Skip to main content
Top
Published in: Gastric Cancer 3/2016

01-07-2016 | Original Article

Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study

Authors: Jota Mikami, Yukinori Kurokawa, Tsuyoshi Takahashi, Yasuhiro Miyazaki, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki

Published in: Gastric Cancer | Issue 3/2016

Login to get access

Abstract

Background

The antitumor effects of antiplatelet agents in gastric cancer cells are not well known. In this study, the possibility of gastric cancer treatment with an antiplatelet agent, mainly aspirin, was examined both in vivo and in vitro.

Methods

For in vivo experiments, tumor-bearing mice were treated by an antiplatelet antibody or aspirin, and the tumor growth was compared. For in vitro experiments, human gastric cancer cell lines were used to confirm the cancer cell growth and inhibition by reducing the platelet count or using aspirin. We also examined several cytokines by using an ELISA assay and conducted microRNA microarray analysis of MKN-45 tumor cells to determine the influence of platelets or aspirin.

Results

In vivo experiments showed that tumor growth was inhibited by halving the circulating platelet count by using an antiplatelet antibody or peroral daily aspirin. In vitro experiments showed that the proliferation rates of gastric cancer cell lines were increased after coincubation with platelets and that the effect was inhibited by aspirin. Although the expression of interleukin-6, platelet-derived growth factor, transforming growth factor-β, and prostaglandin E2 did not correlate with tumor growth inhibition by aspirin, seven microRNAs showed altered expression in cancer cells in response to coincubation with platelets or addition of aspirin. Cells transfected with mir-4670-5p showed a significant increase in proliferation compared to negative control cells.

