Skip to main content
EJNMMI Research
Download PDF

Neurotensin receptors in pancreatic ductal carcinomas

EJNMMI Research volume 5, Article number: 17 (2015) Cite this article

Abstract

Background

The frequent expression of neurotensin receptors (NT-R) in primaries of pancreatic ductal carcinomas has triggered the development of radioactive neurotensin analogs for possible in vivo targeting of these tumors. However, the complete lack of information regarding NT-R in liver metastases of pancreatic cancer and pancreatic intraepithelial neoplasia (PanIN) makes an in vitro study of NT-R in these tissues indispensable.

Methods

Using in vitro receptor autoradiography with 125I-[Tyr3]-neurotensin, NT-R were investigated in 18 primaries and 23 liver metastases of pancreatic ductal carcinomas as well as in 19 PanIN lesions.

Results

We report here that 13 of 18 ductal carcinoma primaries and 14 of 23 liver metastases expressed NT-R. Moreover, none of the six PanIN 1B cases expressed NT-R, while two of six PanIN 2 and five of seven PanIN 3 expressed NT-R. Binding was fully displaced by the type 1 NT-R-selective antagonist SR48692, indicating that the NT-R in the tumors are of the type 1 NT-R subtype.

Conclusions

These in vitro data extend the currently available information on NT-R in invasive and non-invasive pancreatic ductal tumors. They suggest that type 1 NT-R may be a novel, specific marker of PanIN of higher degree. The high expression of NT-R in primaries and metastases of invasive cancer strongly support the need to develop radioactive neurotensin analogs for the diagnosis and therapy of this tumor type.

Background

Two decades ago, neurotensin receptors (NT-R) were found to be expressed in approximately 75% of primary pancreatic ductal adenocarcinomas by NT-R autoradiography [1]. The NT-R were present in high density in the tumor cells, while the non-neoplastic pancreatic ducts did not express NT-R [1]. This suggested for the first time the possibility to specifically target pancreatic tumor cells via NT-R [1]. These expression data were confirmed by Ehlers et al. showing an approximately 90% incidence of NT-R in pancreatic cancers by RT-PCR measurement [2]. Later on, several groups identified NT-R in various other cancer types [3-7]. The role and function of the NT-R in cancer has also been investigated in the past one to two decades [8,9]. It appears to be clear that NT-R (especially the type 1 NT-R (also named NTS1 [10])) mediate a proliferative action of neurotensin in pancreatic cancer and also in other tumors [9,11-14]. There is also strong evidence that the type 1 NT-R-selective antagonist SR48692 [15] can inhibit tumoral proliferation [12-14]. Therefore, the use of neurotensin analogs has been proposed as strategy for the antiproliferative treatment of pancreatic cancer [3,8,16,17].

On the other hand, these in vitro receptor expression data [1,2] also triggered the development of radioactive neurotensin analogs that could be used for the visualization and, eventually, targeted radiotherapy of pancreatic ductal adenocarcinoma and other tumors. The majority of the published compounds are radiolabeled NT-R agonists [18-24], but radiolabeled NT-R antagonists have recently appeared [25,26]. Proof of principle that pancreatic ductal carcinomas can be visualized in patients with radiolabeled NT-R agonists was provided in preliminary studies [27-29]. Indeed, it would be important to have a reliable non-invasive tool permitting to visualize the majority of pancreatic ductal carcinomas in patients. It would be equally important to be able to treat the patients that have a receptor-positive carcinoma by giving them a radiotherapeutic dose of the radiolabeled neurotensin; many of the patients diagnosed with pancreatic ductal carcinomas already have or will soon have metastatic disease. Most patients die due to systemic disease within a short period of time after resection [30].

A targeted therapy of pancreatic cancer would, however, make sense only if all tumor manifestations in a given patient, namely the primary and the metastases, express NT-R. Considering the frequent observation of tumor heterogeneity in cancer in general, in terms of both histopathological features and of biological parameters, it is not possible to simply extrapolate that NT-R-positive primary pancreatic ductal carcinomas will give rise to NT-R-positive metastases. Unfortunately, there are presently no experimental data indicating whether metastases of ductal pancreatic carcinomas express NT-R. This lack of information is due in part to the fact that these metastases are not operated and that metastasis material is hardly available for in vitro investigations. In the present study, we have been able to investigate a significant number of metastases of ductal pancreatic carcinomas, sometimes together with their primaries, using NT-R autoradiography. To complete the study, we have also investigated NT-R in non-invasive, intraductal neoplasia (PanIN) using the same methodology.

