Skip to main content

Advertisement

Springer Nature Link
Log in

Cancer cell lines release glutamate into the extracellular environment

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Bone is one of the most frequent sites for metastasis of breast and prostate cancers. Bone metastases are associated with pathologic changes in bone turnover and severe pain. The mechanisms that trigger these effects are not well understood, but it is postulated that tumour cells release factors which interfere with signalling processes critical to bone homeostasis. We have identified that several cancer cell lines known to cause bone disruption in animal models of bone metastasis appear to secrete glutamate into their extracellular environment in vitro. Although these cells also express specific glutamate receptors, the implications of this potentially disruptive chemical signal are discussed in relation to normal glutamate-dependent communication processes in bone and a possible mechanistic connection is made between tumour cell glutamate release and the development of pathological changes in bone turnover.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Abbreviations

CNS:

Central nervous system

DMEM:

Dulbecco’s modified Eagle’s medium

EDTA:

Ethylenediaminetetraacetic acid (chelating agent)

MEM:

Minimal essential medium

NMDA:

N-methyl-d-aspartate

NMDAR:

N-methyl-d-aspartate receptor (NMDA type glutamate receptor)

RPMI-1640:

Roswell Park Memorial Institute 1640 medium

RT-PCR:

Reverse transcriptase-polymerase chain reaction

References

  1. Coleman RE (1997) Skeletal complications of malignancy. Cancer 80(8, Suppl):1588–1594. doi:10.1002/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G

    Article  PubMed  CAS  Google Scholar 

  2. Orr FW, Lee J, Duivenvoorden WC, Singh G (2000) Pathophysiologic interactions in skeletal metastasis. Cancer 88(12, Suppl):2912–2918. doi:10.1002/1097-0142(20000615)88:12+<2912::AID-CNCR6>3.0.CO;2-8

    Article  PubMed  CAS  Google Scholar 

  3. Vukmirovic-Popovic S, Colterjohn N, Lhotak S, Duivenvoorden WC, Orr FW, Singh G (2002) Morphological, histomorphometric, and microstructural alterations in human bone metastasis from breast carcinoma. Bone 31(4):529–535. doi:10.1016/S8756-3282(02)00847-5

    Article  PubMed  CAS  Google Scholar 

  4. Rose AA, Siegel PM (2006) Breast cancer-derived factors facilitate osteolytic bone metastasis. Bull Cancer 93(9):931–943

    PubMed  CAS  Google Scholar 

  5. Bonfil RD, Chinni S, Fridman R, Kim HR, Cher ML (2007) Proteases, growth factors, chemokines, and the microenvironment in prostate cancer bone metastasis. Urol Oncol 25(5):407–411. doi:10.1016/j.urolonc.2007.05.008

    PubMed  CAS  Google Scholar 

  6. Skerry TM (2008) The role of glutamate in the regulation of bone mass and architecture. J Musculoskelet Neuronal Interact 8(2):166–173

    PubMed  CAS  Google Scholar 

  7. Bussard KM, Gay CV, Mastro AM (2008) The bone microenvironment in metastasis; what is special about bone? Cancer Metastasis Rev 27(1):41–55. doi:10.1007/s10555-007-9109-4

    Article  PubMed  Google Scholar 

  8. Chenu C (2002) Glutamatergic regulation of bone remodeling. J Musculoskelet Neuronal Interact 2(3):282–284

    PubMed  CAS  Google Scholar 

  9. Hinoi E, Takarada T, Yoneda Y (2004) Glutamate signaling system in bone. J Pharmacol Sci 94(3):215–220. doi:10.1254/jphs.94.215

    Article  PubMed  CAS  Google Scholar 

  10. Esquenazi S, Monnerie H, Kaplan P, Le Roux P (2002) BMP-7 and excess glutamate: opposing effects on dendrite growth from cerebral cortical neurons in vitro. Exp Neurol 176(1):41–54. doi:10.1006/exnr.2002.7906

