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Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs

Oncogene volume 27, pages 264–273 (2008)Cite this article

Abstract

Necl-5 is an immunoglobulin (Ig)-like molecule that was originally identified as a poliovirus receptor and is often upregulated in cancer cells. We recently found that it colocalizes with integrin αvβ3 at the leading edges of moving cells and enhances growth factor-induced cell movement and proliferation. Upon cell–cell contact, Necl-5 is removed from the cell surface by its trans-interaction with the cell adhesion molecule nectin-3, resulting in reduced cell movement and proliferation. Here, we investigated the role of Necl-5 in the interaction of cancer cells with platelets. Necl-5 was upregulated in CT26 cells, a colon adenocarcinoma cell line. When CT26 cells were injected into the tail vein of mice, they were arrested in the pulmonary vessels by adhering to platelets and subsequently metastasized to the lungs. Overexpression of Necl-5 in CT26 cells enhanced this metastasis, while inhibition of the trans-interaction of Necl-5 with CD226 by an anti-Necl-5 monoclonal antibody reduced the metastasis. Depletion of platelets by treatment with a rabbit anti-mouse platelet serum reduced the Necl-5-enhanced metastasis in mice. Thus, the trans-interaction of upregulated Necl-5 in cancer cells with its counter-receptor in platelets, probably CD226, is critical for efficient metastasis of cancer cells to the lungs.

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Abbreviations

Necl-5-AP:

extracellular region of Necl-5 fused to alkaline phosphatase

nectin-2-AP:

extracellular region of nectin-2 fused to alkaline phosphatase

PVR:

poliovirus receptor

References

  • Abercrombie M . (1979). Contact inhibition and malignancy. Nature 281: 259–262.

    Article  CAS  PubMed  Google Scholar 

  • Abercrombie M, Heaysman JE . (1953). Observations on the social behaviour of cells in tissue culture. I. Speed of movement of chick heart fibroblasts in relation to their mutual contacts. Exp Cell Res 5: 111–131.

    Article  CAS  PubMed  Google Scholar 

  • Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B et al. (2003). Identification of PVR (CD155) and nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 198: 557–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chadeneau C, LeCabellec M, LeMoullac B, Meflah K, Denis MG . (1996). Over-expression of a novel member of the immunoglobulin superfamily in Min mouse intestinal adenomas. Int J Cancer 68: 817–821.

    Article  CAS  PubMed  Google Scholar 

  • Chadeneau C, LeMoullac B, Denis MG . (1994). A novel member of the immunoglobulin gene superfamily expressed in rat carcinoma cell lines. J Biol Chem 269: 15601–15605.

    CAS  PubMed  Google Scholar 

  • Crissman JD, Hatfield JS, Menter DG, Sloane B, Honn KV . (1988). Morphological study of the interaction of intravascular tumor cells with endothelial cells and subendothelial matrix. Cancer Res 48: 4065–4072.

    CAS  PubMed  Google Scholar 

  • Felding-Habermann B, Habermann R, Saldivar E, Ruggeri ZM . (1996). Role of beta3 integrins in melanoma cell adhesion to activated platelets under flow. J Biol Chem 271: 5892–5900.

    Article  CAS  PubMed  Google Scholar 

  • Fuchs A, Cella M, Giurisato E, Shaw AS, Colonna M . (2004). CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J Immunol 172: 3994–3998.

    Article  CAS  PubMed  Google Scholar 

  • Fujito T, Ikeda W, Kakunaga S, Minami Y, Kajita M, Sakamoto Y et al. (2005). Inhibition of cell movement and proliferation by cell-cell contact-induced interaction of Necl-5 with nectin-3. J Cell Biol 171: 165–173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E . (2000). Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci USA 97: 6803–6808.

    Article  CAS  PubMed  Google Scholar 

  • Guo W, Giancotti FG . (2004). Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5: 816–826.

    Article  CAS  PubMed  Google Scholar 

  • Hirota T, Irie K, Okamoto R, Ikeda W, Takai Y . (2005). Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway. Oncogene 24: 2229–2235.

    Article  CAS  PubMed  Google Scholar 

  • Ikeda W, Kakunaga S, Itoh S, Shingai T, Takekuni K, Satoh K et al. (2003). Tage4/Nectin-like molecule-5 heterophilically trans-interacts with cell adhesion molecule nectin-3 and enhances cell migration. J Biol Chem 278: 28167–28172.

    Article  CAS  PubMed  Google Scholar 

  • Ikeda W, Kakunaga S, Takekuni K, Shingai T, Satoh K, Morimoto K et al. (2004). Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, nectin-3-independent manner. J Biol Chem 279: 18015–18025.

