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Inter-heterogeneity and intra-heterogeneity of αvβ3 in non-small cell lung cancer and small cell lung cancer patients as revealed by 68Ga-RGD2 PET imaging

  • Fei Kang
  • Zhe Wang
  • Guoquan Li
  • Shengjun Wang
  • Daliang Liu
  • Mingru Zhang
  • Mingxuan Zhao
  • Weidong YangEmail author
  • Jing WangEmail author
Original Article

Abstract

Purpose

Integrin αvβ3 is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare αvβ3 levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer 68Ga-labeled dimerized-RGD (68Ga-RGD2).

Methods

Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using 68Ga-RGD2.18F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker αvβ3 in NSCLC and SCLC lesions was analyzed by immunohistochemistry.

Results

The 18F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The 68Ga-RGD2 uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of 68Ga-RGD2 SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that αvβ3 integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression.

Conclusions

The uptake of 68Ga-RGD2 in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower αvβ3 target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of αvβ3 also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of αvβ3 may potentially improve current applications of αvβ3-targeted therapy and diagnostic imaging in lung cancer.

Keywords

Small cell lung cancer Non-small cell lung cancer Integrin αvβ3 Cilengitide 68Ga-labeled dimerized-RGD 

Notes

Acknowledgements

We would like to thank Prof. Xiaoyuan Chen, Prof. Wei Zhang, Prof. Li Fan and Prof. Jing Ye for their generous support and Fan Guo, Chao Wang, Xiaowei Ma, Zhiyong Quan, Guiyu Li, Jin Zeng, Zhiping Yang, Xiaohu Zhao and Mei Yang for their technical assistance.

Compliance with ethical standards

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81401442, 81230033, 81227901, 81371594, 81572252), the Post-doctoral Science Foundation of China (Grant No. 2015M582802) and the National Key Research and Development Program of China (Grant No. 2016YFC0103804).

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

259_2017_3696_MOESM1_ESM.docx (1.4 mb)
ESM 1 (DOCX 1469 kb)

