Inhibition of cancer cell‑platelet adhesion as a promising therapeutic target for preventing peritoneal dissemination of gastric cancer

Nakayama,Takashi; Saito,Ryo; Furuya,Shinji; Shoda,Katsutoshi; Maruyma,Suguru; Takiguchi,Koichi; Shiraishi,Kensuke; Akaike,Hidenori; Kawaguchi,Yoshihiko; Amemiya,Hidetake; Kawaida,Hiromichi; Tsukiji,Nagaharu; Shirai,Toshiaki; Shinmori,Hideyuki; Yamamoto,Masami; Nomura,Sachiyo; Tsukamoto,Tetsuya; Suzuki‑Inoue,Katsue; Ichikawa,Daisuke

doi:10.3892/ol.2023.14125

Inhibition of cancer cell‑platelet adhesion as a promising therapeutic target for preventing peritoneal dissemination of gastric cancer

Authors:
- Takashi Nakayama
- Ryo Saito
- Shinji Furuya
- Katsutoshi Shoda
- Suguru Maruyma
- Koichi Takiguchi
- Kensuke Shiraishi
- Hidenori Akaike
- Yoshihiko Kawaguchi
- Hidetake Amemiya
- Hiromichi Kawaida
- Nagaharu Tsukiji
- Toshiaki Shirai
- Hideyuki Shinmori
- Masami Yamamoto
- Sachiyo Nomura
- Tetsuya Tsukamoto
- Katsue Suzuki‑Inoue
- Daisuke Ichikawa
View Affiliations

Affiliations: First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409‑3898, Japan, Department of Clinical and Laboratory, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409‑3898, Japan, Department of Biotechnology, Faculty of Life and Environmental Science, University of Yamanashi, Kofu, Yamanashi 400‑8510, Japan, Laboratory of Physiological Pathology, Nippon Veterinary and Life Science University, Tokyo 180‑8602, Japan, Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113‑8655, Japan, Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Aichi 470‑1192, Japan
Published online on: November 1, 2023 https://doi.org/10.3892/ol.2023.14125
Article Number: 538
Copyright: © Nakayama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Platelets form complexes with gastric cancer (GC) cells via direct contact, enhancing their malignant behavior. In the present study, the molecules responsible for GC cell‑platelet interactions were examined and their therapeutic application in inhibiting the peritoneal dissemination of GC was investigated. First, the inhibitory effects of various candidate surface molecules were investigated on platelets and GC cells, such as C‑type lectin‑like receptor 2 (CLEC‑2), glycoprotein VI (GPVI) and integrin αIIbβ3, in the platelet‑induced enhancement of GC cell malignant potential. Second, the therapeutic effects of molecules responsible for the development and progression of GC were investigated in a mouse model of peritoneal dissemination. Platelet‑induced enhancement of the migratory ability of GC cells was markedly inhibited by an anti‑GPVI antibody and inhibitor of galectin‑3, a GPVI ligand. However, neither the CLEC‑2 inhibitor nor the integrin‑blocking peptide significantly suppressed this enhanced migratory ability. In experiments using mouse GC cells and platelets, the migratory and invasive abilities enhanced by platelets were significantly suppressed by the anti‑GPVI antibody and galectin‑3 inhibitor. Furthermore, in vivo analyses demonstrated that the platelet‑induced enhancement of peritoneal dissemination was significantly suppressed by the coadministration of anti‑GPVI antibody and galectin‑3 inhibitor, and was nearly eliminated by the combined treatment. The inhibition of adhesion resulting from GPVI‑galectin‑3 interaction may be a promising therapeutic strategy for preventing peritoneal dissemination in patients with GC.

