Clinical & Experimental Metastasis

, Volume 26, Issue 5, pp 403–414 | Cite as

Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model

  • Juan JuanYin
  • Kirsten Tracy
  • Luhua Zhang
  • Jeeva Munasinghe
  • Erik Shapiro
  • Alan Koretsky
  • Kathleen Kelly
Research Paper


Brain metastasis has become an increasing cause of morbidity and mortality in cancer patients as the treatment of systemic disease has improved. Brain metastases frequently are highly vascularized, a process driven primarily by VEGF. VEGF mediates numerous changes within the vasculature including endothelial cell retraction and increased permeability, vasodilation, and new vessel formation. Here we describe a xenograft brain metastasis model that mimics the critical steps of metastasis including tumor cell dissemination and vascular adhesion, tumor growth and tumor associated angiogenesis. Magnetic resonance (MR) imaging was used to evaluate two aspects of the functional response of brain metastasis to the anti-VEGF receptor therapeutic, AZD2171 (Cediranib, RECENTIN™). MR tracking of individual cells demonstrated that cediranib did not impede tumor cell extravasation into the brain parenchyma despite evidence that anti-VEGF treatment decreases the permeability of the blood brain barrier. In a second assay, blood volume imaging using ultrasmall superparamagnetic iron oxide revealed that treatment of well-developed brain metastasis with cediranib for 7 days led to a heterogeneous response with respect to individual tumors. Overall, there was a significant average decrease in the tumor vascular bed volume. The majority of large tumors demonstrated substantially reduced central blood volumes relative to normal brain while retaining a rim of elevated blood volume at the tumor brain interface. Small tumors or occasional large tumors displayed a static response. Models and assays such as those described here will be important for designing mechanism-based approaches to the use of anti-angiogenesis therapies for the treatment of brain metastasis.


Animal model AZD2171/Cediranib Blood volume Brain metastasis MPIO MRI Prostate cancer USPIO 



JJY, KT, LZ, and KK acknowledge the support of the Intramural Research Program, Center for Cancer Research, NCI, and JM, ES, and AK acknowledge the support of the Intramural Research Program NINDS. RECENTIN™ is a trade mark of the AstraZeneca group of companies.


  1. 1.
    Fidler IJ, Yano S, Zhang RD et al (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3(1):53–57PubMedCrossRefGoogle Scholar
  2. 2.
    Posner JB (1992) Management of brain metastases. Rev Neurol (Paris) 148(6–7):477–487Google Scholar
  3. 3.
    Jain RK, di Tomaso E, Duda DG et al (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8(8):610–622PubMedCrossRefGoogle Scholar
  4. 4.
    Palmieri D, Chambers AF, Felding-Habermann B et al (2007) The biology of metastasis to a sanctuary site. Clin Cancer Res 13(6):1656–1662PubMedCrossRefGoogle Scholar
  5. 5.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572PubMedCrossRefGoogle Scholar
  6. 6.
    Lakka SS, Rao JS (2008) Antiangiogenic therapy in brain tumors. Expert Rev Neurother 8(10):1457–1473PubMedCrossRefGoogle Scholar
  7. 7.
    Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–591PubMedCrossRefGoogle Scholar
  8. 8.
    Johansson BB (1990) The physiology of the blood-brain barrier. Adv Exp Med Biol 274:25–39PubMedGoogle Scholar
  9. 9.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603PubMedCrossRefGoogle Scholar
  10. 10.
    Batchelor TT, Sorensen AG, di Tomaso E et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95PubMedCrossRefGoogle Scholar
  11. 11.
    Kim LS, Huang S, Lu W et al (2004) Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis 21(2):107–118PubMedCrossRefGoogle Scholar
  12. 12.
    Leenders WP, Kusters B, Verrijp K 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):6222–6230PubMedCrossRefGoogle Scholar
  13. 13.
    Yano S, Shinohara H, Herbst RS et al (2000) Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res 60(17):4959–4967PubMedGoogle Scholar
  14. 14.
    Price SJ (2007) The role of advanced MR imaging in understanding brain tumour pathology. Br J Neurosurg 21(6):562–575PubMedCrossRefGoogle Scholar
  15. 15.
    Claes A, Gambarota G, Hamans B et al (2008) Magnetic resonance imaging-based detection of glial brain tumors in mice after antiangiogenic treatment. Int J Cancer 122(9):1981–1986PubMedCrossRefGoogle Scholar
  16. 16.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62PubMedCrossRefGoogle Scholar
  17. 17.
    Neuwelt EA, Varallyay CG, Manninger S et al (2007) The potential of ferumoxytol nanoparticle magnetic resonance imaging, perfusion, and angiography in central nervous system malignancy: a pilot study. Neurosurgery 60(4):601–611 (discussion 611–612)PubMedCrossRefGoogle Scholar
  18. 18.
    Corot C, Robert P, Idee JM et al (2006) Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 58(14):1471–1504PubMedCrossRefGoogle Scholar
  19. 19.
    Harisinghani MG, Barentsz J, Hahn PF et al (2003) Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 348(25):2491–2499PubMedCrossRefGoogle Scholar
  20. 20.
    Yin J, Pollock C, Tracy K et al (2007) Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Mol Cell Biol 27(21):7538–7550PubMedCrossRefGoogle Scholar
  21. 21.
    Shapiro EM, Skrtic S, Koretsky AP (2005) Sizing it up: cellular MRI using micron-sized iron oxide particles. Magn Reson Med 53(2):329–338PubMedCrossRefGoogle Scholar
  22. 22.
    Shapiro EM, Skrtic S, Sharer K et al (2004) MRI detection of single particles for cellular imaging. Proc Natl Acad Sci USA 101(30):10901–10906PubMedCrossRefGoogle Scholar
  23. 23.
    Dobrogowska DH, Lossinsky AS, Tarnawski M et al (1998) Increased blood-brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J Neurocytol 27(3):163–173PubMedCrossRefGoogle Scholar
  24. 24.
    Weis S, Cui J, Barnes L et al (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167(2):223–229PubMedCrossRefGoogle Scholar
  25. 25.
    Shah RB, Mehra R, Chinnaiyan AM et al (2004) Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 64(24):9209–9216PubMedCrossRefGoogle Scholar
  26. 26.
    Weis S, Shintani S, Weber A et al (2004) Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest 113(6):885–894PubMedGoogle Scholar
  27. 27.
    Miles FL, Pruitt FL, van Golen KL et al (2008) Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis 25(4):305–324PubMedCrossRefGoogle Scholar
  28. 28.
    Lee TH, Avraham HK, Jiang S et al (2003) Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem 278(7):5277–5284PubMedCrossRefGoogle Scholar
  29. 29.
    Heyn C, Ronald JA, Ramadan SS 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):1001–1010PubMedCrossRefGoogle Scholar
  30. 30.
    Wedge SR, Kendrew J, Hennequin LF et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4400PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media BV 2009

Authors and Affiliations

  • Juan JuanYin
    • 1
  • Kirsten Tracy
    • 1
  • Luhua Zhang
    • 1
  • Jeeva Munasinghe
    • 3
  • Erik Shapiro
    • 2
  • Alan Koretsky
    • 2
  • Kathleen Kelly
    • 1
  1. 1.Cell and Cancer Biology Branch, Center for Cancer Research, NCICCR/NCI, NIHBethesdaUSA
  2. 2.Laboratory of Functional and Molecular ImagingNINDS, NIHBethesdaUSA
  3. 3.Mouse Imaging FacilityNINDS, NIHBethesdaUSA

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