Skip to main content

Advertisement

SpringerLink
Log in

Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and dynamic contrast enhanced MRI

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

Abstract

Pharmacological approaches to treat breast cancer metastases in the brain have been met with limited success. In part, the impermeability of the blood brain barrier (BBB) has hindered delivery of chemotherapeutic agents to metastatic tumors in the brain. BBB-permeable chemotherapeutic drugs are being developed, and noninvasively assessing the efficacy of these agents will be important in both preclinical and clinical settings. In this regard, dynamic contrast enhanced (DCE) and diffusion weighted imaging (DWI) are magnetic resonance imaging (MRI) techniques to monitor tumor vascular permeability and cellularity, respectively. In a rat model of metastatic breast cancer, we demonstrate that brain and bone metastases develop with distinct physiological characteristics as measured with MRI. Specifically, brain metastases have limited permeability of the BBB as assessed with DCE and an increased apparent diffusion coefficient (ADC) measured with DWI compared to the surrounding brain. Microscopically, brain metastases were highly infiltrative, grew through vessel co-option, and caused extensive edema and injury to the surrounding neurons and their dendrites. By comparison, metastases situated in the leptomenengies or in the bone had high vascular permeability and significantly lower ADC values suggestive of hypercellularity. On histological examination, tumors in the bone and leptomenengies were solid masses with distinct tumor margins. The different characteristics of these tissue sites highlight the influence of the microenvironment on metastatic tumor growth. In light of these results, the suitability of DWI and DCE to evaluate the response of chemotherapeutic and anti-angiogenic agents used to treat co-opted brain metastases, respectively, remains a formidable challenge.

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. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ADC:

Apparent diffusion coefficient

BBB:

Blood brain barrier

CNS:

Central nervous system

DCE:

Dynamic contrast enhanced

DWI:

Diffusion weighted imaging

IAUGC:

Initial area under the gadolinium curve

MRI:

Magnetic resonance imaging

MAP2:

Microtubule associated protein 2

RECIST:

Response evaluation criteria in solid tumors (RECIST)

ROI:

Region of interest

References

  1. Tkaczuk KH (2009) Review of the contemporary cytotoxic and biologic combinations available for the treatment of metastatic breast cancer. Clin Ther 31(Pt 2):2273–2289

    Article  PubMed  Google Scholar 

  2. Gril B et al (2010) Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies. Eur J Cancer 46(7):1204–1210

    Article  PubMed  CAS  Google Scholar 

  3. Steeg PS, Theodorescu D (2008) Metastasis: a therapeutic target for cancer. Nat Clin Pract 5(4):206–219

    Article  CAS  Google Scholar 

  4. Weil RJ et al (2005) Breast cancer metastasis to the central nervous system. Am J Pathol 167(4):913–920

    Article  PubMed  CAS  Google Scholar 

  5. Nicolson GL (1988) Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7(2):143–188

    Article  PubMed  CAS  Google Scholar 

  6. Palmieri D et al (2007) The biology of metastasis to a sanctuary site. Clin Cancer Res 13(6):1656–1662

    Article  PubMed  CAS  Google Scholar 

  7. Carbonell WS et al (2009) The vascular basement membrane as “soil” in brain metastasis. PLoS One 4(6):e5857

    Article  PubMed  Google Scholar 

  8. Kienast Y et al (2010) Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16(1):116–122

    Article  PubMed  CAS  Google Scholar 

  9. Lockman PR et al (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16(23):5664–5678

    Article  PubMed  CAS  Google Scholar 

  10. Thomas FC et al (2009) Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res 26(11):2486–2494

    Article  PubMed  CAS  Google Scholar 

  11. Leenders WP et al (2004) Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res 10(18 Pt 1):6222–6230

    Article  PubMed  CAS  Google Scholar 

  12. Lin NU et al (2008) Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26(12):1993–1999

    Article  PubMed  CAS  Google Scholar 

  13. Luu TH et al (2008) A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res 14(21):7138–7142

    Article  PubMed  CAS  Google Scholar 

  14. Trudeau ME et al (2006) Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada—Clinical Trials Group (NCIC-CTG). Ann Oncol 17(6):952–956

