Skip to main content

Advertisement

SpringerLink
Log in

Preliminary characterization of an experimental breast cancer cells brain metastasis mouse model by MRI/MRS

  • Research Article
  • Published:
Magnetic Resonance Materials in Physics, Biology and Medicine Aims and scope Submit manuscript

Abstract

Purpose

Chemotherapy increases survival in breast cancer patients. Consequently, cerebral metastases have recently become a significant clinical problem, with an incidence of 30–40% among breast carcinoma patients. As this phenomenon cannot be studied longitudinally in humans, models which mimic brain metastasis are needed to investigate its pathogenesis. Such models may later be used in experimental therapeutic approaches.

Material and methods/results

We report a model in which 69% of the animals (9/13 BALB/c nude mice) developed MR-detectable abnormal masses in the brain parenchyma within a 20 to 62-day time window post intra-carotid injection of 435-Br1 human cells. The masses detected in vivo were either single (7 animals) or multiple (2 animals). Longitudinal MR (MRI/MRS) studies and post-mortem histological data were correlated, revealing a total incidence of experimental brain metastases of 85% in the cases studied (11/13 animals). ADC maps perfectly differentiated edema and/or CSF areas from metastasis. Preliminary MRS data also revealed additional features: decrease in N-acetyl aspartate (NAA) was the first MRS-based marker of metastasis growth in the brain (micrometastasis); choline-containing compounds (Cho) rose and creatine (Cr) levels decreased as these lesions evolved, with mobile lipids and lactate also becoming visible. Furthermore, MRS pattern recognition-based analysis suggested that this approach may help to discriminate different growth stages.

Conclusions

This study paves the way for further in vivo studies oriented towards detection of different tumor progression states and for improving treatment efficiency.

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

Similar content being viewed by others

Abbreviations

ADC:

Apparent diffusion coefficient

ASCII:

American Standard Code for Information Interchange

CBF:

Cerebral blood flow

CBV:

Cerebral blood volume

CE-T1 MRI:

Contrast-enhanced T1 MRI

DAB:

Diaminobenzidine

DMEM/F12:

Dulbecco’s Modified Eagle Medium with nutrient mixture F12 Ham

d_PI:

Days post-injection

DWI:

Diffusion weighted imaging

FBS:

Fetal bovine serum

FOV:

Field of view

GFP:

Green fluorescent protein

GUI:

Graphical user interface

H&E:

Hematoxylin–eosin

IHC:

Immunohistochemistry

ic :

Intracarotid

ip :

Intraperitoneal

LB:

Line broadening

HBSS:

Hanks’ balanced salt solution

1H MRS:

Proton magnetic resonance spectroscopy

ML:

Mobile lipids

MRI:

magnetic resonance imaging

MTX:

Matrix size

MSME:

multi-slice multi-echo

NEX:

Number of averages

OCT:

Tissue freezing medium

PCNA:

Proliferating cell nuclear antigen

PRESS:

Point resolved spectroscopy

RARE:

Rapid acquisition by relaxation enhancement

sc :

Subcutaneous

SNR:

Signal to noise ratio

SPF:

Specific pathogen free

TAT:

Total acquisition time

TE:

Echo time

TR:

Repetition time

VAPOR:

Variable pulse power and optimized relaxation delays

Δν 1/2 :

MRS peak width at half height

Δ:

Big delta

δ :

Small delta

References

  1. International Agency for Research on Cancer (WHO). http://www.iarc.fr/. Accessed: 16 Oct, 2007

  2. Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS (2005) Breast cancer metastasis to the central nervous system. Am J Pathol 167: 913–920

    PubMed  CAS  Google Scholar 

  3. Sierra A (2005) Metastases and their microenvironments: linking pathogenesis and therapy. Drug Resist Updat 8: 247–257

    Article  PubMed  CAS  Google Scholar 

  4. Carey LA, Ewend MG, Metzger R, Sawyer L, Dees EC, Sartor CI, Moore DT, Graham ML (2004) Central nervous system metastases in women after multimodality therapy for high risk breast cancer. Breast Cancer Res Treat 88: 273–280

    Article  PubMed  Google Scholar 

  5. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2: 563–572

    Article  PubMed  CAS  Google Scholar 

  6. Zhang RD, Fidler IJ, Price JE (1991) Relative malignant potential of human breast cancer carcinoma cell lines established from pleural effusions and a brain metastasis. Invas Metast 11: 204–215

    CAS  Google Scholar 

  7. Schackert G, Fidler IJ (1988) Development of in vivo models for studies of brain metastasis. Int J Cancer. 41: 589–594

    Article  PubMed  CAS  Google Scholar 

  8. Schackert G, Price JE, Bucana CD, Fidler IJ (1989) Unique patterns of brain metastasis produced by different human carcinomas in athymic nude mice. Int J Cancer 44: 892–897