    Article  PubMed  CAS  Google Scholar 

  11. Li T, Ghishan FK, Bai L (2005) Molecular physiology of vesicular glutamate transporters in the digestive system. World J Gastroenterol 11(12):1731–1736

    PubMed  CAS  Google Scholar 

  12. Skerry TM, Genever PG (2001) Glutamate signalling in non-neuronal tissues. Trends Pharmacol Sci 22(4):174–181. doi:10.1016/S0165-6147(00)01642-4

    Article  PubMed  CAS  Google Scholar 

  13. Hinoi E, Takarada T, Ueshima T, Tsuchihashi Y, Yoneda Y (2004) Glutamate signaling in peripheral tissues. Eur J Biochem 271(1):1–13. doi:10.1046/j.1432-1033.2003.03907.x

    Article  PubMed  CAS  Google Scholar 

  14. Serre CM, Farlay D, Delmas PD, Chenu C (1999) Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone 25(6):623–629. doi:10.1016/S8756-3282(99)00215-X

    Article  PubMed  CAS  Google Scholar 

  15. Chenu C (2002) Glutamatergic regulation of bone resorption. J Musculoskelet Neuronal Interact 2(5):423–431

    PubMed  CAS  Google Scholar 

  16. Chenu C (2002) Glutamatergic innervation in bone. Microsc Res Tech 58(2):70–76. doi:10.1002/jemt.10120

    Article  PubMed  CAS  Google Scholar 

  17. Spencer GJ, Genever PG (2003) Long-term potentiation in bone—a role for glutamate in strain-induced cellular memory? BMC Cell Biol 4:9. doi:10.1186/1471-2121-4-9

    Article  PubMed  Google Scholar 

  18. Szczesniak AM, Gilbert RW, Mukhida M, Anderson GI (2005) Mechanical loading modulates glutamate receptor subunit expression in bone. Bone 37(1):63–73. doi:10.1016/j.bone.2003.10.016

    Article  PubMed  CAS  Google Scholar 

  19. Takarada T, Yoneda Y (2008) Pharmacological topics of bone metabolism: glutamate as a signal mediator in bone. J Pharmacol Sci 106(4):536–541. doi:10.1254/jphs.FM0070243

    Article  PubMed  CAS  Google Scholar 

  20. Patton AJ, Genever PG, Birch MA, Suva LJ, Skerry TM (1998) Expression of an N-methyl-D-aspartate-type receptor by human and rat osteoblasts and osteoclasts suggests a novel glutamate signaling pathway in bone. Bone 22(6):645–649. doi:10.1016/S8756-3282(98)00061-1

    Article  PubMed  CAS  Google Scholar 

  21. Chenu C, Serre CM, Raynal C, Burt-Pichat B, Delmas PD (1998) Glutamate receptors are expressed by bone cells and are involved in bone resorption. Bone 22(4):295–299. doi:10.1016/S8756-3282(97)00295-0

    Article  PubMed  CAS  Google Scholar 

  22. Laketic-Ljubojevic I, Suva LJ, Maathuis FJ, Sanders D, Skerry TM (1999) Functional characterization of N-methyl-D-aspartic acid-gated channels in bone cells. Bone 25(6):631–637. doi:10.1016/S8756-3282(99)00224-0

    Article  PubMed  CAS  Google Scholar 

  23. Gu Y, Genever PG, Skerry TM, Publicover SJ (2002) The NMDA type glutamate receptors expressed by primary rat osteoblasts have the same electrophysiological characteristics as neuronal receptors. Calcif Tissue Int 70(3):194–203. doi:10.1007/s00223-001-2004-z

    Article  PubMed  CAS  Google Scholar 

  24. Hinoi E, Fujimori S, Takemori A, Kurabayashi H, Nakamura Y, Yoneda Y (2002) Demonstration of expression of mRNA for particular AMPA and kainate receptor subunits in immature and mature cultured rat calvarial osteoblasts. Brain Res 943(1):112–116. doi:10.1016/S0006-8993(02)02726-9