View Figures

View References

1	Labelle M, Begum S and Hynes RO: Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 20:576–590. 2011. View Article : Google Scholar : PubMed/NCBI
2	Rothwell PM, Wilson M, Price JF, Belch JFF, Mead TW and Mehta Z: Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet. 379:1591–1601. 2012. View Article : Google Scholar : PubMed/NCBI
3	Shirai T, Inoue O, Tamura S, Tsukiji N, Sasaki T, Endo H, Satoh K, Osada M, Sato-Uchida H, Fujii H, et al: C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice. J Thromb Haemost. 15:513–525. 2017. View Article : Google Scholar : PubMed/NCBI
4	Saito R, Shoda K, Maruyama S, Yamamoto A, Takiguchi K, Furuya S, Hosomura N, Akaike H, Kawaguchi Y, Amemiya H, et al: Platelets enhance malignant behaviours of gastric cancer cells via direct contacts. Br J Cancer. 124:570–573. 2021. View Article : Google Scholar : PubMed/NCBI
5	Suzuki-Inoue K, Fuller GL, García A, Eble JA, Pöhlmann S, Inoue O, Gartner TK, Hughan SC, Pearce AC, Laing GD, et al: A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. 107:542–549. 2006. View Article : Google Scholar : PubMed/NCBI
6	Suzuki-Inoue K, Inoue O and Ozaki Y: Novel platelet activation receptor CLEC-2: From discovery to prospects. J Thromb Haemost. 9 (Suppl 1):S44–S55. 2011. View Article : Google Scholar : PubMed/NCBI
7	Suzuki-Inoue K: Roles of the CLEC-2-podoplanin interaction in tumor progression. Platelets. 1–7. 2018.(Epub ahead of print). PubMed/NCBI
8	Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K and Kerjaschki D: Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium. Am J Pathol. 154:385–394. 1999. View Article : Google Scholar : PubMed/NCBI
9	Fujita N and Takagi S: The impact of Aggrus/podoplanin on platelet aggregation and tumour metastasis. J Biochem. 152:407–413. 2012. View Article : Google Scholar : PubMed/NCBI
10	Moroi M, Jung SM, Okuma M and Shinmyozu K: A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest. 84:1440–1445. 1989. View Article : Google Scholar : PubMed/NCBI
11	Sugiyama T, Okuma M, Ushikubi F, Sensaki S, Kanaji K and Uchino H: A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia. Blood. 69:1712–1720. 1987. View Article : Google Scholar : PubMed/NCBI
12	Mammadova-Bach E, Gil-Pulido J, Sarukhanyan E, Burkard P, Shityakov S, Schonhart C, Stegner D, Remer K, Nurden P, Nurden AT, et al: Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived galectin-3. Blood. 135:1146–1160. 2020.PubMed/NCBI
13	Ma YQ, Qin J and Plow EF: Platelet integrin alpha(IIb)beta(3): Activation mechanisms. J Thromb Haemost. 5:1345–1352. 2007. View Article : Google Scholar : PubMed/NCBI
14	Zhang C, Liu Y, Gao Y, Shen J, Zheng S, Wei M and Zeng X: Modified heparins inhibit integrin alpha(IIb)beta(3) mediated adhesion of melanoma cells to platelets in vitro and in vivo. Int J Cancer. 125:2058–2065. 2009. View Article : Google Scholar : PubMed/NCBI
15	Arita T, Ichikawa D, Konishi H, Komatsu S, Shinozaki A, Hiramoto H, Hamada J, Shoda K, Kawaguchi T, Hirajima S, et al: Increase in peritoneal recurrence induced by intraoperative hemorrhage in gastrectomy. Ann Surg Oncol. 22:758–764. 2015. View Article : Google Scholar : PubMed/NCBI
16	Yamamoto M, Nomura S, Hosoi A, Nagaoka K, Iino T, Yasuda T, Saito T, Matsushita H, Uchida E, Seto Y, et al: Established gastric cancer cell lines transplantable into C57BL/6 mice show fibroblast growth factor receptor 4 promotion of tumor growth. Cancer Sci. 109:1480–1492. 2018. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Huan Y, Caixia L and Wei Z: Expression of galectin-3 in mouse endometrium and its effect during embryo implantation. Reprod Biomed Online. 24:116–122. 2012. View Article : Google Scholar : PubMed/NCBI
19	Satoh K, Fukasawa I, Kanemaru K, Yoda S, Kimura Y, Inoue O, Ohta M, Kinouchi H and Ozaki Y: Platelet aggregometry in the presence of PGE(1) provides a reliable method for cilostazol monitoring. Thromb Res. 130:616–621. 2012. View Article : Google Scholar : PubMed/NCBI
20	Suzuki-Inoue K, Inoue O, Frampton J and Watson SP: Murine GPVI stimulates weak integrin activation in PLCgamma2-/-platelets: Involvement of PLCgamma1 and PI3-kinase. Blood. 102:1367–1373. 2003. View Article : Google Scholar : PubMed/NCBI
21	Inoue O, Hokamura K, Shirai T, Osada M, Tsukiji N, Hatakeyama K, Umemura K, Asada Y, Suzuki-Inoue K and Ozaki Y: Vascular smooth muscle cells stimulate platelets and facilitate thrombus formation through platelet CLEC-2: Implications in atherothrombosis. PLoS One. 10:e01393572015. View Article : Google Scholar : PubMed/NCBI