Methods

Tissues

Pancreatic ductal carcinoma samples were collected at the Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany, and at the Institute of Pathology, University of Bern, Bern, Switzerland. The number and types of tissues investigated are listed in Tables 1 and 2. All tissues were frozen in liquid nitrogen or in dry ice immediately after surgical resection and stored at −70°C. Informed consent was available for all patients. The study collection conformed to the ethical guidelines of both centers and was reviewed by the Institutional Review Boards of University Hospital Heidelberg and University of Bern.

Table 1 NT receptors in ductal pancreatic cancer primaries and liver metastases
Full size table
Table 2 Quantification of NT-R in PanIN 1B, 2, and 3 and in concomitant invasive pancreatic carcinoma
Full size table

NT-R autoradiography

Receptor autoradiography was performed on 20-μm-thick cryostat (Microm HM550, Thermo Fisher Scientific, Walldorf, Germany) sections of the tissue samples, mounted on microscopic slides and then stored at −20°C for at least 3 days to improve adhesion of the tissue to the slide. Sections were pre-incubated in 50 mM Tris–HCl pH 7.4 with 0.02% BSA for 3 times at 5 min at 20°C. Slides were then incubated in 50 mM Tris–HCl pH 7.4 containing 0.02% BSA, 1 mM o-phenantroline, 1 mM MgCl2 and 40,000 dpm/100 μl (corresponding to 90 pM) 125I-[Tyr 3]-Neurotensin (2,000 Ci/mmol; ANAWA, Wangen, Switzerland) for 1 h at room temperature. Additional sections were incubated in the presence of 100 nM non-radioactive neurotensin (Bachem, Bubendorf, Switzerland) to assess non-specific binding, as well as in the presence of 1,000 nM of the type 1 NT-R-selective analog SR48692 (Sanofi, Paris, France), for NT-R subtyping. After incubation, the slides were washed for 10 min at 4 °C in four consecutive baths containing 50 mM Tris–HCl pH 7.4 with 0.02% BSA. After a brief dip in buffer without BSA, the sections were dried under a stream of cold air and then exposed to Kodak (Rochester, NY, USA) films Biomax MR for 7 days at 4 °C. The autoradiograms were quantified using a computer-assisted image processing system (Analysis Imaging System, InterFocus, Mering, Germany). Tissue standards for iodinated compounds (Amersham, Aylesbury, UK) were used for this purpose [1,4].

Results and discussion

Table 1 summarizes the data of NT-R incidence and density in pancreatic ductal carcinoma patients. The results are divided into three groups, depending on the availability of the respective frozen tissue: (1) primaries only, (2) primary and liver metastasis of the same patient, and (3) metastases only. It can be seen that not only primaries do often express NT-R in high density but also the liver metastases. The overall incidences of NT-R expression are 73% (8 of 11 cases) in primaries and 63% (14 of 23 cases) in metastases. Interestingly, all NT-R-expressing tumors have a high receptor density, namely above 3,000 dpm/mg tissue. From the six patients of whom primary and metastasis are available, three have high NT-R expression in both primary and metastasis, two have high expression in the primary only, and one is receptor-negative in both. This latter case had chemotherapy (gemcitabine) prior to the surgical resection. It cannot, however, be concluded definitely that chemotherapy is responsible for the lack of NT-R, since another chemotherapy-treated patient (Table 1) had a high NT-R expression over 6,000 dpm/mg tissue in his tumor. As also stated in Table 1, we have also performed displacement experiments with incubation of the 125I-[Tyr3]-neurotensin radioligand in the presence of 1,000 nM of the cold type 1 NT-R-selective analog SR48692. In the tested cases listed in Table 1, radioligand binding could be completely displaced by SR48692 indicating the presence of the type 1 NT-R subtype in these tissues. Three tumors (No. 11, 26, 27) could not be tested for SR48692 due to lack of tissue. Figure 1 illustrates a case of a patient with high NT-R expression in both the primary and the liver metastasis. Here, the NT-R are densely and homogeneously distributed in both tumor manifestations. The adjacent normal pancreas and liver, respectively, are NT-R-negative.