    Article  PubMed  CAS  Google Scholar 

  15. Morris PG, McArthur HL, Hudis CA (2009) Therapeutic options for metastatic breast cancer. Expert Opin Pharmacother 10(6):967–981

    Article  PubMed  CAS  Google Scholar 

  16. Marty M, Pivot X (2008) The potential of anti-vascular endothelial growth factor therapy in metastatic breast cancer: clinical experience with anti-angiogenic agents, focusing on bevacizumab. Eur J Cancer 44(7):912–920

    Article  PubMed  CAS  Google Scholar 

  17. Eisenhauer EA et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247

    Article  PubMed  CAS  Google Scholar 

  18. Moffat BA et al (2005) Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc Natl Acad Sci USA 102(15):5524–5529

    Article  PubMed  CAS  Google Scholar 

  19. Moffat BA et al (2006) The functional diffusion map: an imaging biomarker for the early prediction of cancer treatment outcome. Neoplasia 8(4):259–267

    Article  PubMed  CAS  Google Scholar 

  20. Barrett T et al (2007) MRI of tumor angiogenesis. J Magn Reson Imaging 26(2):235–249

    Article  PubMed  Google Scholar 

  21. Sargent DJ et al (2009) Validation of novel imaging methodologies for use as cancer clinical trial end-points. Eur J Cancer 45(2):290–299

    Article  PubMed  CAS  Google Scholar 

  22. Song HT et al (2009) Rat model of metastatic breast cancer monitored by MRI at 3 tesla and bioluminescence imaging with histological correlation. J Transl Med 7:88

    Article  PubMed  Google Scholar 

  23. Hasan KM, Parker DL, Alexander AL (2001) Comparison of gradient encoding schemes for diffusion-tensor MRI. J Magn Reson Imaging 13(5):769–780

    Article  PubMed  CAS  Google Scholar 

  24. Wang HZ, Riederer SJ, Lee JN (1987) Optimizing the precision in T1 relaxation estimation using limited flip angles. Magn Reson Med 5(5):399–416

    Article  PubMed  CAS  Google Scholar 

  25. Yankeelov TE, Gore JC (2009) Dynamic contrast enhanced magnetic resonance imaging in oncology: theory, data acquisition, analysis, and examples. Curr Med Imaging Rev 3(2):91–107

    Article  PubMed  Google Scholar 

  26. Parker GJ et al (1997) Probing tumor microvascularity by measurement, analysis and display of contrast agent uptake kinetics. J Magn Reson Imaging 7(3):564–574

    Article  PubMed  CAS  Google Scholar 

  27. Noebauer-Huhmann IM et al (2010) Gadolinium-based magnetic resonance contrast agents at 7 Tesla: in vitro T1 relaxivities in human blood plasma. Invest Radiol 45(9):554–558

    Article  PubMed  CAS  Google Scholar 

  28. Woods RP et al (1998) Automated image registration: II. Intersubject validation of linear and nonlinear models. J Comput Assist Tomogr 22(1):153–165

    Article  PubMed  CAS  Google Scholar 

  29. Hawkins BT, Egleton RD (2006) Fluorescence imaging of blood-brain barrier disruption. J Neurosci Methods 151(2):262–267

    Article  PubMed  CAS  Google Scholar 

  30. Bauerle T et al (2010) Drug-induced vessel remodeling in bone metastases as assessed by dynamic contrast enhanced magnetic resonance imaging and vessel size imaging: a longitudinal in vivo study. Clin Cancer Res 16(12):3215–3225

    Article  PubMed  Google Scholar 

  31. Bauerle T et al (2010) Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis. Eur J Radiol 73(2):280–287

    Article  PubMed  Google Scholar 

  32. Lee KC et al (2007) An imaging biomarker of early treatment response in prostate cancer that has metastasized to the bone. Cancer Res 67(8):3524–3528

    Article  PubMed  CAS  Google Scholar 

  33. Lee KC et al (2007) A feasibility study evaluating the functional diffusion map as a predictive imaging biomarker for detection of treatment response in a patient with metastatic prostate cancer to the bone. Neoplasia 9(12):1003–1011

    Article  PubMed  Google Scholar 

  34. Blasberg RG et al (1984) Local blood-to-tissue transport in Walker 256 metastatic brain tumors. J Neurooncol 2(3):205–218

