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CCL2 promotes integrin-mediated adhesion of prostate cancer cells in vitro

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Abstract

Purpose

Chemokines undergo alterations during neoplasia. However, knowledge about their functional significance in prostate cancer (PCa) progression is still sparse. Since chemokine (C–C motif) ligand 2 (CCL2) is significantly up-regulated in patients with PCa, aim of the current study was to assess whether CCL2 contributes to invasive behavior of prostate cancer cells in vitro.

Methods

The human PCa cell line PC3 was stimulated with CCL2. Cell growth was investigated by MTT dye reduction assay. Cell adhesion was analyzed by measuring attachment to a human endothelial cell (HUVEC) monolayer and immobilized collagen. Cell migration was assessed by a chemotactic assay. Integrin expression on the cell surface was evaluated by Western blot. Blocking studies were performed with anti-integrin α3, anti-integrin α6 and anti-integrin β4 monoclonal antibodies.

Results

PC3 cell growth 72 h after CCL2 exposure was significantly increased, compared to controls. Activation of tumor cells by CCL2 significantly enhanced tumor cell adhesion to HUVEC and immobilized collagen. CCL2, added for 4 or 24 h, elevated α6 and β4 (4 > 24 h) integrin expression. α3 was enhanced after 4 h, but reduced after 24 h. Blocking either α3, α6 or β4 led to significant suppression of tumor cell binding to immobilized collagen.

Conclusions

CCL2 stimulates PCa cell adhesion and induces alterations in α3-, α6- and β4-integrin expression on the cell surface. Blocking these integrins leads to a significant reduction in cell adhesion.

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References

  1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374–1403

    Article  CAS  PubMed  Google Scholar 

  2. Perlroth DJ, Bhattacharya J, Goldman DP, Garber AM (2012) An economic analysis of conservative management versus active treatment for men with localized prostate cancer. J Natl Cancer Inst Monogr 2012:250–257

    Article  PubMed Central  PubMed  Google Scholar 

  3. Welty CJ, Carroll PR (2014) The ongoing need for improved risk stratification and monitoring for those on active surveillance for early stage prostate cancer. Eur Urol 65(6):1032–1033. doi:10.1016/j.eururo.2014.02.044

  4. Wang SY, Cowan JE, Cary KC, Chan JM, Carroll PR, Cooperberg MR (2013) Limited ability of existing nomograms to predict outcomes in men undergoing active surveillance for prostate cancer. BJU Int. doi:10.1111/bju.12554

  5. Craig MJ, Loberg RD (2006) CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases. Cancer Metastasis Rev 25:611–619

    Article  CAS  PubMed  Google Scholar 

  6. Homey B, Muller A, Zlotnik A (2002) Chemokines: agents for the immunotherapy of cancer? Nat Rev Immunol 2:175–184

    Article  CAS  PubMed  Google Scholar 

  7. Kulbe H, Levinson NR, Balkwill F, Wilson JL (2004) The chemokine network in cancer—much more than directing cell movement. Int J Dev Biol 48:489–496

    Article  CAS  PubMed  Google Scholar 

  8. Zlotnik A (2004) Chemokines in neoplastic progression. Semin Cancer Biol 14:181–185

    Article  CAS  PubMed  Google Scholar 

  9. Strieter RM, Belperio JA, Phillips RJ, Keane MP (2004) CXC chemokines in angiogenesis of cancer. Semin Cancer Biol 14:195–200

    Article  CAS  PubMed  Google Scholar 

  10. Wedel SA, Raditchev IN, Jones J, Juengel E, Engl T, Jonas D, Blaheta RA (2008) CXC chemokine mRNA expression as a potential diagnostic tool in prostate cancer. Mol Med Rep 1:257–262

    CAS  PubMed  Google Scholar 

  11. Tsaur I, Noack A, Makarevic J, Oppermann E, Waaga-Gasser AM, Gasser M, Borgmann H, Huesch T, Gust KM, Reiter M, Schilling D, Bartsch G, Haferkamp A, Blaheta RA (2014) CCL2 chemokine as a potential biomarker for prostate cancer: a pilot study. Cancer Res Treat (in press)

  12. Zhang J, Patel L, Pienta KJ (2010) CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev 21:41–48

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ (1989) Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS Lett 244:487–493

    Article  CAS  PubMed  Google Scholar 

  14. Lu Y, Cai Z, Galson DL, Xiao G, Liu Y, George DE, Melhem MF, Yao Z, Zhang J (2006) Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate 66:1311–1318

    Article  CAS  PubMed  Google Scholar 

  15. Li X, Loberg R, Liao J, Ying C, Snyder LA, Pienta KJ, McCauley LK (2009) A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res 69:1685–1692

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Loberg RD, Day LL, Harwood J, Ying C, St John LN, Giles R, Neeley CK, Pienta KJ (2006) CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia 8:578–586

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Lu Y, Cai Z, Xiao G, Keller ET, Mizokami A, Yao Z, Roodman GD, Zhang J (2007) Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption. Cancer Res 67:3646–3653

    Article  CAS  PubMed  Google Scholar 

  18. Irmisch A (2013) Huelsken J. Metastasis, New insights into organ-specific extravasation and metastatic niches. Exp Cell Res

