Skip to main content
SpringerLink
Log in

Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Pancreatic cancer is one of the deadliest human malignancies and lack of effective diagnostic and therapeutic methods. Accumulating evidence suggests that the neurotensin (NT) and neurotensin receptors (NTRs) play key roles in pancreatic adenocarcinoma growth and survival. In this study, we not only evaluate the NTR1 expression in pancreatic cancer patient samples, but also explore the PET and fluorescence imaging of NTR1 expression in pancreatic cancer animal models. The NTR1 expression was evaluated by immunohistochemistry staining in clinical patient tissue samples with pancreatic ductal adenocarcinoma, insulinoma, and pancreatitis. The results showed 79.4% positive rate of NRT1 expression in pancreatic ductal adenocarcinoma, compared with 33.3 and 22.7% in insulinoma and pancreatitis samples, respectively. High NTR1 gene expression was also found in Panc-1 cells and confirmed by cell immunofluorescence. 64Cu-AmBaSar-NT and IRDye800-NT were synthesized as imaging probes and maintained the majority of NTR1-binding affinity. In vivo imaging demonstrated that 64Cu-AmBaSar-NT has prominent tumor uptake (3.76 ± 1.45 and 2.29 ± 0.10%ID/g at 1 and 4 h post-injection). NIR fluorescent imaging with IRDye800-NT demonstrated good tumor-to-background contrast (8.09 ± 0.38 × 108 and 6.67 ± 0.43 × 108 (p/s/cm2/sr)/(μW/cm2) at 30 and 60 min post-injection). Fluorescence guided surgery was also performed as a proof of principle experiment. In summary, our results indicated that NTR1 is a promising target for pancreatic ductal adenocarcinoma imaging and therapy. The imaging probes reported here may not only be considered for improved diagnosis of pancreatic ductal adenocarcinoma, but also has the potential to be fully integrated into patient screening and treatment monitoring of future NTR1 targeted 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
Fig. 6

Similar content being viewed by others

References

  • Alshoukr F et al (2011) Novel DOTA-neurotensin analogues for 111In scintigraphy and 68Ga PET imaging of neurotensin receptor-positive tumors. Bioconjug Chem 22:1374–1385. doi:10.1021/bc200078p

    Article  CAS  PubMed  Google Scholar 

  • Beer AJ, Kessler H, Wester H-J, Schwaiger M (2011) PET imaging of integrin αVβ3 expression. Theranostics 1:48–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchegger F et al (2003) Radiolabeled neurotensin analog, 99mTc-NT-XI, evaluated in ductal pancreatic adenocarcinoma patients. J Nucl Med 44:1649–1654

    CAS  PubMed  Google Scholar 

  • Chakraborty S, Baine MJ, Sasson AR, Batra SK (2011) Current status of molecular markers for early detection of sporadic pancreatic cancer. Biochim Biophys Acta (BBA) Rev Cancer 1815:44–64

    Article  CAS  Google Scholar 

  • Chen K, Li Z-B, Wang H, Cai W, Chen X (2008) Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots. Eur J Nucl Med Mol Imaging 35:2235–2244

    Article  CAS  PubMed  Google Scholar 

  • Deng H, Wang H, Wang M, Li Z, Wu Z (2015) Synthesis and evaluation of 64Cu-DOTA-NT-Cy5.5 as a dual-modality PET/fluorescence probe to image neurotensin receptor-positive tumor. Mol Pharm 12:3054–3061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng H et al (2016) The synthesis and evaluation of 64Cu-DOTA-NT, 64Cu-NOTA-NT and 64Cu-AmBaSar-NT for PET imaging of neurotensin receptor in prostate cancer. J Nucl Med 57(suppl):1067

    Google Scholar 

  • Ehlers RA et al (2000) Gut peptide receptor expression in human pancreatic cancers. Ann Surg 231:838–848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evers BM, Ishizuka J, Chung DH, Townsend CM, Thompson JC (1992) Neurotensin expression and release in human colon cancers. Ann Surg 216:423–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamada S, Shimosegawa T (2011) Biomarkers of pancreatic cancer. Pancreatology 11:14–19

