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Multimodal Genetic Approach for Molecular Imaging of Vasculature in a Mouse Model of Melanoma

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Abstract

Purpose

In this study, we evaluated a genetic approach for in vivo multimodal molecular imaging of vasculature in a mouse model of melanoma.

Procedures

We used a novel transgenic mouse, Ts-Biotag, that genetically biotinylates vascular endothelial cells. After inoculating these mice with B16 melanoma cells, we selectively targeted endothelial cells with (strept)avidinated contrast agents to achieve multimodal contrast enhancement of Tie2-expressing blood vessels during tumor progression.

Results

This genetic targeting system provided selective labeling of tumor vasculature and showed in vivo binding of avidinated probes with high specificity and sensitivity using microscopy, near infrared, ultrasound, and magnetic resonance imaging. We further demonstrated the feasibility of conducting longitudinal three-dimensional (3D) targeted imaging studies to dynamically assess changes in vascular Tie2 from early to advanced tumor stages.

Conclusions

Our results validated the Ts-Biotag mouse as a multimodal targeted imaging system with the potential to provide spatio-temporal information about dynamic changes in vasculature during tumor progression.

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References

  1. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J (1971) Tumor angiogenesis: therapeutic implications. New Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  3. Hlatky L, Hahnfeldt P, Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J Natl Cancer Instit 94:883–893

    Article  Google Scholar 

  4. Angst E, Chen M, Mojadidi M et al (2010) Bioluminescence imaging of angiogenesis in a murine orthotopic pancreatic cancer model. Mol Imaging Biol 12:570–575

    Article  PubMed  PubMed Central  Google Scholar 

  5. De Leon-Rodriguez LM, Lubag A, Udugamasooriya DG et al (2010) MRI detection of VEGFR2 in vivo using a low molecular weight peptoid-(Gd)8-dendron for targeting. J Am Chem Soc 132:12829–12831

    Article  PubMed  PubMed Central  Google Scholar 

  6. Deshpande N, Pysz MA, Willmann JK (2010) Molecular ultrasound assessment of tumor angiogenesis. Angiogenesis 13:175–188

    Article  PubMed  PubMed Central  Google Scholar 

  7. Deshpande N, Ren Y, Foygel K et al (2011) Tumor angiogenic marker expression levels during tumor growth: longitudinal assessment with molecularly targeted microbubbles and US imaging. Radiology 258:804–811

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lee DJ, Lyshchik A, Huamani J et al (2008) Relationship between retention of a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted ultrasonographic contrast agent and the level of VEGFR2 expression in an in vivo breast cancer model. J Ultrasound Med 27:855–866

    Article  PubMed  Google Scholar 

  9. Willmann JK, Lutz AM, Paulmurugan R et al (2008) Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo. Radiology 248:936–944

    Article  PubMed  PubMed Central  Google Scholar 

  10. Willmann JK, Paulmurugan R, Chen K et al (2008) US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice. Radiology 246:508–518

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ellegala DB, Leong-Poi H, Carpenter JE et al (2003) Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3. Circulation 108:336–341

    Article  PubMed  Google Scholar 

  12. Hsu AR, Hou LC, Veeravagu A et al (2006) In vivo near-infrared fluorescence imaging of integrin alphavbeta3 in an orthotopic glioblastoma model. Mol Imaging Biol 8:315–323

    Article  PubMed  Google Scholar 

  13. Jarzyna PA, Deddens LH, Kann BH et al (2012) Tumor angiogenesis phenotyping by nanoparticle-facilitated magnetic resonance and near-infrared fluorescence molecular imaging. Neoplasia 14:964–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pan D, Pramanik M, Senpan A et al (2011) Molecular photoacoustic imaging of angiogenesis with integrin-targeted gold nanobeacons. FASEB J 25:875–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schmieder AH, Winter PM, Caruthers SD et al (2005) Molecular MR imaging of melanoma angiogenesis with alphanubeta3-targeted paramagnetic nanoparticles. Magn Reson Med 53:621–627