Figure 1
figure 1

Expression of NT-R by in vitro receptor autoradiography. NT-R expressed in a ductal pancreatic carcinoma: primary (A-C) and liver metastasis (D-F). As negative control, a NT-R-negative liver metastasis is also shown (G-I). (A), (D), (G) Hematoxylin-eosin-stained sections showing tumor tissue (Tu) and the adjacent pancreas (P) or liver (L), respectively. Bars = 1 mm. (B), (E) Autoradiograms showing total binding of 125I-[Tyr3]-neurotensin. High density of NT-R is found in the tumors but not in the pancreas or liver. (H) Autoradiogram showing total binding of 125I-neurotensin. This metastasis lacks NT-R. (C), (F), (I) Autoradiograms showing non-specific binding of 125I-[Tyr3]-neurotensin (in the presence of 100 nM neurotensin).

Full size image

Table 2 shows samples of additional pancreatic ductal tumor patients with resected pancreatic tissue containing various stages of PanIN with or without the corresponding invasive ductal carcinoma. Here, there is a clear difference in NT-R expression depending on the PanIN stage: None of the six PanIN 1B cases expresses NT-R, and only two out of the six PanIN 2 cases express NT-R, whereas the majority of the PanIN 3 cases (five out of seven cases) express NT-R. Interesting is the observation that in the two latter NT-R-negative PanIN 3 patients, their corresponding invasive ductal carcinomas (and their PanIN 1B and 2 stages as well) are also NT-R-negative. In three other cases, we see the NT-R expressed in PanIN 3 stages as well as in invasive ductal carcinomas, while adjacent PanIN 1B and/or PanIN 2 stages in these patients are NT-R-negative. Figure 2 illustrates the NT-R status in various PanIN lesions.

Figure 2
figure 2

NT-R in vitro receptor autoradiography in PanIN. In vitro receptor autoradiography of NT-R in various PanIN, PanIN 1B (A-C), PanIN 2 (D-F), and PanIN 3 (G-I), and in invasive cancer (J-L). (A), (D), (G), (J) Hematoxylin-eosin-stained sections (bars = 0.1 mm), including insert of representative area at high magnification. (B), (E), (H), (K) Autoradiograms showing total binding of 125I-[Tyr3]-neurotensin. While the PanIN 1 case (B) is NT-R-negative, PanIN 2 (E), PanIN 3 (H), and invasive cancer (K) are NT-R-positive. (C), (F), (I), (L) Autoradiograms showing non-specific binding of 125I-[Tyr3]-neurotensin (in the presence of 100 nM neurotensin).

Full size image

As seen in Table 2, we have performed in the NT-R-expressing PanIN 2 and PanIN 3 and invasive ductal cancer cases displacement experiments with incubation of the 125I-[Tyr3]-neurotensin radioligand in presence of 1,000 nM of the cold type 1 NT-R-selective analog SR48692. In all cases, radioligand binding could be completely displaced by SR48692, reaching low binding levels corresponding to non-specific binding, similar to that identified in the presence of 100 nM cold neurotensin. This is illustrated in Figure 3 for a PanIN 3 lesion and an adenocarcinoma. This set of experiments indicates that the NT-R in these tissues are of the type 1 subtype.

Figure 3
figure 3

Autoradiography of NT-R and competition by SR48692. NT-R autoradiography of PanIN 3 (A-D) and of an adenocarcinoma (E-H) with neurotensin and the type 1 NT-R-selective SR48692 as displacer. (A), (E) Hematoxylin-eosin-stained sections (bars = 0.1 mm). (B), (F) Autoradiograms showing total binding of 125I-[Tyr3]-neurotensin. (C), (G) Autoradiograms showing non-specific binding (in the presence of 100 nM neurotensin). (D), (H) Autoradiograms showing full displacement of 125I-[Tyr3]-neurotensin binding in the presence of 1,000 nM SR48692. The detected NT-R are therefore the type 1 NT-R.

