Skip to main content

Advertisement

SpringerLink
Log in

Positron emission tomography imaging of CD105 expression during tumor angiogenesis

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel density (MVD) assessed by CD105 staining is the current gold standard for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging CD105 expression.

Methods

TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 64Cu. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 64Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control.

Results

FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. 64Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, respectively (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with 64Cu-DOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of 64Cu-DOTA-TRC105.

Conclusion

This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was observed. Further studies are warranted and currently underway.

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

Similar content being viewed by others

References

  1. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438:932–6.

    Article  PubMed  CAS  Google Scholar 

  2. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.

    Article  PubMed  CAS  Google Scholar 

  3. Cai W, Chen X. Multimodality imaging of vascular endothelial growth factor and vascular endothelial growth factor receptor expression. Front Biosci 2007;12:4267–79.

    Article  PubMed  CAS  Google Scholar 

  4. Cai W, Niu G, Chen X. Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 2008;14:2943–73.

    Article  PubMed  CAS  Google Scholar 

  5. Dijkgraaf I, Boerman OC. Radionuclide imaging of tumor angiogenesis. Cancer Biother Radiopharm 2009;24:637–47.

    Article  PubMed  CAS  Google Scholar 

  6. Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem 1999;274:584–94.

    Article  PubMed  CAS  Google Scholar 

  7. Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 1990;265:8361–4.

    PubMed  CAS  Google Scholar 

  8. Fonsatti E, Del Vecchio L, Altomonte M, Sigalotti L, Nicotra MR, Coral S, et al. Endoglin: an accessory component of the TGF-beta-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies. J Cell Physiol 2001;188:1–7.

    Article  PubMed  CAS  Google Scholar 

  9. Wang JM, Kumar S, Pye D, van Agthoven AJ, Krupinski J, Hunter RD. A monoclonal antibody detects heterogeneity in vascular endothelium of tumours and normal tissues. Int J Cancer 1993;54:363–70.

    Article  PubMed  CAS  Google Scholar 

  10. Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW, et al. Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1995;1:1623–34.

    PubMed  CAS  Google Scholar 

  11. Fonsatti E, Jekunen AP, Kairemo KJ, Coral S, Snellman M, Nicotra MR, et al. Endoglin is a suitable target for efficient imaging of solid tumors: in vivo evidence in a canine mammary carcinoma model. Clin Cancer Res 2000;6:2037–43.

    PubMed  CAS  Google Scholar 

  12. Wikström P, Lissbrant IF, Stattin P, Egevad L, Bergh A. Endoglin (CD105) is expressed on immature blood vessels and is a marker for survival in prostate cancer. Prostate 2002;51:268–75.

    Article  PubMed  Google Scholar 

  13. Dallas NA, Samuel S, Xia L, Fan F, Gray MJ, Lim SJ, et al. Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clin Cancer Res 2008;14:1931–7.

    Article  PubMed  CAS  Google Scholar 

  14. Kumar S, Ghellal A, Li C, Byrne G, Haboubi N, Wang JM, et al. Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res 1999;59:856–61.

    PubMed  CAS  Google Scholar 

  15. Fonsatti E, Nicolay HJ, Altomonte M, Covre A, Maio M. Targeting cancer vasculature via endoglin/CD105: a novel antibody-based diagnostic and therapeutic strategy in solid tumours. Cardiovasc Res 2010;86:12–9.

    PubMed  CAS  Google Scholar 

  16. Cai W, Rao J, Gambhir SS, Chen X. How molecular imaging is speeding up antiangiogenic drug development. Mol Cancer Ther 2006;5:2624–33.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang D, Feng XY, Henning TD, Wen L, Lu WY, Pan H, et al. MR imaging of tumor angiogenesis using sterically stabilized Gd-DTPA liposomes targeted to CD105. Eur J Radiol 2009;70:180–9.

    Article  PubMed  Google Scholar 

  18. Bredow S, Lewin M, Hofmann B, Marecos E, Weissleder R. Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin. Eur J Cancer 2000;36:675–81.

    Article  PubMed  CAS  Google Scholar 

  19. Costello B, Li C, Duff S, Butterworth D, Khan A, Perkins M, et al. Perfusion of 99mTc-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target. Int J Cancer 2004;109:436–41.

    Article  PubMed  CAS  Google Scholar 

  20. Korpanty G, Carbon JG, Grayburn PA, Fleming JB, Brekken RA. Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature. Clin Cancer Res 2007;13:323–30.

    Article  PubMed  CAS  Google Scholar 

  21. Korpanty G, Grayburn PA, Shohet RV, Brekken RA. Targeting vascular endothelium with avidin microbubbles. Ultrasound Med Biol 2005;31:1279–83.

    Article  PubMed  Google Scholar 

  22. Cui S, Lü SZ, Chen YD, He GX, Liu JP, Song ZY, et al. Relationship between intravascular ultrasound imaging features of coronary plaques and soluble CD105 level in patients with coronary heart disease. Chin Med J (Engl) 2007;120:595–7.

    Google Scholar 

  23. Lee SY, Hong YD, Felipe PM, Pyun MS, Choi SJ. Radiolabeling of monoclonal anti-CD105 with (177)Lu for potential use in radioimmunotherapy. Appl Radiat Isot 2009;67:1366–9.

    Article  PubMed  CAS  Google Scholar 

  24. Tsujie M, Tsujie T, Toi H, Uneda S, Shiozaki K, Tsai H, et al. Anti-tumor activity of an anti-endoglin monoclonal antibody is enhanced in immunocompetent mice. Int J Cancer 2008;122:2266–73.