    Article  PubMed  CAS  Google Scholar 

  9. Dome B, Timar J, Paku S (2003) A novel concept of glomeruloid body formation in experimental cerebral metastases. J Neuropathol Exp Neurol 62: 655–661

    PubMed  Google Scholar 

  10. Leenders W, Kusters B, Pikkemaat J, Wesseling P, Ruiter D, Heerschap A, Barentsz J, de Waal RM (2003) Vascular endothelial growth factor-A determines detectability of experimental melanoma brain metastasis in GD-DTPA-enhanced MRI. Int J Cancer 105: 437–443

    Article  PubMed  CAS  Google Scholar 

  11. Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R (2001) A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res 16: 1486–1495

    Article  PubMed  CAS  Google Scholar 

  12. Heyn C, Ronald JA, Ramadan SS, Snir JA, Barry AM, MacKenzie LT, Mikulis DJ, Palmieri D, Bronder JL, Steeg PS, Yoneda T, MacDonald IC, Chambers AF, Rutt BK, Foster PJ (2006) In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn Reson Med 56: 1001–1010

    Article  PubMed  Google Scholar 

  13. Howe FA, Opstad KS (2003) 1H MR spectroscopy of brain tumors and masses. NMR Biomed 16: 123–131

    Article  PubMed  CAS  Google Scholar 

  14. Griffin JL, Kauppinen RA (2007) A metabolomics perspective of human brain tumours. FEBS J 274: 1132–1139

    Article  PubMed  CAS  Google Scholar 

  15. Griffin JL, Kauppinen RA (2007) Tumour metabolomics in animal models of human cancer. J Proteome Res 6: 498–505

    Article  PubMed  CAS  Google Scholar 

  16. Tate AR, Griffiths JR, Martinez-Perez I, Moreno A, Barba I, Cabañas ME, Watson D, Alonso J, Bartumeus F, Isamat F, Ferrer I, Vila F, Ferrer E, Capdevila A, Arús C (1998) Towards a method for automated classification of 1H MRS spectra from brain tumors. NMR Biomed 11: 177–191

    Article  PubMed  CAS  Google Scholar 

  17. Sierra A, Price JE, Garcia-Ramirez M, Mendez O, Lopez L, Fabra A (1997) Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Invest 77: 357–368

    PubMed  CAS  Google Scholar 

  18. Paris S, Sesboue R (2004) Metastasis models:the green fluorescent revolution?. Carcinogenesis 25: 2285–2292

    Article  PubMed  CAS  Google Scholar 

  19. Schmidt CM, Settle SL, Keene JL, Westlin WF, Nickols GA, Griggs DW (1999) Characterization of spontaneous metastasis in an aggressive breast carcinoma model using flow cytometry. Clin Expr Metastasis 17: 537–544

    Article  CAS  Google Scholar 

  20. Al-Attar SA, Pollex RL, Robinson JF, Miskie BA, Walcarius R, Rutt BK, Hegele RA (2006) Semi-automated segmentation and quantification of adipose tissue in calf and thigh by MRI: a preliminary study in patients with monogenic metabolic syndrome. BMC Med Imaging 6: 11–19

    Article  PubMed  Google Scholar 

  21. García-Martín ML, Martinez GV, Raghunand N, Sherry AD, Zhang S, Gillies RJ (2006) High resolution pH(e) imaging of rat glioma using pH-dependent relaxivity. Magn Reson Med 55: 309–315

    Article  PubMed  CAS  Google Scholar 

  22. Navarro-Vazquez A, Cobas JC, Sardina FJ, Casanueva J, Diez E (2004) A graphical tool for the prediction of vicinal proton-proton 3J(HH) coupling constants. J Chem Inf Comput Sci 44: 1680–1685

    PubMed  CAS  Google Scholar 

  23. Interpret Project: http://azizu.uab.es/INTERPRET/. Accessed: 16 Oct 2007

  24. Tate AR, Underwood J, Acosta DM, Julià-Sapé M, Majós C, Moreno-Torres A, Howe FA, van der Graaf M, Lefournier V, Murphy MM, Loosemore A, Ladroue C, Wesseling P, Luc Bosson J, Cabañas ME, Simonetti AW, Gajewicz W, Calvar J, Capdevila A, Wilkins PR, Bell BA, Rémy C, Heerschap A, Watson D, Griffiths JR, Arús C (2006) Development of a decision support system for diagnosis and grading of brain tumours using in vivo magnetic resonance single voxel spectra. NMR Biomed 19: 411–434

    Article  PubMed  CAS  Google Scholar 

  25. Pilheu FR, Fefer SA (1961) Mandibular metastasis secondary to a cancer of the breast. Sem Med 118: 95–97

    PubMed  CAS  Google Scholar 

  26. van der Waal RI, Buter J, van der Waal I (2003) Oral metastases: report of 24 cases. Br J Oral Maxillofac Surg 41: 3–6