    Article  CAS  PubMed  Google Scholar 

  • Im JH, Fu W, Wang H, Bhatia SK, Hammer DA, Kowalska MA et al. (2004). Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 64: 8613–8619.

    Article  CAS  PubMed  Google Scholar 

  • Kakunaga S, Ikeda W, Shingai T, Fujito T, Yamada A, Minami Y et al. (2004). Enhancement of serum- and platelet-derived growth factor-induced cell proliferation by Necl-5/Tage4/poliovirus receptor/CD155 through the Ras-Raf-MEK-ERK signaling. J Biol Chem 279: 36419–36425.

    Article  CAS  PubMed  Google Scholar 

  • Kato Y, Fujita N, Kunita A, Sato S, Kaneko M, Osawa M et al. (2003). Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J Biol Chem 278: 51599–51605.

    Article  CAS  PubMed  Google Scholar 

  • Koike S, Horie H, Ise I, Okitsu A, Yoshida M, Iizuka N et al. (1990). The poliovirus receptor protein is produced both as membrane-bound and secreted forms. EMBO J 9: 3217–3224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kojima H, Kanada H, Shimizu S, Kasama E, Shibuya K, Nakauchi H et al. (2003). CD226 mediates platelet and megakaryocytic cell adhesion to vascular endothelial cells. J Biol Chem 278: 36748–36753.

    Article  CAS  PubMed  Google Scholar 

  • Martin-Villar E, Megias D, Castel S, Yurrita MM, Vilaro S, Quintanilla M . (2006). Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J Cell Sci 119: 4541–4553.

    Article  CAS  PubMed  Google Scholar 

  • Masson D, Jarry A, Baury B, Blanchardie P, Laboisse C, Lustenberger P et al. (2001). Overexpression of the CD155 gene in human colorectal carcinoma. Gut 49: 236–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mendelsohn CL, Wimmer E, Racaniello VR . (1989). Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56: 855–865.

    Article  CAS  PubMed  Google Scholar 

  • Mueller S, Cao X, Welker R, Wimmer E . (2002). Interaction of the poliovirus receptor CD155 with the dynein light chain Tctex-1 and its implication for poliovirus pathogenesis. J Biol Chem 277: 7897–7904.

    Article  CAS  PubMed  Google Scholar 

  • Nash GF, Turner LF, Scully MF, Kakkar AK . (2002). Platelets and cancer. Lancet Oncol 3: 425–430.

    Article  CAS  PubMed  Google Scholar 

  • Reymond N, Imbert AM, Devilard E, Fabre S, Chabannon C, Xerri L et al. (2004). DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J Exp Med 199: 1331–1341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sherrington PD, Scott JL, Jin B, Simmons D, Dorahy DJ, Lloyd J et al. (1997). TLiSA1 (PTA1) activation antigen implicated in T cell differentiation and platelet activation is a member of the immunoglobulin superfamily exhibiting distinctive regulation of expression. J Biol Chem 272: 21735–21744.

    Article  CAS  PubMed  Google Scholar 

  • Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T et al. (1996). DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4: 573–581.

    Article  CAS  PubMed  Google Scholar 

  • Shibuya K, Lanier LL, Phillips JH, Ochs HD, Shimizu K, Nakayama E et al. (1999). Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11: 615–623.

    Article  CAS  PubMed  Google Scholar 

  • Sloan KE, Eustace BK, Stewart JK, Zehetmeier C, Torella C, Simeone M et al. (2004). CD155/PVR plays a key role in cell motility during tumor cell invasion and migration. BMC Cancer 4: 73.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sloan KE, Stewart JK, Treloar AF, Matthews RT, Jay DG . (2005). CD155/PVR enhances glioma cell dispersal by regulating adhesion signaling and focal adhesion dynamics. Cancer Res 65: 10930–10937.

    Article  CAS  PubMed  Google Scholar 

  • Takai Y, Irie K, Shimizu K, Sakisaka T, Ikeda W . (2003). Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization. Cancer Sci 94: 655–667.

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP . (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr H Yamauchi (KAN Research Institute Inc.) for helpful comments and encouragement.

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Authors and Affiliations

  1. KAN Research Institute Inc., Kobe MI R&D Center, Kobe, Hyogo, Japan

    K Morimoto, K Satoh-Yamaguchi, A Hamaguchi, Y Inoue, M Takeuchi, M Okada & T Imai

  2. Department of Molecular Biology and Biochemistry, Faculty of Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    W Ikeda & Y Takai

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  1. K Morimoto
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  2. K Satoh-Yamaguchi
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  4. Y Inoue
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  7. W Ikeda
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Correspondence to T Imai.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Morimoto, K., Satoh-Yamaguchi, K., Hamaguchi, A. et al. Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs. Oncogene 27, 264–273 (2008). https://doi.org/10.1038/sj.onc.1210645

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