    Article  PubMed  CAS  Google Scholar 

  25. She X, Matsuno F, Harada N, Tsai H, Seon BK. Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-beta in suppression of growth of human endothelial cells. Int J Cancer 2004;108:251–7.

    Article  PubMed  CAS  Google Scholar 

  26. Tsujie M, Uneda S, Tsai H, Seon BK. Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: differences in growth rate and therapeutic response between tumors growing at different sites. Int J Oncol 2006;29:1087–94.

    PubMed  CAS  Google Scholar 

  27. Mendelson DS, Gordon MS, Rosen LS, Hurwitz H, Wong MK, Adams BJ, et al. Phase I study of TRC105 (anti-CD105 [endoglin] antibody) therapy in patients with advanced refractory cancer. J Clin Oncol 2010;28:15s.

    Google Scholar 

  28. Wang H, Cai W, Chen K, Li ZB, Kashefi A, He L, et al. A new PET tracer specific for vascular endothelial growth factor receptor 2. Eur J Nucl Med Mol Imaging 2007;34:2001–10.

    Article  PubMed  CAS  Google Scholar 

  29. Cai W, Chen K, He L, Cao Q, Koong A, Chen X. Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody. Eur J Nucl Med Mol Imaging 2007;34:850–8.

    Article  PubMed  CAS  Google Scholar 

  30. Cai W, Wu Y, Chen K, Cao Q, Tice DA, Chen X. In vitro and in vivo characterization of 64Cu-labeled Abegrin™, a humanized monoclonal antibody against integrin αvβ3. Cancer Res 2006;66:9673–81.

    Article  PubMed  CAS  Google Scholar 

  31. Takahashi N, Haba A, Matsuno F, Seon BK. Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res 2001;61:7846–54.

    PubMed  CAS  Google Scholar 

  32. Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS, Rosenblum MG, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006;47:2048–56.

    PubMed  CAS  Google Scholar 

  33. Cai W, Ebrahimnejad A, Chen K, Cao Q, Li ZB, Tice DA, et al. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging 2007;34:2024–36.

    Article  PubMed  CAS  Google Scholar 

  34. Duff SE, Li C, Garland JM, Kumar S. CD105 is important for angiogenesis: evidence and potential applications. FASEB J 2003;17:984–92.

    Article  PubMed  CAS  Google Scholar 

  35. Fonsatti E, Sigalotti L, Arslan P, Altomonte M, Maio M. Emerging role of endoglin (CD105) as a marker of angiogenesis with clinical potential in human malignancies. Curr Cancer Drug Targets 2003;3:427–32.

    Article  PubMed  CAS  Google Scholar 

  36. Matsuno F, Haruta Y, Kondo M, Tsai H, Barcos M, Seon BK. Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies. Clin Cancer Res 1999;5:371–82.

    PubMed  CAS  Google Scholar 

  37. Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease. Chem Rev 2010;110:2858–902.

    Article  PubMed  CAS  Google Scholar 

  38. Völkel T, Hölig P, Merdan T, Müller R, Kontermann RE. Targeting of immunoliposomes to endothelial cells using a single-chain Fv fragment directed against human endoglin (CD105). Biochim Biophys Acta 2004;1663:158–66.

    Article  PubMed  Google Scholar 

  39. Müller D, Trunk G, Sichelstiel A, Zettlitz KA, Quintanilla M, Kontermann RE. Murine endoglin-specific single-chain Fv fragments for the analysis of vascular targeting strategies in mice. J Immunol Methods 2008;339:90–8.

    Article  PubMed  Google Scholar 

  40. Nettelbeck DM, Miller DW, Jérôme V, Zuzarte M, Watkins SJ, Hawkins RE, et al. Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105). Mol Ther 2001;3:882–91.

    Article  PubMed  CAS  Google Scholar 

  41. Korn T, Müller R, Kontermann RE. Bispecific single-chain diabody-mediated killing of endoglin-positive endothelial cells by cytotoxic T lymphocytes. J Immunother 2004;27:99–106.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported, in part, by the Wisconsin Partnership Program, the University of Wisconsin Carbone Cancer Center, NCRR 1UL1RR025011, a Susan G. Komen Postdoctoral Fellowship (to H. Hong), and a DOD PCRP IDEA Award.

Conflicts of interest

BRL is an employee of TRACON Pharmaceuticals, Inc. The other authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Wisconsin - Madison, Madison, WI, USA

    Hao Hong, Yunan Yang & Weibo Cai

  2. Department of Medical Physics, University of Wisconsin - Madison, Madison, WI, USA

    Yin Zhang, Jonathan W. Engle, Todd E. Barnhart, Robert J. Nickles & Weibo Cai

  3. TRACON Pharmaceuticals, Inc., San Diego, CA, USA

    Bryan R. Leigh

  4. University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    Weibo Cai

  5. Department of Ultrasound, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People’s Republic of China

    Yunan Yang

  6. Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin - Madison, 1111 Highland Ave, Room 7137, Madison, WI, 53705–2275, USA

    Weibo Cai

Authors
  1. Hao Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan W. Engle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Todd E. Barnhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert J. Nickles
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bryan R. Leigh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weibo Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weibo Cai.

Additional information

Hao Hong, Yunan Yang, and Yin Zhang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, H., Yang, Y., Zhang, Y. et al. Positron emission tomography imaging of CD105 expression during tumor angiogenesis. Eur J Nucl Med Mol Imaging 38, 1335–1343 (2011). https://doi.org/10.1007/s00259-011-1765-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-011-1765-5

Keywords

Search

Navigation