Skip to main content

Advertisement

SpringerLink
Log in

Anandamide is an endogenous inhibitor for the migration of tumor cells and T lymphocytes

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Cell migration is of paramount importance in physiological processes such as immune surveillance, but also in the pathological processes of tumor cell migration and metastasis development. The factors that regulate this tumor cell migration, most prominently neurotransmitters, have thus been the focus of intense investigation. While the majority of neurotransmitters have a stimulatory effect on cell migration, we herein report the inhibitory effect of the endogenous substance anandamide on both tumor cell and lymphocyte migration. Using a collagen-based three-dimensional migration assay and time-lapse videomicroscopy, we have observed that the anandamide-mediated signals for CD8+ T lymphocytes and SW 480 colon carcinoma cells are each mediated by distinct cannabinoid receptors (CB-Rs). Using the specific agonist docosatetraenoylethanolamide (DEA), we have observed that the norepinephrine-induced migration of colon carcinoma cells is inhibited by the CB1-R. The SDF-1–induced migration of CD8+ T lymphocytes was, however, inhibited via the CB2-R, as shown by using the specific agonist JWH 133. Therefore, specific inhibition of tumor cell migration via CB1-R engagement might be a selective tool to prevent metastasis formation without depreciatory effects on the immune system of cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A–D
Fig. 2A–C
Fig. 3

Similar content being viewed by others

References

  1. Barg J, Fride E, Hanus L, Levy R, Matus-Leibovitch N, Heldman E, Bayewitch M, Mechoulam R, Vogel Z (1995) Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides. Eur J Pharmacol 287:145–152

    Article  CAS  PubMed  Google Scholar 

  2. Behar TN, Smith SV, Kennedy RT, McKenzie JM, Maric I, Barker JL (2001) GABA(B) receptors mediate motility signals for migrating embryonic cortical cells. Cereb Cortex 11:744–753

    Article  CAS  PubMed  Google Scholar 

  3. Berdyshev E, Boichot E, Corbel M, Germain N, Lagente V (1998) Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice. Life Sci 63:PL125–PL129

    Google Scholar 

  4. De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A 95:8375–8380

    Article  PubMed  Google Scholar 

  5. De Petrocellis L, Melck D, Bisogno T, Di Marzo V (2000) Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders. Chem Phys Lipids 108:191–209

    PubMed  Google Scholar 

  6. Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613

    CAS  PubMed  Google Scholar 

  7. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    CAS  PubMed  Google Scholar 

  8. Drell TL 4th, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F (2003) Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat 80:63–70

    Article  CAS  PubMed  Google Scholar 

  9. Eason MG, Kurose H, Holt BD, Raymond JR, Liggett SB (1992) Simultaneous coupling of alpha 2-adrenergic receptors to two G-proteins with opposing effects: subtype-selective coupling of alpha 2C10, alpha 2C4, and alpha 2C2 adrenergic receptors to Gi and Gs. J Biol Chem 267:15795–15801

    CAS  PubMed  Google Scholar 

  10. Entschladen F, Niggemann B, Zanker KS, Friedl P (1997) Differential requirement of protein tyrosine kinases and protein kinase C in the regulation of T cell locomotion in three-dimensional collagen matrices. J Immunol 159:3203–3210

    CAS  PubMed  Google Scholar 

  11. Entschladen F, Gunzer M, Scheuffele CM, Niggemann B, Zanker KS (2000) T lymphocytes and neutrophil granulocytes differ in regulatory signaling and migratory dynamics with regard to spontaneous locomotion and chemotaxis. Cell Immunol 199:104–114

    Article  CAS  PubMed  Google Scholar 

  12. Entschladen F, Lang K, Drell TL, Joseph J, Zaenker KS (2002) Neurotransmitters are regulators for the migration of tumor cells and leukocytes. Cancer Immunol Immunother 51:467–482

    Article  CAS  PubMed  Google Scholar 

  13. Entschladen F, Drell TL 4th, Lang K, Joseph J, Zaenker KS (2004) Tumor cell migration, invasion and metastasis: navigation by neurotransmitters. Lancet Oncol 5:254–258

    Google Scholar 

  14. Friedl P, Noble PB, Zanker KS (1993) Lymphocyte locomotion in three-dimensional collagen gels: comparison of three quantitative methods for analysing cell trajectories. J Immunol Methods 165:157–165