    Article  CAS  PubMed  Google Scholar 

  16. van Tilborg GA, Mulder WJ, van der Schaft DW et al (2008) Improved magnetic resonance molecular imaging of tumor angiogenesis by avidin-induced clearance of nonbound bimodal liposomes. Neoplasia 10:1459–1469

    Article  PubMed  PubMed Central  Google Scholar 

  17. Winter PM, Caruthers SD, Allen JS et al (2010) Molecular imaging of angiogenic therapy in peripheral vascular disease with alphanubeta3-integrin-targeted nanoparticles. Magn Reson Med 64:369–376

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Schnall M, Rosen M (2006) Primer on imaging technologies for cancer. J Clin Oncol 24:3225–3233

    Article  CAS  PubMed  Google Scholar 

  19. Condeelis J, Weissleder R (2010) In vivo imaging in cancer. Cold Spring Harb Perspect Biol 2:a003848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Weissleder R (2002) Scaling down imaging: molecular mapping of cancer in mice. Nat Rev Cancer 2:11–18

    Article  CAS  PubMed  Google Scholar 

  21. Weissleder R (2006) Molecular imaging in cancer. Science 312:1168–1171

    Article  CAS  PubMed  Google Scholar 

  22. Choyke P (2011) Science to practice: angiogenic marker expression during tumor growth—can targeted US microbubbles help monitor molecular changes in the microvasculature? Radiology 258:655–656

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fraser ST, Hadjantonakis AK, Sahr KE et al (2005) Using a histone yellow fluorescent protein fusion for tagging and tracking endothelial cells in ES cells and mice. Genesis 42:162–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Larina IV, Shen W, Kelly OG et al (2009) A membrane associated mCherry fluorescent reporter line for studying vascular remodeling and cardiac function during murine embryonic development. Anat Rec (Hoboken) 292:333–341

    Article  Google Scholar 

  25. Motoike T, Loughna S, Perens E et al (2000) Universal GFP reporter for the study of vascular development. Genesis 28:75–81

    Article  CAS  PubMed  Google Scholar 

  26. Schlaeger TM, Bartunkova S, Lawitts JA et al (1997) Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice. Proc Natl Acad Sci U S A 94:3058–3063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bartelle BB, Berrios-Otero CA, Rodriguez JJ et al (2012) Novel genetic approach for in vivo vascular imaging in mice. Circ Res 110:938–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dhenain M, Ruffins SW, Jacobs RE (2001) Three-dimensional digital mouse atlas using high-resolution MRI. Dev Biol 232:458–470

    Article  CAS  PubMed  Google Scholar 

  29. Deans AE, Wadghiri YZ, Berrios-Otero CA, Turnbull DH (2008) Mn enhancement and respiratory gating for in utero MRI of the embryonic mouse central nervous system. Magn Reson Med 59:1320–1328

    Article  PubMed  PubMed Central  Google Scholar 

  30. Szulc KU, Nieman BJ, Houston EJ et al (2013) MRI analysis of cerebellar and vestibular developmental phenotypes in Gbx2 conditional knockout mice. Magn Reson Med 70:1707–1717

    Article  PubMed  Google Scholar 

  31. McDonald DM, Choyke PL (2003) Imaging of angiogenesis: from microscope to clinic. Nat Med 9:713–725

    Article  CAS  PubMed  Google Scholar 

  32. Turkbey B, Kobayashi H, Ogawa M et al (2009) Imaging of tumor angiogenesis: functional or targeted? AJR Am J Roentgenol 193:304–313

    Article  PubMed  PubMed Central  Google Scholar 

  33. Laitinen OH, Nordlund HR, Hytonen VP, Kulomaa MS (2007) Brave new (strept)avidins in biotechnology. Trends Biotechnol 25:269–277

