Skip to main content
SpringerLink
Log in

Visualization of rodent brain tumor angiogenesis and effects of antiangiogenic treatment using 3D ΔR2-μMRA

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Understanding of structural and functional characteristics of the vascular microenvironment in gliomas and the impact of antiangiogenic treatments is essential for developing better therapeutic strategies. Although a number of methods exist in which this process can be studied experimentally, no single noninvasive test has the capacity to provide information concerning both microvascular function and morphology. The purpose of present study is to demonstrate the feasibility of using a novel three-dimensional ΔR2-based microscopic magnetic resonance angiography (3D ΔR2-μMRA) technique for longitudinal imaging of tumor angiogenesis and monitoring the effects of antiangiogenic treatment in rodent brain tumor models. Using 3D ΔR2-μMRA, a generally consistent early pattern of vascular development in gliomas was revealed, in which a single feeding vessel was visualized first (arteriogenesis), followed by sprouting angiogenesis. Considerable variability of the tumor-associated vasculature was then noted at later stages of tumor evolution. ΔR2-μMRA revealed that anti-vascular endothelial growth factor treatment induced a rapid and significant alteration of the intratumoral angiogenic phenotype. In summary, 3D ΔR2-μMRA enables high-resolution visualization of tumor-associated vessels while simultaneously providing functional information on the tumor microvasculature. It can serve as a useful tool for monitoring both the temporal evolution of tumor angiogenesis and the impact of antiangiogenic therapies.

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

Similar content being viewed by others

References

  1. Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G (2009) American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 27(36):6251–6266. doi:10.1200/JCO.2009.23.5622

    Article  PubMed  CAS  Google Scholar 

  2. Engstrom PF (2008) Systemic therapy for advanced or metastatic colorectal cancer: National Comprehensive Cancer Network guidelines for combining anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies with chemotherapy. Pharmacotherapy 28(11 Pt 2):18S–22S. doi:10.1592/phco.28.11-supp.18S

    Article  PubMed  CAS  Google Scholar 

  3. Bellmunt J, Calvo E, Castellano D, Climent MA, Esteban E, Garcia del Muro X, Gonzalez-Larriba JL, Maroto P, Trigo JM (2009) Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer. Cancer Chemother Pharmacol 63(Suppl 1):S1–S13. doi:10.1007/s00280-009-0955-3

    Article  PubMed  Google Scholar 

  4. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259. doi:10.1158/1078-0432.CCR-06-2309

    Article  PubMed  CAS  Google Scholar 

  5. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729. doi:10.1200/JCO.2007.12.2440

    Article  PubMed  CAS  Google Scholar 

  6. Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF (2006) MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66(8):1258–1260. doi:10.1212/01.wnl.0000208958.29600.87

    Article  PubMed  CAS  Google Scholar 

  7. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95. doi:10.1016/j.ccr.2006.11.021

    Article  PubMed  CAS  Google Scholar 

  8. Tateishi U, Kusumoto M, Nishihara H, Nagashima K, Morikawa T, Moriyama N (2002) Contrast-enhanced dynamic computed tomography for the evaluation of tumor angiogenesis in patients with lung carcinoma. Cancer 95(4):835–842. doi:10.1002/cncr.10730

    Article  PubMed  Google Scholar 

  9. Raatschen HJ, Fu Y, Brasch RC, Pietsch H, Shames DM, Yeh BM (2009) In vivo monitoring of angiogenesis inhibitory treatment effects by dynamic contrast-enhanced computed tomography in a xenograft tumor model. Invest Radiol 44(5):265–270. doi:10.1097/RLI.0b013e31819f1b60

    Article  PubMed  CAS  Google Scholar 

  10. Vakoc BJ, Lanning RM, Tyrrell JA, Padera TP, Bartlett LA, Stylianopoulos T, Munn LL, Tearney GJ, Fukumura D, Jain RK, Bouma BE (2009) Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat Med 15(10):1219–1223. doi:10.1038/nm.1971

