/A:1013095329825.CrossRefPubMed Tuck A, Hota C, Chambers A: Osteopontin(OPN)-induced increase in human mammary epithelial cell invasiveness is urokinase (uPA)-dependent. Breast Cancer Res Treat. 2001, 70: 197-204. 10.1023/A:1013095329825.CrossRefPubMed
35.
go back to reference Evans DM, Sloan-Stakleff K, Arvan M, Guyton DP: Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride. Clin Exp Metastasis. 1998, 16: 353-357.CrossRefPubMed Evans DM, Sloan-Stakleff K, Arvan M, Guyton DP: Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride. Clin Exp Metastasis. 1998, 16: 353-357.CrossRefPubMed
36.
go back to reference Evans DM, Sloan-Stakleff KD: Maximum effect of urokinase plasminogen activator inhibitors in the control of invasion and metastasis of Rat mammary cancer. Invasion Metastasis. 1998, 18: 252-260. 10.1159/000024518.CrossRefPubMed Evans DM, Sloan-Stakleff KD: Maximum effect of urokinase plasminogen activator inhibitors in the control of invasion and metastasis of Rat mammary cancer. Invasion Metastasis. 1998, 18: 252-260. 10.1159/000024518.CrossRefPubMed
Metadata
Title
u-PA inhibitor amiloride suppresses peritoneal metastasis in gastric cancer
Authors
Youcheng Ding
Hui Zhang
Zhuqing Zhou
Mingan Zhong
Qiliang Chen
Xujing Wang
Zhenggang Zhu
Publication date
01-12-2012
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2012
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/1477-7819-10-270

Other articles of this Issue 1/2012

World Journal of Surgical Oncology 1/2012 Go to the issue