Conclusions

Our study showed that platelets increased the proliferation of gastric cancer cells and that this increase was inhibited by antiplatelet antibody or aspirin. Mir-4670-5p may play an important role in these responses.
Appendix
Available only for authorised users
Literature
1.
go back to reference Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol. 2014;229:1005–15.CrossRefPubMed Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol. 2014;229:1005–15.CrossRefPubMed
3.
go back to reference Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost. 2011;9:237–49.CrossRefPubMed Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost. 2011;9:237–49.CrossRefPubMed
4.
go back to reference Goubran HA, Burnouf T, Radosevic M, El-Ekiaby M. The platelet-cancer loop. Eur J Intern Med. 2013;24:393–400.CrossRefPubMed Goubran HA, Burnouf T, Radosevic M, El-Ekiaby M. The platelet-cancer loop. Eur J Intern Med. 2013;24:393–400.CrossRefPubMed
5.
go back to reference Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11:123–34.CrossRefPubMed Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11:123–34.CrossRefPubMed
6.
go back to reference Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost. 2004;30:95–108.CrossRefPubMed Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost. 2004;30:95–108.CrossRefPubMed
7.
go back to reference Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012;366:610–8.CrossRefPubMedPubMedCentral Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012;366:610–8.CrossRefPubMedPubMedCentral
8.
go back to reference Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591–601.CrossRefPubMed Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591–601.CrossRefPubMed
9.
11.
go back to reference Okumura H, Uchikado Y, Setoyama T, Matsumoto M, Owaki T, Ishigami S, et al. Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy. Surg Today. 2014;44:421–8.CrossRefPubMed Okumura H, Uchikado Y, Setoyama T, Matsumoto M, Owaki T, Ishigami S, et al. Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy. Surg Today. 2014;44:421–8.CrossRefPubMed
12.
go back to reference Reimers MS, Bastiaannet E, Langley RE, van Eijk R, van Vlierberghe RL, Lemmens VE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med. 2014;174:732–9.CrossRefPubMed Reimers MS, Bastiaannet E, Langley RE, van Eijk R, van Vlierberghe RL, Lemmens VE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med. 2014;174:732–9.CrossRefPubMed
13.
go back to reference Mahmoud NN, Dannenberg AJ, Mestre J, Bilinski RT, Churchill MR, Martucci C, et al. Aspirin prevents tumors in a murine model of familial adenomatous polyposis. Surgery. 1998;124:225–31.CrossRefPubMed Mahmoud NN, Dannenberg AJ, Mestre J, Bilinski RT, Churchill MR, Martucci C, et al. Aspirin prevents tumors in a murine model of familial adenomatous polyposis. Surgery. 1998;124:225–31.CrossRefPubMed
14.
go back to reference Ford TC, Graham J, Rickwood D. A new, rapid, one-step method for the isolation of platelets from human blood. Clin Chim Acta. 1990;192:115–9.CrossRefPubMed Ford TC, Graham J, Rickwood D. A new, rapid, one-step method for the isolation of platelets from human blood. Clin Chim Acta. 1990;192:115–9.CrossRefPubMed
15.
go back to reference Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2[-Delta Delta C(T)] method. Methods. 2001;25:402–8.CrossRefPubMed Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2[-Delta Delta C(T)] method. Methods. 2001;25:402–8.CrossRefPubMed
16.
go back to reference Cho MS, Bottsford-Miller J, Vasquez HG, Stone R, Zand B, Kroll MH, et al. Platelets increase the proliferation of ovarian cancer cells. Blood. 2012;120:4869–72.CrossRefPubMedPubMedCentral Cho MS, Bottsford-Miller J, Vasquez HG, Stone R, Zand B, Kroll MH, et al. Platelets increase the proliferation of ovarian cancer cells. Blood. 2012;120:4869–72.CrossRefPubMedPubMedCentral
17.
go back to reference Ikeda M, Furukawa H, Imamura H, Shimizu J, Ishida H, Masutani S, et al. Poor prognosis associated with thrombocytosis in patients with gastric cancer. Ann Surg Oncol. 2002;9:287–91.CrossRefPubMed Ikeda M, Furukawa H, Imamura H, Shimizu J, Ishida H, Masutani S, et al. Poor prognosis associated with thrombocytosis in patients with gastric cancer. Ann Surg Oncol. 2002;9:287–91.CrossRefPubMed
18.
go back to reference Takahashi K, Murata S, Ohkohchi N. Novel therapy for liver regeneration by increasing the number of platelets. Surg Today. 2013;43:1081–7.CrossRefPubMed Takahashi K, Murata S, Ohkohchi N. Novel therapy for liver regeneration by increasing the number of platelets. Surg Today. 2013;43:1081–7.CrossRefPubMed
19.
go back to reference Dovizio M, Maier TJ, Alberti S, Di Francesco L, Marcantoni E, Munch G, et al. Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol Pharmacol. 2013;84:25–40.CrossRefPubMed Dovizio M, Maier TJ, Alberti S, Di Francesco L, Marcantoni E, Munch G, et al. Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol Pharmacol. 2013;84:25–40.CrossRefPubMed
20.
go back to reference Uddin S, Ahmed M, Hussain A, Assad L, Al-Dayel F, Bavi P, et al. Cyclooxygenase-2 inhibition inhibits PI3 K/AKT kinase activity in epithelial ovarian cancer. Int J Cancer. 2010;126:382–94.CrossRefPubMed Uddin S, Ahmed M, Hussain A, Assad L, Al-Dayel F, Bavi P, et al. Cyclooxygenase-2 inhibition inhibits PI3 K/AKT kinase activity in epithelial ovarian cancer. Int J Cancer. 2010;126:382–94.CrossRefPubMed
21.
go back to reference Henrich KO, Bauer T, Schulte J, Ehemann V, Deubzer H, Gogolin S, et al. CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells. Cancer Res. 2011;71:3142–51.CrossRefPubMed Henrich KO, Bauer T, Schulte J, Ehemann V, Deubzer H, Gogolin S, et al. CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells. Cancer Res. 2011;71:3142–51.CrossRefPubMed
22.
go back to reference Langley RE, Burdett S, Tierney JF, Cafferty F, Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer. 2011;105:1107–13.CrossRefPubMedPubMedCentral Langley RE, Burdett S, Tierney JF, Cafferty F, Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer. 2011;105:1107–13.CrossRefPubMedPubMedCentral
23.
go back to reference Goel A, Chang DK, Ricciardiello L, Gasche C, Boland CR. A novel mechanism for aspirin-mediated growth inhibition of human colon cancer cells. Clin Cancer Res. 2003;9:383–90.PubMed Goel A, Chang DK, Ricciardiello L, Gasche C, Boland CR. A novel mechanism for aspirin-mediated growth inhibition of human colon cancer cells. Clin Cancer Res. 2003;9:383–90.PubMed
25.
go back to reference Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20:576–90.CrossRefPubMedPubMedCentral Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20:576–90.CrossRefPubMedPubMedCentral
26.
go back to reference Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009;16:961–6.CrossRefPubMedPubMedCentral Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009;16:961–6.CrossRefPubMedPubMedCentral
27.
go back to reference Schraivogel D, Weinmann L, Beier D, Tabatabai G, Eichner A, Zhu JY, et al. CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells. EMBO J. 2011;30:4309–22.CrossRefPubMedPubMedCentral Schraivogel D, Weinmann L, Beier D, Tabatabai G, Eichner A, Zhu JY, et al. CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells. EMBO J. 2011;30:4309–22.CrossRefPubMedPubMedCentral
Metadata
Title
Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study
Authors
Jota Mikami
Yukinori Kurokawa
Tsuyoshi Takahashi
Yasuhiro Miyazaki
Makoto Yamasaki
Hiroshi Miyata
Kiyokazu Nakajima
Shuji Takiguchi
Masaki Mori
Yuichiro Doki
Publication date
01-07-2016
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 3/2016
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-015-0556-2

Other articles of this Issue 3/2016

Gastric Cancer 3/2016 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.