    Article  PubMed  CAS  Google Scholar 

  11. van Vliet M, van Dijke CF, Wielopolski PA, ten Hagen TL, Veenland JF, Preda A, Loeve AJ, Eggermont AM, Krestin GP (2005) MR angiography of tumor-related vasculature: from the clinic to the micro-environment. Radiographics 25(Suppl 1):S85–S97; discussion S97–S88. doi:10.1148/rg.25si055512

    Google Scholar 

  12. Valable S, Lemasson B, Farion R, Beaumont M, Segebarth C, Remy C, Barbier EL (2008) Assessment of blood volume, vessel size, and the expression of angiogenic factors in two rat glioma models: a longitudinal in vivo and ex vivo study. NMR Biomed 21(10):1043–1056. doi:10.1002/nbm.1278

    Article  PubMed  CAS  Google Scholar 

  13. Lemasson B, Valable S, Farion R, Krainik A, Remy C, Barbier EL (2012) In vivo imaging of vessel diameter, size, and density: a comparative study between MRI and histology. Magn Reson Med. doi:10.1002/mrm.24218

    PubMed  Google Scholar 

  14. Peng SL, Chen CF, Liu HL, Lui CC, Huang YJ, Lee TH, Chang CC, Wang FN (2012) Analysis of parametric histogram from dynamic contrast-enhanced MRI: application in evaluating brain tumor response to radiotherapy. NMR Biomed. doi:10.1002/nbm.2882

    PubMed  Google Scholar 

  15. Coenegrachts K, Bols A, Haspeslagh M, Rigauts H (2012) Prediction and monitoring of treatment effect using T1-weighted dynamic contrast-enhanced magnetic resonance imaging in colorectal liver metastases: potential of whole tumour ROI and selective ROI analysis. Eur J Radiol. doi:10.1016/j.ejrad.2012.07.022

    PubMed  Google Scholar 

  16. Shih TT, Hou HA, Liu CY, Chen BB, Tang JL, Chen HY, Wei SY, Yao M, Huang SY, Chou WC, Hsu SC, Tsay W, Yu CW, Hsu CY, Tien HF, Yang PC (2009) Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival. Blood 113(14):3161–3167. doi:10.1182/blood-2008-08-173104

    Article  PubMed  CAS  Google Scholar 

  17. Bullitt E, Zeng D, Gerig G, Aylward S, Joshi S, Smith JK, Lin W, Ewend MG (2005) Vessel tortuosity and brain tumor malignancy: a blinded study. Acad Radiol 12(10):1232–1240. doi:10.1016/j.acra.2005.05.027

    Article  PubMed  Google Scholar 

  18. Nishimura S, Hirai T, Shigematsu Y, Kitajima M, Morioka M, Kai Y, Minoda R, Uetani H, Murakami R, Yamashita Y (2012) Evaluation of brain and head and neck tumors with 4D contrast-enhanced MR angiography at 3T. AJNR Am J Neuroradiol 33(3):445–448. doi:10.3174/ajnr.A2819

    Article  PubMed  CAS  Google Scholar 

  19. Zou Z, Ma L, Cheng L, Cai Y, Meng X (2008) Time-resolved contrast-enhanced MR angiography of intracranial lesions. J Magn Reson Imaging (JMRI) 27(4):692–699. doi:10.1002/jmri.21303

    Article  Google Scholar 

  20. Pipe JG (2001) Limits of time-of-flight magnetic resonance angiography. Top Magn Reson Imaging (TMRI) 12(3):163–174

    Article  CAS  Google Scholar 

  21. Lin CY, Lin MH, Cheung WM, Lin TN, Chen JH, Chang C (2009) In vivo cerebromicrovasculatural visualization using 3D DeltaR2-based microscopy of magnetic resonance angiography (3DDeltaR2-mMRA). NeuroImage 45(3):824–831. doi:10.1016/j.neuroimage.2008.12.030

    Article  PubMed  Google Scholar 

  22. Jang T, Litofsky NS, Smith TW, Ross AH, Recht LD (2004) Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis. Neurobiol Dis 15(3):544–552. doi:10.1016/j.nbd.2003.11.016