    Article  CAS  PubMed  Google Scholar 

  • Herranz M, Ruibal A (2012) Optical imaging in breast cancer diagnosis: the next evolution. J Oncol 2012:10

    Article  Google Scholar 

  • Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617

    Article  CAS  PubMed  Google Scholar 

  • Jennings LE, Long NJ (2009) ‘Two is better than one’—probes for dual-modality molecular imaging. Chem Commun, 3511–3524

  • Kapuscinski M, Shulkes A, Read D, Hardy KJ (1990) Expression of neurotensin in endocrine tumors. J Clin Endocrinol Metab 70:100–106

    Article  CAS  PubMed  Google Scholar 

  • Körner M, Waser B, Strobel O, Büchler M, Reubi JC (2015) Neurotensin receptors in pancreatic ductal carcinomas. EJNMMI Res 5:17

    Article  PubMed  PubMed Central  Google Scholar 

  • Kruttika B, Fengfei W, Qingyong M, Qinyu L, Sanku M, Tze-chen H, Erxi W (2012) Advances in biomarker research for pancreatic cancer. Curr Pharm Des 18:2439–2451

    Article  Google Scholar 

  • Kulinska-Niedziela I, Paluszak J (1997) Neurotensin—structure, origin and biological function. Postępy Higieny i Medycyny Doświadczalnej 51:329–342

    CAS  PubMed  Google Scholar 

  • Kulkarni H, Schuchardt C, Wiessalla S, Smerling C, Reineke U, Osterkamp F, Baum R (2015) Radiopeptide therapy using Lu-177 3BP-227 in a patient with pancreatic adenocarcinoma. J Nucl Med 56(suppl):1235

    Google Scholar 

  • Lamerz R (1999) Role of tumour markers, cytogenetics. Ann Oncol 10:S145–S149

    Article  Google Scholar 

  • Liu S et al (2012) The efficient synthesis and biological evaluation of novel bi-functionalized sarcophagine for 64Cu radiopharmaceuticals. Theranostics 2:589–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S et al (2013) Lewis acid-assisted isotopic 18F–19F exchange in BODIPY dyes: facile generation of positron emission tomography/fluorescence dual modality agents for tumor imaging. Theranostics 3:181–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maschauer S, Einsiedel J, Hübner H, Gmeiner P, Prante O (2016) 18F- and 68Ga-labeled neurotensin peptides for PET imaging of neurotensin receptor 1. J Med Chem 59:6480–6492

    Article  CAS  PubMed  Google Scholar 

  • Mijatovic T, Gailly P, Mathieu V, De Nève N, Yeaton P, Kiss R, Decaestecker C (2007) Neurotensin is a versatile modulator of in vitro human pancreatic ductal adenocarcinoma cell (PDAC) migration. Cell Oncol 29:315–326

    CAS  PubMed  PubMed Central  Google Scholar 

  • Na Y et al (2015) Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model. J Control Release 220, Part B:766–782

    Article  Google Scholar 

  • Naghibalhossaini F, Yoder AD, Tobi M, Stanners CP (2007) Evolution of a tumorigenic property conferred by glycophosphatidyl-inositol membrane anchors of carcinoembryonic antigen gene family members during the primate radiation. Mol Biol Cell 18:1366–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olszewski U, Hamilton G (2009) Neurotensin signaling induces intracellular alkalinization and interleukin-8 expression in human pancreatic cancer cells. Mol Oncol 3:204–213

    Article  CAS  PubMed  Google Scholar 

  • Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921

    Article  CAS  PubMed  Google Scholar 

  • Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R (2010) Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol 24:349–358

    Article  PubMed  Google Scholar 

  • Reubi JC, Waser B, Friess H, Büchler M, Laissue J (1998) Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma. Gut 42:546–550. doi:10.1136/gut.42.4.546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reubi JC, Waser B, Schaer J-C, Laissue JA (1999) Neurotensin receptors in human neoplasms: high incidence in Ewing’s sarcomas. Int J Cancer 82:213–218