    Article  CAS  PubMed  Google Scholar 

  15. Huffman JW, Liddle J, Yu S, Aung MM, Abood ME, Wiley JL, Martin BR (1999) 3-(1’,1’-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg Med Chem 7:2905–2914

    CAS  PubMed  Google Scholar 

  16. Jorda MA, Rayman N, Valk P, De Wee E, Delwel R (2003) Identification, characterization, and function of a novel oncogene: the peripheral cannabinoid receptor Cb2. Ann N Y Acad Sci 996:10–16

    CAS  PubMed  Google Scholar 

  17. Joseph J, Niggemann B, Zaenker KS, Entschladen F (2002) The neurotransmitter gamma-aminobutyric acid is an inhibitory regulator for the migration of SW 480 colon carcinoma cells. Cancer Res 62:6467–6469

    CAS  PubMed  Google Scholar 

  18. Kaminski NE, Koh WS, Yang KH, Lee M, Kessler FK (1994) Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. Biochem Pharmacol 48:1899–1908

    CAS  PubMed  Google Scholar 

  19. Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T (2003) 2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism. J Biol Chem 278:24469–24475

    Article  CAS  PubMed  Google Scholar 

  20. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74:486–496

    Article  CAS  PubMed  Google Scholar 

  21. Lang K, Niggemann B, Zanker KS, Entschladen F (2002) Signal processing in migrating T24 human bladder carcinoma cells: role of the autocrine interleukin-8 loop. Int J Cancer 99:673–680

    CAS  Google Scholar 

  22. Masur K, Niggemann B, Zanker KS, Entschladen F (2001) Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res 61:2866–2869

    CAS  PubMed  Google Scholar 

  23. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    CAS  PubMed  Google Scholar 

  24. Melck D, De Petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M, Di Marzo V (2000) Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141:118–126

    CAS  PubMed  Google Scholar 

  25. Mimeault M, Pommery N, Wattez N, Bailly C, Henichart JP (2003) Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. Prostate 56:1–12

    Article  CAS  PubMed  Google Scholar 

  26. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    CAS  PubMed  Google Scholar 

  27. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    CAS  PubMed  Google Scholar 

  28. Nong L, Newton C, Friedman H, Klein TW (2001) CB1 and CB2 receptor mRNA expression in human peripheral blood mononuclear cells (PBMC) from various donor types. Adv Exp Med Biol 493:229–233

    CAS  PubMed  Google Scholar 

  29. Ortega A (2003) A new role for GABA: inhibition of tumor cell migration. Trends Pharmacol Sci 24:151–154

    Article  CAS  PubMed  Google Scholar 

  30. Pertwee RG (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635–664

    PubMed  Google Scholar 

  31. Roth MD, Baldwin GC, Tashkin DP (2002) Effects of delta-9-tetrahydrocannabinol on human immune function and host defense. Chem Phys Lipids 121:229–239

    Article  CAS  PubMed  Google Scholar 

  32. Slipetz DM, O’Neill GP, Favreau L, Dufresne C, Gallant M, Gareau Y, Guay D, Labelle M, Metters KM (1995) Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. Mol Pharmacol 48:352–361

    CAS  PubMed  Google Scholar 

  33. Song ZH, Zhong M (2000) CB1 cannabinoid receptor-mediated cell migration. J Pharmacol Exp Ther 294:204–209

    CAS  PubMed  Google Scholar 

  34. Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405

    CAS  PubMed  Google Scholar 

  35. Yuan M, Kiertscher SM, Cheng Q, Zoumalan R, Tashkin DP, Roth MD (2002) Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J Neuroimmunol 133:124–131

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Fritz Bender Foundation, Munich, Germany, and the Bruno and Helene Joester Foundation, Cologne, Germany. We thank Beate Mainusch for excellent technical assistance and Theodore L. Drell IV for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Institute of Immunology, Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany

    Jan Joseph, Bernd Niggemann, Kurt S. Zaenker & Frank Entschladen

Authors
  1. Jan Joseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernd Niggemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kurt S. Zaenker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frank Entschladen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Entschladen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joseph, J., Niggemann, B., Zaenker, K.S. et al. Anandamide is an endogenous inhibitor for the migration of tumor cells and T lymphocytes. Cancer Immunol Immunother 53, 723–728 (2004). https://doi.org/10.1007/s00262-004-0509-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-004-0509-9

Keywords

Search

Navigation