    Google Scholar 

  19. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Felding-Habermann B (2003) Integrin adhesion receptors in tumor metastasis. Clin Exp Metastasis 20:203–213

    Article  CAS  PubMed  Google Scholar 

  21. Lin TH, Liu HH, Tsai TH, Chen CC, Hsieh TF, Lee SS, Lee YJ, Chen WC, Tang CH (2013) CCL2 increases alphavbeta3 integrin expression and subsequently promotes prostate cancer migration. Biochim Biophys Acta 1830:4917–4927

    Article  CAS  PubMed  Google Scholar 

  22. Dedhar S, Saulnier R, Nagle R, Overall CM (1993) Specific alterations in the expression of alpha 3 beta 1 and alpha 6 beta 4 integrins in highly invasive and metastatic variants of human prostate carcinoma cells selected by in vitro invasion through reconstituted basement membrane. Clin Exp Metastasis 11:391–400

    Article  CAS  PubMed  Google Scholar 

  23. Cress AE, Rabinovitz I, Zhu W, Nagle RB (1995) The alpha 6 beta 1 and alpha 6 beta 4 integrins in human prostate cancer progression. Cancer Metastasis Rev 14:219–228

    Article  CAS  PubMed  Google Scholar 

  24. Pouliot N, Nice EC, Burgess AW (2001) Laminin-10 mediates basal and EGF-stimulated motility of human colon carcinoma cells via alpha(3)beta(1) and alpha(6)beta(4) integrins. Exp Cell Res 266:1–10

    Article  CAS  PubMed  Google Scholar 

  25. Rabinovitz I, Mercurio AM (1997) The integrin alpha6beta4 functions in carcinoma cell migration on laminin-1 by mediating the formation and stabilization of actin-containing motility structures. J Cell Biol 139:1873–1884

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Chintala SK, Sawaya R, Gokaslan ZL, Rao JS (1996) Modulation of matrix metalloprotease-2 and invasion in human glioma cells by alpha 3 beta 1 integrin. Cancer Lett 103:201–208

    Article  CAS  PubMed  Google Scholar 

  27. Melchiori A, Mortarini R, Carlone S, Marchisio PC, Anichini A, Noonan DM, Albini A (1995) The alpha 3 beta 1 integrin is involved in melanoma cell migration and invasion. Exp Cell Res 219:233–242

    Article  CAS  PubMed  Google Scholar 

  28. Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2:91–100

    Article  PubMed  Google Scholar 

  29. Moschos SJ, Drogowski LM, Reppert SL, Kirkwood JM (2007) Integrins and cancer. Oncology (Williston Park) 21:13–20

    Google Scholar 

  30. Tsaur I, Makarevic J, Juengel E, Gasser M, Waaga-Gasser AM, Kurosch M, Reiter M, Wedel S, Bartsch G, Haferkamp A, Wiesner C, Blaheta RA (2012) Resistance to the mTOR-inhibitor RAD001 elevates integrin alpha2- and beta1-triggered motility, migration and invasion of prostate cancer cells. Br J Cancer 107:847–855

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Ding X, Yang DR, Lee SO, Chen YL, Xia L, Lin SJ, Yu S, Niu YJ, Li G, Chang C (2014) TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling. Int J Cancer. doi:10.1002/ijc.29049

  32. Izhak L, Wildbaum G, Zohar Y, Anunu R, Klapper L, Elkeles A, Seagal J, Yefenof E, Ayalon-Soffer M, Karin N (2009) A novel recombinant fusion protein encoding a 20-amino acid residue of the third extracellular (E3) domain of CCR2 neutralizes the biological activity of CCL2. J Immunol 183:732–739

    Article  CAS  PubMed  Google Scholar 

  33. Sandhu SK, Papadopoulos K, Fong PC, Patnaik A, Messiou C, Olmos D, Wang G, Tromp BJ, Puchalski TA, Balkwill F, Berns B, Seetharam S, de Bono JS, Tolcher AW (2013) A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother Pharmacol 71:1041–1050

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the “Dr. Illing Stiftung”.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Urology and Pediatric Urology, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Igor Tsaur, Jochen Rutz, Jasmina Makarević, Eva Juengel, Kilian M. Gust, Hendrik Borgmann, David Schilling, Axel Haferkamp, Georg Bartsch & Roman A. Blaheta

  2. Department of Vascular and Endovascular Surgery, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Karen Nelson

Authors
  1. Igor Tsaur
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  2. Jochen Rutz
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  3. Jasmina Makarević
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  4. Eva Juengel
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  5. Kilian M. Gust
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  6. Hendrik Borgmann
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  8. Karen Nelson
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  9. Axel Haferkamp
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  10. Georg Bartsch
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  11. Roman A. Blaheta
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Corresponding author

Correspondence to Igor Tsaur.

Additional information

Georg Bartsch and Roman A. Blaheta have contributed equally as senior authors.

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Tsaur, I., Rutz, J., Makarević, J. et al. CCL2 promotes integrin-mediated adhesion of prostate cancer cells in vitro. World J Urol 33, 1051–1056 (2015). https://doi.org/10.1007/s00345-014-1389-z

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  • DOI: https://doi.org/10.1007/s00345-014-1389-z

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