    Article  CAS  PubMed  Google Scholar 

  • Schlyer D (2004) PET tracers and radiochemistry. Ann Acad Med Singapore 33:146–154

    CAS  PubMed  Google Scholar 

  • Schulz J et al (2016) Comparative evaluation of the biodistribution profiles of a series of nonpeptidic neurotensin receptor-1 antagonists reveals a promising candidate for theranostic applications. J Nucl Med 57:1120–1123

    Article  PubMed  Google Scholar 

  • Sehgal I, Powers S, Huntley B, Powis G, Pittelkow M, Maihle NJ (1994) Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer. Proc Natl Acad Sci USA 91:4673–4677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seibold U et al (2014) Bimodal imaging probes for combined PET and OI: recent developments and future directions for hybrid agent development. Biomed Res Int 2014:13

    Article  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29

    Article  PubMed  Google Scholar 

  • Tsavaris N et al (2009) CEA and CA-19.9 serum tumor markers as prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis. J Chemother 21:673–680

    Article  CAS  PubMed  Google Scholar 

  • Valerie NCK, Casarez EV, DaSilva JO, Dunlap-Brown ME, Parsons SJ, Amorino GP, Dziegielewski J (2011) Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation. Cancer Res 71:6817

    Article  CAS  PubMed  Google Scholar 

  • Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet (London, England) 378:607–620

    Article  Google Scholar 

  • Wang L et al (2000a) Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease. Clin Cancer Res 6:566–571

    CAS  PubMed  Google Scholar 

  • Wang L et al (2000b) Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease. Clin Cancer Res 6:566

    CAS  PubMed  Google Scholar 

  • Wang Q, Zhou Y, Evers BM (2006) Neurotensin phosphorylates GSK-3α/β through the activation of PKC in human colon cancer cells. Neoplasia (New York, NY) 8:781–787

    Article  CAS  Google Scholar 

  • Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH (2013) Recent progress in pancreatic cancer. CA Cancer J Clin 63:318–348

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu Z et al (2014) Facile preparation of a thiol-reactive 18F-labeling agent and synthesis of 18F-DEG-VS-NT for PET imaging of a neurotensin receptor-positive tumor. J Nucl Med 55:1178–1184

    Article  CAS  PubMed  Google Scholar 

  • Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA (2016) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30:355–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by UNC Lineberger Comprehensive Cancer Center (pilot fund to Wu), Radiology Department and BRIC, P30-CA016086-35-37 from the National Cancer Institute, and the National Natural Science Foundation of China (NSFC) (Grant No. 81471689). We would also like to acknowledge Dr. Jen Jen Yeh at UNC for proof reading and editing the manuscript.

Author information

Author notes

  1. Xiaoqin Yin and Mengzhe Wang contributed equally.

Authors and Affiliations

  1. PET Center of Xiangya Hospital, Central South University, Changsha, China

    Xiaoqin Yin, Tingting He, Yue Tan, Zehua Zhu & Shuo Hu

  2. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Mengzhe Wang, Hui Wang, Huaifu Deng, Zhanhong Wu & Zibo Li

Authors
  1. Xiaoqin Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mengzhe Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huaifu Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tingting He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yue Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zehua Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhanhong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shuo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zibo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shuo Hu or Zibo Li.

Ethics declarations

Conflict of interest

The authors declare that no conflicts of interest were disclosed.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. 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. Human subjects were recruited from the Pathology Department of Xiangya Hospital of Central South University from April 2010 to October 2015. All tissues were fully anonymized and de-identification before they were accessed for this study. Informed consent was obtained from all individual participants included in the study.

Informed consent

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

Additional information

Handling Editor: T. Harkany.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, X., Wang, M., Wang, H. et al. Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma. Amino Acids 49, 1325–1335 (2017). https://doi.org/10.1007/s00726-017-2430-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-017-2430-5

Keywords

Search

Navigation