    PubMed  CAS  Google Scholar 

  35. Zhang RD et al (1992) Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 141(5):1115–1124

    PubMed  CAS  Google Scholar 

  36. Duygulu G et al (2010) Intracerebral metastasis showing restricted diffusion: correlation with histopathologic findings. Eur J Radiol 74(1):117–120

    Article  PubMed  CAS  Google Scholar 

  37. Krabbe K et al (1997) MR diffusion imaging of human intracranial tumours. Neuroradiology 39(7):483–489

    Article  PubMed  CAS  Google Scholar 

  38. Yoneda T et al (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(8):1486–1495

    Article  PubMed  CAS  Google Scholar 

  39. Song HT et al. (2010) Quantitative T(2)* imaging of metastatic human breast cancer to brain in the nude rat at 3 T. NMR Biomed 24:325–334

    Google Scholar 

  40. Palmieri D et al (2007) Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67(9):4190–4198

    Article  PubMed  CAS  Google Scholar 

  41. Charles N, Holland EC (2010) The perivascular niche microenvironment in brain tumor progression. Cell Cycle 9(15):3012–3021

    Article  PubMed  CAS  Google Scholar 

  42. Fitzgerald DP et al (2008) Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis 25(7):799–810

    Article  PubMed  Google Scholar 

  43. Park JS, Bateman MC, Goldberg MP (1996) Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation. Neurobiol Dis 3(3):215–227

    Article  PubMed  CAS  Google Scholar 

  44. Rzeski W, Turski L, Ikonomidou C (2001) Glutamate antagonists limit tumor growth. Proc Natl Acad Sci USA 98(11):6372–6377

    Article  PubMed  CAS  Google Scholar 

  45. Takano T et al (2001) Glutamate release promotes growth of malignant gliomas. Nat Med 7(9):1010–1015

    Article  PubMed  CAS  Google Scholar 

  46. Seidlitz EP et al (2009) Cancer cell lines release glutamate into the extracellular environment. Clin Exp Metastasis 26(7):781–787

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  48. Brat DJ, Van Meir EG (2004) Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 84(4):397–405

    Article  PubMed  CAS  Google Scholar 

  49. Dome B et al (2007) Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am J Pathol 170(1):1–15

    Article  PubMed  CAS  Google Scholar 

  50. Indelicato M et al (2010) Role of hypoxia and autophagy in MDA-MB-231 invasiveness. J Cell Physiol 223(2):359–368

    PubMed  CAS  Google Scholar 

  51. Hayashida Y et al (2006) Diffusion-weighted imaging of metastatic brain tumors: comparison with histologic type and tumor cellularity. AJNR Am J Neuroradiol 27(7):1419–1425

    PubMed  CAS  Google Scholar 

  52. Sugahara T et al (1999) Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 9(1):53–60

    Article  PubMed  CAS  Google Scholar 

  53. Prasad SR et al (2003) Radiological measurement of breast cancer metastases to lung and liver: comparison between WHO (bidimensional) and RECIST (unidimensional) guidelines. J Comput Assist Tomogr 27(3):380–384

    Article  PubMed  Google Scholar 

  54. Shelton LM et al (2010) A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion. J Neurooncol 99(2):165–176

    Article  PubMed  CAS  Google Scholar 

  55. Heyn C et al (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(5):1001–1010

    Article  PubMed  Google Scholar 

  56. Leenders W et al (2003) Vascular endothelial growth factor-A determines detectability of experimental melanoma brain metastasis in GD-DTPA-enhanced MRI. Int J Cancer 105(4):437–443

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Intramural Research Program of the Clinical Center at the National Institutes of Health. We thank Molly Resnick for assistance with data analysis.

Author information

Authors and Affiliations

  1. Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Building 10, B1N256, Bethesda, MD, 20892, USA

    Matthew D. Budde, Eric Gold, E. Kay Jordan & Joseph A. Frank

  2. National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA

    Joseph A. Frank

Authors
  1. Matthew D. Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Kay Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph A. Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthew D. Budde.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Budde, M.D., Gold, E., Jordan, E.K. et al. Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and dynamic contrast enhanced MRI. Clin Exp Metastasis 29, 51–62 (2012). https://doi.org/10.1007/s10585-011-9428-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-011-9428-2

Keywords

Search

Navigation