    Article  PubMed  CAS  Google Scholar 

  25. Mason DJ, Suva LJ, Genever PG, Patton AJ, Steuckle S, Hillam RA et al (1997) Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone 20(3):199–205. doi:10.1016/S8756-3282(96)00386-9

    Article  PubMed  CAS  Google Scholar 

  26. Stains JP, Civitelli R (2005) Cell-to-cell interactions in bone. Biochem Biophys Res Commun 328(3):721–727. doi:10.1016/j.bbrc.2004.11.078

    Article  PubMed  CAS  Google Scholar 

  27. Kato S, Negishi K, Mawatari K, Kuo CH (1992) A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion. Neuroscience 48(4):903–914. doi:10.1016/0306-4522(92)90278-A

    Article  PubMed  CAS  Google Scholar 

  28. Ye ZC, Sontheimer H (1999) Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59(17):4383–4391

    PubMed  CAS  Google Scholar 

  29. Kim JY, Kanai Y, Chairoungdua A, Cha SH, Matsuo H, Kim DK et al (2001) Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. Biochim Biophys Acta 1512(2):335–344. doi:10.1016/S0005-2736(01)00338-8

    Article  PubMed  CAS  Google Scholar 

  30. Sontheimer H (2003) Malignant gliomas: perverting glutamate and ion homeostasis for selective advantage. Trends Neurosci 26(10):543–549. doi:10.1016/j.tins.2003.08.007

    Article  PubMed  CAS  Google Scholar 

  31. Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY et al (2005) Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci 25(31):7101–7110. doi:10.1523/JNEUROSCI.5258-04.2005

    Article  PubMed  CAS  Google Scholar 

  32. Duivenvoorden WC, Popovic SV, Lhotak S, Seidlitz E, Hirte HW, Tozer RG et al (2002) Doxycycline decreases tumor burden in a bone metastasis model of human breast cancer. Cancer Res 62(6):1588–1591

    PubMed  CAS  Google Scholar 

  33. Duivenvoorden WC, Vukmirovic-Popovic S, Kalina M, Seidlitz E, Singh G (2007) Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer. Br J Cancer 96:1526–1531. doi:10.1038/sj.bjc.6603740

    Article  PubMed  CAS  Google Scholar 

  34. Hinoi E, Fujimori S, Yoneda Y (2003) Modulation of cellular differentiation by N-methyl-D-aspartate receptors in osteoblasts. FASEB J 17(11):1532–1534

    PubMed  CAS  Google Scholar 

  35. Merle B, Itzstein C, Delmas PD, Chenu C (2003) NMDA glutamate receptors are expressed by osteoclast precursors and involved in the regulation of osteoclastogenesis. J Cell Biochem 90(2):424–436. doi:10.1002/jcb.10625

    Article  PubMed  CAS  Google Scholar 

  36. Morimoto R, Uehara S, Yatsushiro S, Juge N, Hua Z, Senoh S et al (2006) Secretion of L-glutamate from osteoclasts through transcytosis. EMBO J 25(18):4175–4186. doi:10.1038/sj.emboj.7601317

    Article  PubMed  CAS  Google Scholar 

  37. Taylor AF (2002) Functional osteoblastic ionotropic glutamate receptors are a prerequisite for bone formation. J Musculoskelet Neuronal Interact 2(5):415–422

    PubMed  CAS  Google Scholar 

  38. Bhangu PS, Genever PG, Spencer GJ, Grewal TS, Skerry TM (2001) Evidence for targeted vesicular glutamate exocytosis in osteoblasts. Bone 29(1):16–23. doi:10.1016/S8756-3282(01)00482-3

    Article  PubMed  CAS  Google Scholar 

  39. Bhangu PS (2003) ‘Pre-synaptic’ vesicular glutamate release mechanisms in osteoblasts. J Musculoskelet Neuronal Interact 3(1):17–29

    PubMed  CAS  Google Scholar 

  40. Genever PG, Skerry TM (2001) Regulation of spontaneous glutamate release activity in osteoblastic cells and its role in differentiation and survival: evidence for intrinsic glutamatergic signaling in bone. FASEB J 15(9):1586–1588