    Article  CAS  PubMed  Google Scholar 

  34. Eisenbrey JR, Sridharan A, Machado P et al (2012) Three-dimensional subharmonic ultrasound imaging in vitro and in vivo. Acad Radiol 19:732–739

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wang H, Hristov D, Qin J et al (2015) Three-dimensional dynamic contrast-enhanced US imaging for early antiangiogenic treatment assessment in a mouse colon cancer model. Radiology 277:424–434

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang H, Kaneko OF, Tian L et al (2015) Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer. Investig Radiol 50:322–329

    Article  CAS  Google Scholar 

  37. Zhou J, Wang H, Zhang H et al (2016) VEGFR2-targeted three-dimensional ultrasound imaging can predict responses to anti-angiogenic therapy in preclinical models of colon cancer. Cancer Res. doi:10.1158/0008-5472.CAN-15-3271

    Google Scholar 

  38. De Palma M, Naldini L (2011) Angiopoietin-2 TIEs up macrophages in tumor angiogenesis. Clin Cancer Res 17:5226–5232

    Article  PubMed  Google Scholar 

  39. Fukuhara S, Sako K, Noda K et al (2009) Tie2 is tied at the cell-cell contacts and to extracellular matrix by angiopoietin-1. Exp Mol Med 41:133–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fukuhara S, Sako K, Noda K et al (2010) Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis. Histol Histopathol 25:387–396

    CAS  PubMed  Google Scholar 

  41. Shimoda H (2009) Immunohistochemical demonstration of angiopoietin-2 in lymphatic vascular development. Histochem Cell Biol 131:231–238

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by NIH grant R01HL078665 (to DHT). The authors thank Dr. Michelle Krogsgaard (NYU School of Medicine, NYUSoM) for providing the B16 melanoma cells and Dr. Eva Hernando (NYUSoM) for scientific guidance. We thank the Preclinical Imaging Core (NYUSoM) for help with the in vivo imaging and the Histopathology Core (NYUSoM) for help with the histology and IHC analyses. Finally, we thank Daniel Colon and Kristy Mungal for technical assistance with segmentation and volumetric analysis.

Author information

Author notes

  1. Benjamin B. Bartelle

    Present address: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

Authors and Affiliations

  1. Skirball Institute of Biomolecular Medicine, New York University School of Medicine (NYUSoM), 540 First Ave, New York, NY, 10016, USA

    Giselle A. Suero-Abreu, Orlando Aristizábal, Benjamin B. Bartelle, Eugenia Volkova, Joe J. Rodríguez & Daniel H. Turnbull

  2. Biomedical Imaging Graduate Program, NYUSoM, New York, NY, USA

    Giselle A. Suero-Abreu & Daniel H. Turnbull

  3. Department of Radiology, NYUSoM, New York, NY, USA

    Giselle A. Suero-Abreu & Daniel H. Turnbull

  4. Department of Pathology, NYUSoM, New York, NY, USA

    Daniel H. Turnbull

Authors
  1. Giselle A. Suero-Abreu
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  2. Orlando Aristizábal
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  3. Benjamin B. Bartelle
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  4. Eugenia Volkova
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  5. Joe J. Rodríguez
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  6. Daniel H. Turnbull
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Corresponding author

Correspondence to Daniel H. Turnbull.

Ethics declarations

All mice used in this study were maintained under protocols approved by the Institutional Animal Care and Use Committee at New York University School of Medicine.

Conflict of interest

The authors declare that they have no conflict of interest.

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Suero-Abreu, G.A., Aristizábal, O., Bartelle, B.B. et al. Multimodal Genetic Approach for Molecular Imaging of Vasculature in a Mouse Model of Melanoma. Mol Imaging Biol 19, 203–214 (2017). https://doi.org/10.1007/s11307-016-1006-1

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  • DOI: https://doi.org/10.1007/s11307-016-1006-1

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