Full size image

This study confirms on the one hand that pancreatic ductal cancers frequently express a high density of NT-R, as reported previously [1,2]. However, it expands this information in two ways: (1) it clearly shows that liver metastases also frequently express NT-R in high amounts. It thus closes an information gap and has clinical significance: indeed, the current knowledge of a NT-R expression solely in primaries would not be sufficient to legitimate NT-R targeted diagnostic or therapeutic interventions, since many of ductal pancreatic patients have metastases at the time of diagnosis. (2) The study also provides novel information on NT-R expression in putative pancreatic cancer precursor lesions, namely PanIN. It suggests an increase in NT-R expression from PanIN 1B to PanIN 3, with PanIN 1B completely lacking NT-R, as it is the case for normal pancreatic ducts [1], while PanIN 3 frequently expresses NT-R in high amounts. It is further of interest that in cases with NT-R-expressing PanIN 3, accompanying primary carcinomas also express NT-R, in line with the concomitant expression of many other biologic markers in high-grade PanIN and invasive cancer. Therefore, NT-R, in particular the type 1 NT-R detected in this study, may be considered as a novel, specific marker of pancreatic intraepithelial neoplasia of higher degree.

These data may have potential clinical implications. Indeed, knowing that NT stimulates pancreatic tumor growth [11,13,14] and that the type 1 NT-R-selective antagonist SR48692 inhibits tumor cell proliferation [13], it could be speculated that type 1 NT-R antagonists may be used for treatment of pancreatic cancer primaries, but also of their liver metastases and, speculatively, of the putative cancer precursors, the NT-R-expressing PanIN 2 and 3.

The data may also have more immediate diagnostic and radiotherapeutic implications. There are several newly designed neurotensin analogs which can be labeled with radioactive compounds [18,20,21,23] and that can be used either for SPECT or for PET diagnostic evaluation. Preliminary clinical evaluation was performed with two of them, however, with limited success probably due to rapid degradation of the tracers [27,28]. Recently, in line with the observation that somatostatin and bombesin receptor antagonists may be advantageous for tumor radiotargeting [31-34], radiolabeled NT-R antagonists have been developed aimed at greater metabolic stability, less side effects than agonists, and increased tumor uptake compared with agonists [25,26,29]. Such radioactive neurotensin analogs may become useful as diagnostics for the visualization of primary pancreatic carcinoma and their metastases and therefore help to decide on the therapeutic strategy. These radiolabeled neurotensin analogs may also be used for targeted radiotherapy of primaries and metastases, in particular since the NT-R expression is often very high. Moreover, at the same time, the putative precursor lesions, the NT-R-expressing PanIN 2 and PanIN 3, may also be destroyed. The amount of NT-R expressed in all these lesions appears clearly high enough for such a clinical application.

Conclusions

These in vitro data extend the currently available information on NT-R in invasive and non-invasive pancreatic ductal tumors. They suggest that type 1 NT-R may be a novel, specific marker of PanIN of higher degree. The high expression of NT-R in primaries and metastases of invasive cancer strongly support the need to develop radioactive neurotensin analogs for the diagnosis and therapy of this tumor type.

References

  1. Reubi JC, Waser B, Friess H, Büchler MW, Laissue JA. Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma. Gut. 1998;42:546–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Ehlers RA, Kim S, Zhang Y, Ethridge RT, Murrilo C, Hellmich MR, et al. Gut peptide receptor expression in human pancreatic cancers. Ann Surg. 2000;231:838–48.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Carraway RE, Plona AM. Involvement of neurotensin in cancer growth: evidence, mechanisms and development of diagnostic tools. Peptides. 2006;27:2445–60.

    Article  CAS  PubMed  Google Scholar 

  4. Reubi JC, Waser B, Schaer JC, Laissue JA. Neurotensin receptors in human neoplasms: high incidence in Ewing sarcomas. Int J Cancer. 1999;82:213–8.

    Article  CAS  PubMed  Google Scholar 

  5. Gromova P, Rubin BP, Thys A, Erneux C, Vanderwinden JM. Neurotensin receptor 1 is expressed in gastrointestinal stromal tumors but not in interstitial cells of Cajal. PLoS One. 2011;6:e14710.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Alifano M, Souaze F, Dupouy S, Camilleri-Broet S, Younes M, Ahmed-Zaid SM, et al. Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin Cancer Res. 2010;16:4401–10.

