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. 2023 Nov 1;26(6):538.
doi: 10.3892/ol.2023.14125. eCollection 2023 Dec.

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

Takashi Nakayama  1 , Ryo Saito  1 , Shinji Furuya  1 , Katsutoshi Shoda  1 , Suguru Maruyma  1 , Koichi Takiguchi  1 , Kensuke Shiraishi  1 , Hidenori Akaike  1 , Yoshihiko Kawaguchi  1 , Hidetake Amemiya  1 , Hiromichi Kawaida  1 , Nagaharu Tsukiji  2 , Toshiaki Shirai  2 , Hideyuki Shinmori  3 , Masami Yamamoto  4 , Sachiyo Nomura  5 , Tetsuya Tsukamoto  6 , Katsue Suzuki-Inoue  2 , Daisuke Ichikawa  1
Affiliations

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

Takashi Nakayama et al. Oncol Lett. .

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.

Keywords: direct contact; gastric cancer; peritoneal dissemination; platelet; therapeutic application.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Major candidate molecules involved in the interaction between cancer cells and platelets. Inhibitors targeting the candidate molecules are shown. CLEC-2, C-type lectin-like receptor 2; Co-HP, cobalt hematoporphyrin; GPVI, glycoprotein VI; Gal-3, galectin-3; PDPN, podoplanin.
Figure 2.
Figure 2.
Inhibitory effects in migratory ability by various candidate molecules. (A) Comparison of the number of migrated cells to each control in response to various inhibitors. (B) Microscopic images of migration assays with and without each inhibitor shows that antimouse monoclonal antibodies against GPVI and JAQ1 significantly suppress the migration of GC cells (NUGC-3), which is enhanced by platelet contact. Conversely, inhibitory assays using Co-HP for CLEC-2 and GRGDSP peptides for integrin show no considerable inhibition (magnification, ×100). Co-HP, cobalt hematoporphyrin; GRGDSP, Gly-Arg-Gly-Asp-Ser-Pro; hPLT, human platelets; mPLT, mouse platelets; NS, not significant.
Figure 3.
Figure 3.
Inhibitory effect of GPVI/galectin-3 inhibitors on tumor development in mouse cell lines (YTN16). Results of the (A) migration and (B) invasion assays and (C and D) their microscopic images show that JAQ1 significantly suppresses both the platelet-induced enhancement of migratory and invasive abilities of YTN16 cells (P=0.004, vs. mPLT group, and P=0.003, vs. mPLT group, respectively; magnification, ×100). Furthermore, the Gal-3 inhibitor GB1107 tended to suppress this enhanced ability, especially in migration assays (P=0.044 vs. mPLT group, and P=0.071 vs. mPLT group, respectively; magnification, ×100). Gal-3, galectin-3; hPLT, human platelets; mPLT, mouse platelets.
Figure 4.
Figure 4.
Therapeutic effects of JAQ1 and GB1107 in peritoneal dissemination. Trends in (A) mouse weight, (B) number of peritoneal tumors, (C) weight of the tumor mass and (D) findings from each representative abdominal cavity can be observed. All groups, except for the mPLT group, show similar increasing trends in mouse weight. Both the number of tumors and their weights are enhanced by platelet contact (P=0.040 vs. NT group and P=0.037 vs. NT group, respectively) and reduced by coadministration of JAQ1 and GB1107 (P=0.042 vs. mPLT group). NT, nontreatment; mPLT, mouse platelet.
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References

    1. 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;20:576–590. doi: 10.1016/j.ccr.2011.09.009. - DOI - PMC - PubMed
    1. Rothwell PM, Wilson M, Price JF, Belch JFF, Mead TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591–1601. doi: 10.1016/S0140-6736(12)60209-8. - DOI - PubMed
    1. 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. 2017;15:513–525. doi: 10.1111/jth.13604. - DOI - PubMed
    1. 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. 2021;124:570–573. doi: 10.1038/s41416-020-01134-7. - DOI - PMC - PubMed
    1. 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. 2006;107:542–549. doi: 10.1182/blood-2005-05-1994. - DOI - PubMed

Grants and funding

The present study was partially supported by the Japan Society for the Promotion of Science (JSPS KAKENHI grant nos. 20K17642 and 20K09031).