    PubMed  CAS  Google Scholar 

  41. Kalariti N, Lembessis P, Papageorgiou E, Pissimissis N, Koutsilieris M (2007) Regulation of the mGluR5, EAAT1 and GS expression by glucocorticoids in MG-63 osteoblast-like osteosarcoma cells. J Musculoskelet Neuronal Interact 7(2):113–118

    PubMed  CAS  Google Scholar 

  42. Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H (2007) Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 67(19):9463–9471. doi:10.1158/0008-5472.CAN-07-2034

    Article  PubMed  CAS  Google Scholar 

  43. Wu Y, Shen D, Chen Z, Clayton S, Vadgama JV (2007) Taxol induced apoptosis regulates amino acid transport in breast cancer cells. Apoptosis 12(3):593–612. doi:10.1007/s10495-006-0007-y

    Article  PubMed  CAS  Google Scholar 

  44. Franklin RB, Zou J, Yu Z, Costello LC (2006) EAAC1 is expressed in rat and human prostate epithelial cells; functions as a high-affinity L-aspartate transporter; and is regulated by prolactin and testosterone. BMC Biochem 7:10. doi:10.1186/1471-2091-7-10

    Article  PubMed  CAS  Google Scholar 

  45. Carrascosa JM, Martinez P, Nunez de Castro I (1984) Nitrogen movement between host and tumor in mice inoculated with Ehrlich ascitic tumor cells. Cancer Res 44(9):3831–3835

    PubMed  CAS  Google Scholar 

  46. Collins CL, Wasa M, Souba WW, Abcouwer SF (1998) Determinants of glutamine dependence and utilization by normal and tumor-derived breast cell lines. J Cell Physiol 176(1):166–178. doi:10.1002/(SICI)1097-4652(199807)176:1<166::AID-JCP18>3.0.CO;2-5

    Article  PubMed  CAS  Google Scholar 

  47. Gonzalez-Cadavid NF, Ryndin I, Vernet D, Magee TR, Rajfer J (2000) Presence of NMDA receptor subunits in the male lower urogenital tract. J Androl 21(4):566–578

    PubMed  CAS  Google Scholar 

  48. Maxwell M, McCoy TA, Neuman RE (1956) The amino acid requirements of the Walker carcinosarcoma 256 in vitro. Cancer Res 16(10 Part 1):979–984

    PubMed  CAS  Google Scholar 

  49. Abdul M, Hoosein N (2005) N-methyl-D-aspartate receptor in human prostate cancer. J Membr Biol 205(3):125–128. doi:10.1007/s00232-005-0777-0

    Article  PubMed  CAS  Google Scholar 

  50. Rzeski W, Turski L, Ikonomidou C (2001) Glutamate antagonists limit tumor growth. Proc Natl Acad Sci USA 98(11):6372–6377. doi:10.1073/pnas.091113598

    Article  PubMed  CAS  Google Scholar 

  51. Rzeski W, Ikonomidou C, Turski L (2002) Glutamate antagonists limit tumor growth. Biochem Pharmacol 64(8):1195–1200. doi:10.1016/S0006-2952(02)01218-2

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by operating grants from the Canadian Institutes of Health Research to G.S.

Author information

Authors and Affiliations

  1. Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Eric P. Seidlitz, Mohit K. Sharma, Zeina Saikali, Michelle Ghert & Gurmit Singh

  2. Department of Surgery, McMaster University, Hamilton, ON, Canada

    Michelle Ghert

  3. Research Department, Juravinski Cancer Centre, 699 Concession St., Hamilton, ON, Canada

    Michelle Ghert & Gurmit Singh

Authors
  1. Eric P. Seidlitz
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Mohit K. Sharma
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Zeina Saikali
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Michelle Ghert
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Gurmit Singh
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Gurmit Singh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seidlitz, E.P., Sharma, M.K., Saikali, Z. et al. Cancer cell lines release glutamate into the extracellular environment. Clin Exp Metastasis 26, 781–787 (2009). https://doi.org/10.1007/s10585-009-9277-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-009-9277-4

Keywords