    Article  CAS  PubMed  Google Scholar 

  7. Swift SL, Burns JE, Maitland NJ. Altered expression of neurotensin receptors is associated with the differentiation state of prostate cancer. Cancer Res. 2010;70:347–56.

    Article  CAS  PubMed  Google Scholar 

  8. Mustain WC, Rychahou PG, Evers BM. The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes. 2011;18:75–82.

    Article  CAS  PubMed  Google Scholar 

  9. Thomas RP, Hellmich MR, Townsend Jr CM, Evers BM. Role of gastrointestinal hormones in the proliferation of normal and neoplastic tissues. Endocr Rev. 2003;24:571–99.

    Article  CAS  PubMed  Google Scholar 

  10. Vincent JP, Mazella J, Kitabgi P. Neurotensin and neurotensin receptors. Trends Pharmacol Sci. 1999;20:302–9.

    Article  CAS  PubMed  Google Scholar 

  11. Olszewski U, Hamilton G. Neurotensin signaling induces intracellular alkalinization and interleukin-8 expression in human pancreatic cancer cells. Mol Oncol. 2009;3:204–13.

    Article  CAS  PubMed  Google Scholar 

  12. Moody TW, Chan DC, Mantey SA, Moreno P, Jensen RT. SR48692 inhibits non-small cell lung cancer proliferation in an EGF receptor-dependent manner. Life Sci. 2014;100:25–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Wang JG, Li NN, Li HN, Cui L, Wang P. Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1. Neuropeptides. 2011;45:151–6.

    Article  CAS  PubMed  Google Scholar 

  14. Guha S, Lunn JA, Santiskulvong C, Rozengurt E. Neurotensin stimulates protein kinase C-dependent mitogenic signaling in human pancreatic carcinoma cell line PANC-1. Cancer Res. 2003;63:2379–87.

    CAS  PubMed  Google Scholar 

  15. Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard J, Poncelet M, et al. Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor. Proc Natl Acad Sci U S A. 1993;90:65–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Evers BM. Neurotensin and growth of normal and neoplastic tissues. Peptides. 2006;27:2424–33.

    Article  PubMed  Google Scholar 

  17. Kitabgi P. Targeting neurotensin receptors with agonists and antagonists for therapeutic purposes. Curr Opin Drug Discov Devel. 2002;5:764–76.

    CAS  PubMed  Google Scholar 

  18. Bergmann R, Scheunemann M, Heichert C, Mäding P, Wittrisch H, Kretzschmar M, et al. Biodistribution and catabolism of 18 F-labeled neurotensin(8–13) analogs. Nucl Med Biol. 2002;29:61–72.

    Article  CAS  PubMed  Google Scholar 

  19. Alshoukr F, Prignon A, Brans L, Jallane A, Mendes S, Talbot JN, et al. Novel DOTA-neurotensin analogues for 111In scintigraphy and 68Ga PET imaging of neurotensin receptor-positive tumors. Bioconjug Chem. 2011;22:1374–85.

    Article  CAS  PubMed  Google Scholar 

  20. Garcia-Garayoa E, Blauenstein P, Blanc A, Maes V, Tourwe D, Schubiger PA. A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours. Eur J Nucl Med Mol Imaging. 2009;36:37–47.

    Article  CAS  PubMed  Google Scholar 

  21. Sparr C, Purkayastha N, Yoshinari T, Seebach D, Maschauer S, Prante O, et al. Syntheses, receptor bindings, in vitro and in vivo stabilities and biodistributions of DOTA-neurotensin(8–13) derivatives containing beta-amino acid residues - a lesson about the importance of animal experiments. Chem Biodivers. 2013;10:2101–21.

    Article  CAS  PubMed  Google Scholar 

  22. Wu Z, Li L, Liu S, Yakushijin F, Yakushijin K, Horne D, et al. Facile preparation of a thiol-reactive 18 F-labeling agent and synthesis of 18 F-DEG-VS-NT for PET imaging of a neurotensin receptor-positive tumor. J Nucl Med. 2014;55:1178–84.