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011;378:1741–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, et al. Non-small cell lung cancer, version 6.2015. Natl Compr Canc Netw. 2015;13:515–24.CrossRefGoogle Scholar
  4. 4.
    Howlader N, Noone A, Krapcho M, Miller D, K. Bishop, Altekruse SF, et al. SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.
  5. 5.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Boger C, Kalthoff H, Goodman SL, Behrens HM, Rocken C. Integrins and their ligands are expressed in non-small cell lung cancer but not correlated with parameters of disease progression. Virchows Arch. 2014;464:69–78.CrossRefPubMedGoogle Scholar
  7. 7.
    Liu Z, Jia B, Shi J, Jin X, Zhao H, Li F, et al. Tumor uptake of the RGD dimeric probe (99m)Tc-G3-2P4-RGD2 is correlated with integrin alphavbeta3 expressed on both tumor cells and neovasculature. Bioconjug Chem. 2010;21:548–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F. Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J. 1999;18:882–92.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV. Integrin signaling is critical for pathological angiogenesis. J Exp Med. 2006;203:2495–507.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Robinson SD, Hodivala-Dilke KM. The role of beta3-integrins in tumor angiogenesis: context is everything. Curr Opin Cell Biol. 2011;23:630–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Smith JW. Cilengitide Merck. Curr Opin Investig Drugs. 2003;4:741–5.PubMedGoogle Scholar
  12. 12.
    Manegold C, Vansteenkiste J, Cardenal F, Schuette W, Woll PJ, Ulsperger E, et al. Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer. Investig New Drugs. 2013;31:175–82.CrossRefGoogle Scholar
  13. 13.
    Vansteenkiste J, Barlesi F, Waller CF, Bennouna J, Gridelli C, Goekkurt E, et al. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO). Ann Oncol. 2015;26:1734–40.CrossRefPubMedGoogle Scholar
  14. 14.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.CrossRefPubMedGoogle Scholar
  15. 15.
    Roviello G, Generali D. Is there a place for bevacizumab in patients with extensive-stage small cell lung cancer? Curr Cancer Drug Targets. 2016;16:209–14.CrossRefPubMedGoogle Scholar
  16. 16.
    Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–34.CrossRefPubMedGoogle Scholar
  17. 17.
    Lu X, Wang RF. A concise review of current radiopharmaceuticals in tumor angiogenesis imaging. Curr Pharm Des. 2012;18:1032–40.CrossRefPubMedGoogle Scholar
  18. 18.
    Chen H, Niu G, Wu H, Chen X. Clinical application of radiolabeled RGD peptides for PET imaging of integrin alphavbeta3. Theranostics. 2016;6:78–92.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Guo J, Guo N, Lang L, Kiesewetter DO, Xie Q, Li Q, et al. (18)F-alfatide II and (18)F-FDG dual-tracer dynamic PET for parametric, early prediction of tumor response to therapy. J Nucl Med. 2014;55:154–60.CrossRefPubMedGoogle Scholar
  20. 20.
    Kang F, Wang S, Tian F, Zhao M, Zhang M, Wang Z, et al. Comparing the diagnostic potential of 68Ga-Alfatide II and 18F-FDG in differentiating between non-small cell lung cancer and tuberculosis. J Nucl Med. 2016;57:672–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med. 2006;47:885–95.PubMedGoogle Scholar
  22. 22.
    Kang F, Ma W, Ma X, Shao Y, Yang W, Chen X, et al. Propranolol inhibits glucose metabolism and 18F-FDG uptake of breast cancer through posttranscriptional downregulation of hexokinase-2. J Nucl Med. 2014;55:439–45.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zheng K, Liang N, Zhang J, Lang L, Zhang W, Li S, et al. 68Ga-NOTA-PRGD2 PET/CT for integrin imaging in patients with lung cancer. J Nucl Med. 2015;56:1823–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Minamimoto R, Jamali M, Barkhodari A, Mosci C, Mittra E, Shen B, et al. Biodistribution of the (1)(8)F-FPPRGD(2) PET radiopharmaceutical in cancer patients: an atlas of SUV measurements. Eur J Nucl Med Mol Imaging. 2015;42:1850–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Gao S, Wu H, Li W, Zhao S, Teng X, Lu H, et al. A pilot study imaging integrin alphavbeta3 with RGD PET/CT in suspected lung cancer patients. Eur J Nucl Med Mol Imaging. 2015;42:2029–37.CrossRefPubMedGoogle Scholar
  26. 26.
    Iagaru A, Mosci C, Mittra E, Zaharchuk G, Fischbein N, Harsh G, et al. Glioblastoma Multiforme recurrence: an exploratory study of (18)F FPPRGD2 PET/CT. Radiology. 2015;277:497–506.CrossRefPubMedGoogle Scholar
  27. 27.
    Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008;26:5610–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1100–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Chinot OL. Cilengitide in glioblastoma: when did it fail? Lancet Oncol. 2014;15:1044–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15:392–400.CrossRefPubMedGoogle Scholar
  31. 31.
    Minamimoto R, Karam A, Jamali M, Barkhodari A, Gambhir SS, Dorigo O, et al. Pilot prospective evaluation of (18)F-FPPRGD2 PET/CT in patients with cervical and ovarian cancer. Eur J Nucl Med Mol Imaging. 2016;43:1047–55.CrossRefPubMedGoogle Scholar
  32. 32.
    Iagaru A, Mosci C, Shen B, Chin FT, Mittra E, Telli ML, et al. (18)F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. Radiology. 2014;273:549–59.CrossRefPubMedGoogle Scholar
  33. 33.
    Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2:e70.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med. 2008;49:879–86.CrossRefPubMedGoogle Scholar
  35. 35.
    Bach-Gansmo T, Danielsson R, Saracco A, Wilczek B, Bogsrud TV, Fangberget A, et al. Integrin receptor imaging of breast cancer: a proof-of-concept study to evaluate 99mTc-NC100692. J Nucl Med. 2006;47:1434–9.PubMedGoogle Scholar
  36. 36.
    Zhu Z, Miao W, Li Q, Dai H, Ma Q, Wang F, et al. 99mTc-3PRGD2 for integrin receptor imaging of lung cancer: a multicenter study. J Nucl Med. 2012;53:716–22.CrossRefPubMedGoogle Scholar
  37. 37.
    Kim JH, Lee JS, Kang KW, Lee H-Y, Han S-W, Kim T-Y, et al. Whole-body distribution and radiation dosimetry of 68Ga-NOTA-RGD, a positron emission tomography agent for angiogenesis imaging. Cancer Biother Radiophar. 2012;27:65–71.CrossRefGoogle Scholar
  38. 38.
    Mittra ES, Goris ML, Iagaru AH, Kardan A, Burton L, Berganos R, et al. Pilot pharmacokinetic and dosimetric studies of 18F-FPPRGD2: a PET radiopharmaceutical agent for imaging αvβ3 integrin levels. Radiology. 2011;260:182–91.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Fei Kang
    • 1
  • Zhe Wang
    • 1
    • 2
  • Guoquan Li
    • 1
  • Shengjun Wang
    • 1
  • Daliang Liu
    • 1
  • Mingru Zhang
    • 1
  • Mingxuan Zhao
    • 1
  • Weidong Yang
    • 1
    Email author
  • Jing Wang
    • 1
    Email author
  1. 1.Department of Nuclear Medicine, Xijing HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  2. 2.Department of Pathology, Xijing HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China

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