    Article  PubMed  CAS  Google Scholar 

  23. Lee CV, Liang WC, Dennis MS, Eigenbrot C, Sidhu SS, Fuh G (2004) High-affinity human antibodies from phage-displayed synthetic Fab libraries with a single framework scaffold. J Mol Biol 340(5):1073–1093. doi:10.1016/j.jmb.2004.05.051

    Article  PubMed  CAS  Google Scholar 

  24. Fuh G, Wu P, Liang WC, Ultsch M, Lee CV, Moffat B, Wiesmann C (2006) Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab. J Biol Chem 281(10):6625–6631. doi:10.1074/jbc.M507783200

    Article  PubMed  CAS  Google Scholar 

  25. Liang WC, Wu X, Peale FV, Lee CV, Meng YG, Gutierrez J, Fu L, Malik AK, Gerber HP, Ferrara N, Fuh G (2006) Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem 281(2):951–961. doi:10.1074/jbc.M508199200

    Article  PubMed  CAS  Google Scholar 

  26. Bagri A, Berry L, Gunter B, Singh M, Kasman I, Damico LA, Xiang H, Schmidt M, Fuh G, Hollister B, Rosen O, Plowman GD (2010) Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin Cancer Res 16(15):3887–3900. doi:10.1158/1078-0432.CCR-09-3100

    Article  PubMed  CAS  Google Scholar 

  27. Wu EX, Wong KK, Andrassy M, Tang H (2003) High-resolution in vivo CBV mapping with MRI in wild-type mice. Magn Reson Med 49(4):765–770. doi:10.1002/mrm.10425

    Article  PubMed  Google Scholar 

  28. Law M, Yang S, Babb JS, Knopp EA, Golfinos JG, Zagzag D, Johnson G (2004) Comparison of cerebral blood volume and vascular permeability from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade. Am J Neuroradiol (AJNR) 25(5):746–755

    Google Scholar 

  29. Law M, Yang S, Wang H, Babb JS, Johnson G, Cha S, Knopp EA, Zagzag D (2003) Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. Am J Neuroradiol (AJNR) 24(10):1989–1998

    Google Scholar 

  30. Shin JH, Lee HK, Kwun BD, Kim JS, Kang W, Choi CG, Suh DC (2002) Using relative cerebral blood flow and volume to evaluate the histopathologic grade of cerebral gliomas: preliminary results. Am J Roentgenol (AJR) 179(3):783–789

    Article  Google Scholar 

  31. Ludemann L, Grieger W, Wurm R, Budzisch M, Hamm B, Zimmer C (2001) Comparison of dynamic contrast-enhanced MRI with WHO tumor grading for gliomas. Eur Radiol 11(7):1231–1241

    Article  PubMed  CAS  Google Scholar 

  32. Siegal T, Rubinstein R, Tzuk-Shina T, Gomori JM (1997) Utility of relative cerebral blood volume mapping derived from perfusion magnetic resonance imaging in the routine follow up of brain tumors. J Neurosurg 86(1):22–27. doi:10.3171/jns.1997.86.1.0022

    Article  PubMed  CAS  Google Scholar 

  33. Sugahara T, Korogi Y, Tomiguchi S, Shigematsu Y, Ikushima I, Kira T, Liang L, Ushio Y, Takahashi M (2000) Posttherapeutic intraaxial brain tumor: the value of perfusion-sensitive contrast-enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue. Am J Neuroradiol (AJNR) 21(5):901–909

    CAS  Google Scholar 

  34. Cha S, Knopp EA, Johnson G, Litt A, Glass J, Gruber ML, Lu S, Zagzag D (2000) Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin. Am J Neuroradiol (AJNR) 21(5):881–890

    CAS  Google Scholar 

  35. Akella NS, Twieg DB, Mikkelsen T, Hochberg FH, Grossman S, Cloud GA, Nabors LB (2004) Assessment of brain tumor angiogenesis inhibitors using perfusion magnetic resonance imaging: quality and analysis results of a phase I trial. J Magn Reson Imaging (JMRI) 20(6):913–922. doi:10.1002/jmri.20202