    Article  CAS  PubMed  Google Scholar 

  23. Nock BA, Nikolopoulou A, Reubi JC, Maes V, Conrath P, Tourwe D, et al. Toward stable N(4)-modified neurotensins for NTS1-receptor-targeted tumor imaging with (99 m)Tc. J Med Chem. 2006;49:4767–76.

    Article  CAS  PubMed  Google Scholar 

  24. De Visser M, Janssen PJ, Srinivasan A, Reubi JC, Waser B, Erion JL, et al. Stabilised (111)In-labelled DTPA- and DOTA-conjugated neurotensin analogues for imaging and therapy of exocrine pancreatic cancer. Eur J Nucl Med Mol Imaging. 2003;30:1134–9.

    Article  PubMed  Google Scholar 

  25. Lang C, Maschauer S, Hubner H, Gmeiner P, Prante O. Synthesis and evaluation of a (18)F-labeled diarylpyrazole glycoconjugate for the imaging of NTS1-positive tumors. J Med Chem. 2013;56:9361–5.

    Article  CAS  PubMed  Google Scholar 

  26. Amthauer H, Stiebler M, Goldschmidt J, Pethe A, Schulz J, Rohracker M, et al. Neurotensin receptor 1-targeted radionuclide therapy of HT29 xenografts: a randomized treatment study with Lu-177-labeled 3BP-227. Eur J Nucl Med Mol Imaging. 2014;41:S317. PW002.

    Google Scholar 

  27. Buchegger F, Bonvin F, Kosinski M, Schaffland AO, Prior J, Reubi JC, et al. Radiolabeled neurotensin analog, (99 m)Tc-NT-XI, evaluated in ductal pancreatic adenocarcinoma patients. J Nucl Med. 2003;44:1649–54.

    CAS  PubMed  Google Scholar 

  28. Gabriel M, Decristoforo C, Woll E, Eisterer W, Nock B, Maina T, et al. 99mTc]demotensin VI: biodistribution and initial clinical results in tumor patients of a pilot/phase I study. Cancer Biother Radiopharm. 2011;26:557–63.

    Article  CAS  PubMed  Google Scholar 

  29. Schuchardt C, Kulkarni HR, Smerling C, Osterkamp F, Haase C, Reineke U, et al. First dosimetric results with Lu-177 3BP-227 in a patient with pancreatic cancer. Eur J Nucl Med Mol Imaging. 2014;41:S332. PW049.

    Google Scholar 

  30. Hartwig W, Werner J, Jager D, Debus J, Buchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14:e476–85.

    Article  PubMed  Google Scholar 

  31. Cescato R, Maina T, Nock B, Nikolopoulou A, Charalambidis D, Piccand V, et al. Bombesin receptor antagonists may be preferable to agonists for tumor targeting. J Nucl Med. 2008;49:318–26.

    Article  CAS  PubMed  Google Scholar 

  32. Ginj M, Zhang H, Waser B, Cescato R, Wild D, Wang X, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103:16436–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Wild D, Fani M, Fischer R, Del Pozzo L, Kaul F, Krebs S, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med. 2014;55:1248–52.

    Article  CAS  PubMed  Google Scholar 

  34. Wieser G, Mansi R, Grosu AL, Schultze-Seemann W, Dumont-Walter RA, Meyer PT, et al. Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide receptor antagonist–from mice to men. Theranostics. 2014;4:412–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, PO Box 62, Murtenstrasse 31, CH-3010, Berne, Switzerland

    Meike Körner, Beatrice Waser & Jean Claude Reubi

  2. Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany

    Oliver Strobel & Markus Büchler

Authors
  1. Meike Körner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beatrice Waser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oliver Strobel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Markus Büchler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean Claude Reubi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean Claude Reubi.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MK analyzed and interpreted the data, BW performed all experiments, OS and MB selected and provided the tissues and reviewed the manuscript, and JCR designed the study, analyzed the data, and wrote the manuscript. All authors read and approved the manuscript.

Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Körner, M., Waser, B., Strobel, O. et al. Neurotensin receptors in pancreatic ductal carcinomas. EJNMMI Res 5, 17 (2015). https://doi.org/10.1186/s13550-015-0094-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13550-015-0094-2

Keywords