22	Tsukiji N, Osada M, Sasaki T, Shirai T, Satoh K, Inoue O, Umetani N, Mochizuki C, Saito T, Kojima S, et al: Cobalt hematoporphyrin inhibits CLEC-2-podoplanin interaction, tumor metastasis, and arterial/venous thrombosis in mice. Blood Adv. 2:2214–2225. 2018. View Article : Google Scholar : PubMed/NCBI
23	Kawai S, Takagi Y, Kaneko S and Kurosawa T: Effect of three types of mixed anesthetic agents alternate to ketamine in mice. Exp Anim. 60:481–487. 2011. View Article : Google Scholar : PubMed/NCBI
24	Narikiyo K, Mizuguchi R, Ajima A, Shiozaki M, Hamanaka H, Johansen JP, Mori K and Yoshihara Y: The claustrum coordinates cortical slow-wave activity. Nat Neurosci. 23:741–753. 2020. View Article : Google Scholar : PubMed/NCBI
25	Olajide OJ, Gbadamosi IT, Yawson EO, Arogundade T, Lewu FS, Ogunrinola KY, Adigun OO, Bamisi O, Lambe E, Arietarhire LO, et al: Hippocampal degeneration and behavioral impairment during alzheimer-like pathogenesis involves glutamate excitotoxicity. J mol Neurosci. 71:1205–1220. 2021. View Article : Google Scholar : PubMed/NCBI
26	Kanda Y: Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 48:452–458. 2013. View Article : Google Scholar : PubMed/NCBI
27	Suzuki-Inoue K: Platelets and cancer-associated thrombosis: Focusing on the platelet activation receptor CLEC-2 and podoplanin. Blood. 134:1912–1918. 2019. View Article : Google Scholar : PubMed/NCBI
28	Hwang BO, Park SY, Cho ES, Zhang X, Lee SK, Ahn HJ, Chun KS, Chung WY and Song NY: Platelet CLEC2-podoplanin axis as a promising target for oral cancer treatment. Front Immunol. 12:8076002021. View Article : Google Scholar : PubMed/NCBI
29	Sasaki T, Shirai T, Tsukiji N, Otake S, Tamura S, Ichikawa J, Osada M, Satoh K, Ozaki Y and Suzuki-Inoue K: Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2/podoplanin-dependent platelet aggregation and lung metastasis. J Thromb Haemost. 16:960–972. 2018. View Article : Google Scholar : PubMed/NCBI
30	Huang J, Li X, Shi X, Zhu M, Wang J, Huang S, Huang X, Wang H, Li L, Deng H, et al: Platelet integrin αIIbβ3: Signal transduction, regulation, and its therapeutic targeting. J Hematol Oncol. 12:262019. View Article : Google Scholar : PubMed/NCBI
31	Obermann WMJ, Brockhaus K and Eble JA: Platelets, constant and cooperative companions of sessile and disseminating tumor cells, crucially contribute to the tumor microenvironment. Front Cell Dev Biol. 9:6745532021. View Article : Google Scholar : PubMed/NCBI
32	Kitayama J, Ishigami H, Yamaguchi H, Sakuma Y, Horie H, Hosoya Y, Lefor AK and Sata N: Treatment of patients with peritoneal metastases from gastric cancer. Ann Gastroenterol Surg. 2:116–123. 2018. View Article : Google Scholar : PubMed/NCBI
33	Huang B, Rouvelas I and Nilsson M: Gastric and gastroesophageal junction cancer: Risk factors and prophylactic treatments for prevention of peritoneal recurrence after curative intent surgery. Ann Gastroenterol Surg. 6:474–485. 2022. View Article : Google Scholar : PubMed/NCBI
34	Kamei T, Kitayama J, Yamashita H and Nagawa H: Intraoperative blood loss is a critical risk factor for peritoneal recurrence after curative resection of advanced gastric cancer. World J Surg. 33:1240–1246. 2009. View Article : Google Scholar : PubMed/NCBI
35	Miyashita T, Tajima H, Gabata R, Okazaki M, Shimbashi H, Ohbatake Y, Okamoto K, Nakanuma S, Sakai S, Makino I, et al: Impact of extravasated platelet activation and podoplanin-positive cancer-associated fibroblasts in pancreatic cancer stroma. Anticancer Res. 39:5565–5572. 2019. View Article : Google Scholar : PubMed/NCBI
36	Yamaguchi T, Fushida S, Kinoshita J, Okazaki M, Ishikawa S, Ohbatake Y, Terai S, Okamoto K, Nakanuma S, Makino I, et al: Extravasated platelet aggregation contributes to tumor progression via the accumulation of myeloid-derived suppressor cells in gastric cancer with peritoneal metastasis. Oncol Lett. 20:1879–1887. 2020. View Article : Google Scholar : PubMed/NCBI
37	Lee JJ, Hsu YC, Li YS and Cheng SP: Galectin-3 inhibitors suppress anoikis resistance and invasive capacity in thyroid cancer cells. Int J Endocrinol. 2021:55834912021. View Article : Google Scholar : PubMed/NCBI
38	World Medical Association, . World medical association declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 310:2191–2194. 2013. View Article : Google Scholar : PubMed/NCBI
39	Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, et al: Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 18:e30004112020. View Article : Google Scholar : PubMed/NCBI
40	National Research Council (US), . Committee for the update of the guide for the care and use of laboratory animals: Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press; Washington, DC: 2011