    Article  PubMed  Google Scholar 

  27. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM (2005) Molecular mechanisms of breast cancer metastases to bone. Clin Breast Cancer 5: S46–53

    Article  PubMed  CAS  Google Scholar 

  28. Sasaki A, Yoneda T, Terakado N, Alcalde RE, Suzuki A, Matsumura T (1998) Experimental bone metastasis model of the oral and maxillofacial region. Anticancer Res 18: 1579–1584

    PubMed  CAS  Google Scholar 

  29. Bandyopadhyay A, Elkahloun A, Baysa SJ, Wang L, Sun LZ (2005) Development and gene expression profiling of a metastatic variant of the human breast cancer MDA-MB-435 cells. Cancer Biol Ther 4: 168–174

    PubMed  CAS  Google Scholar 

  30. Kirsch M, Schackert G, Black PM (2000) Angiogenesis, metastasis, and endogenous inhibition. J Neurooncol 50: 173–180

    Article  PubMed  CAS  Google Scholar 

  31. Kauppinen RA (2002) Monitoring cytotoxic tumor treatment response by diffusion magnetic resonance imaging and proton spectroscopy. NMR Biomed 15: 6–17

    Article  PubMed  CAS  Google Scholar 

  32. Sun Y, Mulkern RV, Schmidt K, Doshi S, Albert MS, Schmidt NO, Ziu M, Black P, Carrol R, Kieran MW (2004) Quantification of water diffusion and relaxation times of human U87 tumors in a mouse model. NMR Biomed 17: 399–404

    Article  PubMed  Google Scholar 

  33. Lu S, Ahn D, Johnson G, Cha S (2003) Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors. AJNR Am J Neuroradiol 24: 937–941

    PubMed  Google Scholar 

  34. García-Martín ML, Herigault G, Rémy C, Farion R, Ballesteros P, Coles JA, Cerdán S, Ziegler A (2001) Mapping extracellular pH in rat brain gliomas in vivo by 1H magnetic resonance spectroscopic imaging: comparison with maps of metabolites. Cancer Res 61: 6524–6531

    PubMed  Google Scholar 

  35. Rémy C, Arús C, Ziegler A, Lai ES, Moreno A, Le Fur Y, Decorps M (1994) In vivo, ex vivo, and in vitro one- and two-dimensional nuclear magnetic resonance spectroscopy of an intracerebral glioma in rat brain: assignment of resonances. J Neurochem 62: 166–179

    Article  PubMed  Google Scholar 

  36. Barba I, Cabañas ME, Arús C (1999) The relationship between nuclear magnetic resonance-visible lipids, lipid droplets, and cell proliferation in cultured C6 cells. Cancer Res 59: 1861–1868

    PubMed  CAS  Google Scholar 

  37. Rémy C, Fouilhe N, Barba I, Sam-Lai E, Lahrech H, Cucurella MG, Izquierdo M, Moreno A, Ziegler A, Massarelli R, Decorps M, Arús C (1997) Evidence that mobile lipids detected in rat brain glioma by 1H nuclear magnetic resonance correspond to lipid droplets. Cancer Res 57: 407–414

    PubMed  Google Scholar 

  38. Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, Waltham M, Pergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24: 227–235

    Article  PubMed  CAS  Google Scholar 

  39. Diekman C, Simões RV, Pohman R, Cerdán S, Arús C (2006) Proton chemical shift imaging of mouse brain tumors at 7T. Bruker SpinReport. 2006; 157:18–21 http://www.bruker-biospin.com/spin_report.html

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Grup d’Aplicacions Biomèdiques de la Ressonància Magnètica Nuclear (GABRMN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain

    R. V. Simões & C. Arús

  2. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès, Spain

    R. V. Simões & C. Arús

  3. Centro de Neurociências e Biologia Celular de Coimbra (CNC), Universidade de Coimbra, Coimbra, Portugal

    R. V. Simões

  4. Centre d’Oncologia Molecular, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), CSUB, Barcelona, Spain

    A. Martinez-Aranda, B. Martín & A. Sierra

  5. Departamento de Modelos experimentales de enfermedades humanas, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Madrid, Spain

    S. Cerdán

Authors
  1. R. V. Simões
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Martinez-Aranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Cerdán
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Sierra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Arús
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. V. Simões.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simões, R.V., Martinez-Aranda, A., Martín, B. et al. Preliminary characterization of an experimental breast cancer cells brain metastasis mouse model by MRI/MRS. Magn Reson Mater Phy 21, 237–249 (2008). https://doi.org/10.1007/s10334-008-0114-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10334-008-0114-6

Keywords

Search

Navigation