    Article  Google Scholar 

  36. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. doi:10.1126/science.1104819

    Article  PubMed  CAS  Google Scholar 

  37. Constable RT, Anderson AW, Zhong J, Gore JC (1992) Factors influencing contrast in fast spin-echo MR imaging. Magn Reson Imaging 10(4):497–511

    Article  PubMed  CAS  Google Scholar 

  38. Constable RT, Gore JC (1992) The loss of small objects in variable TE imaging: implications for FSE, RARE, and EPI. Magn Reson Med 28(1):9–24

    Article  PubMed  CAS  Google Scholar 

  39. Busse RF, Hariharan H, Vu A, Brittain JH (2006) Fast spin echo sequences with very long echo trains: design of variable refocusing flip angle schedules and generation of clinical T2 contrast. Magn Reson Med 55(5):1030–1037. doi:10.1002/mrm.20863

    Article  PubMed  Google Scholar 

  40. Lebel RM, Wilman AH (2009) Time-efficient fast spin echo imaging at 4.7 T with low refocusing angles. Magn Reson Med 62(1):96–105. doi:10.1002/mrm.21999

    Article  PubMed  Google Scholar 

  41. Boxerman JL, Hamberg LM, Rosen BR, Weisskoff RM (1995) MR contrast due to intravascular magnetic susceptibility perturbations. Magn Reson Med 34(4):555–566

    Article  PubMed  CAS  Google Scholar 

  42. Buschmann I, Schaper W (1999) Arteriogenesis versus angiogenesis: two mechanisms of vessel growth. News Physiol Sci 14:121–125

    PubMed  Google Scholar 

  43. Heil M, Eitenmuller I, Schmitz-Rixen T, Schaper W (2006) Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 10(1):45–55

    Article  PubMed  CAS  Google Scholar 

  44. Jang T, Sathy B, Hsu YH, Merchant M, Recht B, Chang C, Recht L (2008) A distinct phenotypic change in gliomas at the time of magnetic resonance imaging detection. J Neurosurg 108(4):782–790. doi:10.3171/JNS/2008/108/4/0782

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Research Program for Genomic Medicine, National Science Council, Taiwan, Republic of China (Grant Number: NSC100-2319-B-001-003).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All animal procedures were approved by the Academia Sinica Institutional Animal Care and Utilization Committee, Taipei, Taiwan.

Author information

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, N123, 128 Sec. 2, Academia Road, Nankang, Taipei, 11529, Taiwan, ROC

    Chien-Yuan Lin, Tiing Yee Siow, Ming-Huang Lin, Yi-Hua Hsu, Yu-Yin Tung & Chen Chang

  2. Functional and Micro-magnetic Resonance Imaging Center, Academic Sinica, No. 128 Sec. 2, Academia Road, Nankang, Taipei, 11529, Taiwan, ROC

    Chien-Yuan Lin, Tiing Yee Siow, Ming-Huang Lin, Yi-Hua Hsu, Yu-Yin Tung & Chen Chang

  3. Far-eastern Memorial Hospital, No. 21, Sec. 2, Nanya South Road, Pan-Chiao District, New Taipei City, 22060, Taiwan, ROC

    Tiing Yee Siow

  4. Department of Neurology and Clinical Neurosciences, Stanford University School of Medicine, No. 875 Blake Wilbur Drive, Rm CC2221, Palo Alto, CA, 94305, USA

    Taichang Jang & Lawrence Recht

Authors
  1. Chien-Yuan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiing Yee Siow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming-Huang Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Hua Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-Yin Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taichang Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lawrence Recht
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chen Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lawrence Recht or Chen Chang.

Additional information

Chien-Yuan Lin and Tiing Yee Siow contributioned equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, CY., Siow, T.Y., Lin, MH. et al. Visualization of rodent brain tumor angiogenesis and effects of antiangiogenic treatment using 3D ΔR2-μMRA. Angiogenesis 16, 785–793 (2013). https://doi.org/10.1007/s10456-013-9355-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-013-9355-8

Keywords

Search

Navigation