Abstract
Purpose
Lung cancer is highly prevalent and has an especially poor prognosis. Thus, new diagnostic and therapeutic targets are necessary. Two potential targets are somatostatin receptors (SST), which are overexpressed in well-differentiated neuroendocrine neoplasms, and the chemokine receptor CXCR4, which is present mainly in highly proliferative and advanced tumours. Although their expression is relatively well characterized in small cell lung cancer (SCLC), in non-small cell lung cancer (NSCLC), data on SST and CXCR4 expression are scarce and contradictory.
Methods
We comparatively evaluated 83 tumour samples from a total of 57 lung cancer patients, of which 22 had adenocarcinoma (ADC), 21 had squamous cell carcinoma (SQC), and 15 had SCLC. Samples were evaluated for SST and CXCR4 expression using immunohistochemistry with well-characterized rabbit monoclonal antibodies.
Results
In the samples investigated, the most prominently expressed receptors were CXCR4 and SST5. Specifically, CXCR4 was detected with high expression intensity in more than 60% of ADC samples, about 90% of SQC, and 100% of SCLC. SST5 was present in about 75% of ADC and SQC samples and in more than 90% of SCLC. Although not noticeably expressed in ADC and SQC samples, SST2 was detected in 50% of SCLC cases, with a subset of patients displaying exceptionally high expression. The comparison of the three tumour entities revealed that SCLC samples had higher SST2, SST5, and CXCR4 expression, but lower SST3 and SST1 relative to ADC or SQC samples.
Conclusion
CXCR4 may be a promising target for diagnostics and therapy in both SCLC and NSCLC.
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Abbreviations
- ADC:
-
Adenocarcinoma
- CXCR4:
-
C-X-C motif chemokine receptor 4
- MTS:
-
Metastases
- NSCLC:
-
Non-small cell lung cancer
- PRRT:
-
Peptide receptor radionuclide therapy
- SQC:
-
Squamous cell carcinoma
- SCLC:
-
Small cell lung cancer
- SST:
-
Somatostatin receptor
References
Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD (2013) Epidemiology of lung cancer. Diagnosis and Management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:e1S–e19S
Anthony L, Johnson D, Hande K, Shaff M, Winn S, Krozely M, Oates J (1993) Somatostatin analogue phase I trials in neuroendocrine neoplasms. Acta Oncol 32:217–223
Bearz A, Lleshi A, Perin T, Fratino L, Venturini S, Giacalcone A, Sartor I, Berretta M, Sulfaro S, Tirelli U (2011) Small cell lung cancer in an elderly patient: efficacy of somatostatin analog treatment, a case report. Onkologie 34:117–120
Callison JC, Walker RC, Massion PP (2011) Somatostatin receptors in lung cancer: from function to molecular imaging and therapeutics. J Lung Cancer 10:69–76
Callison JC, Chen H, Rezzak M, Eisenberg R, Massion PP (2012) Expression of somatostatin receptor 2 predicts outcome in small cell lung cancer. Am J Resp Crit Care Med 185:A6363
Chen G, Wang Z, Liu XY, Liu FY (2011) High-level CXCR4 expression correlates with brain-specific metastasis of non-small cell lung cancer. World J Surg 1:56–61
Chinezu L, Vasiljevic A, Jouanneau E, François P, Borda A, Trouillas J, Raverot G (2014) Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies. Hum Pathol 45:71–77
Corleto VD, Falconi M, Panzuto F, Milione M, De Luca O, Perri P, Cannizzaro R, Bordi C, Pederzoli P, Scarpa A, Delle Fave G (2009) Somatostatin receptor subtypes 2 and 5 are associated with better survival in well-differentiated endocrine carcinomas. Neuroendocrinol 89:223–230
Cotto C, Quoix E, Thomas F, Henane S, Trillet-Lenoir V (1994) Phase I study of the somatostatin analogue somatuline in refractory small cell lung carcinoma. Ann Oncol 5:290–291
Dela Cruz CS, Tanoue LT, Matthay RA (2011) Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 32:605–644
Fischer T, Doll C, Jacobs S, Kolodziej A, Stumm R, Schulz S (2008a) Reassessment of sst2 somatostatin receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-1. J Clin Endocrinol Metab 93:4519–4524
Fischer T, Nagel F, Jacobs S, Stumm R, Schulz (2008b) Reassessment of CXCR4 chemokine receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-2. PLoS One 3:e4069
Furusato B, Rhim JS (2010) CXCR4 and cancer. Pathol Internat 7:497–505
Herlin G, Kölbeck KG, Menzel PL, Svensson L, Aspelin P, Capitanio A, Axelson R (2009) Quantitative assessment of 99mTC-depreotide uptake in patients with non-small-cell lung cancer: Immunohistochemical correlations. Acta Radiol 50:902–908
Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, Mäcke HR, Rochlitz C, Müller-Brand J, Walter MA (2011) Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 29:2416–2423
Kaemmerer D, Specht E, Sänger J, Wirtz RM, Sayeg M, Schulz S, Lupp A (2015a) Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers. J Clin Endocrinol Metab 100:831–840
Kaemmerer D, Reimann C, Specht E, Wirtz RM, Sayeg M, Baum RP, Schulz S, Lupp A (2015b) Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms. Oncotarget 6:3346–3358
Kaemmerer D, Träger T, Hoffmeister M, Sipos B, Hommann M, Sänger J, Schulz S, Lupp A (2015c) Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget 6:27566–27579
Kaemmerer D, Sänger J, Arsenic R, D’Haese JG, Neumann J, Schmitt-Graeff A, Wirtz RM, Schulz S, Lupp A (2017) Evaluation of somatostatin, CXCR4 chemokine and endothelin A receptor expression in a large set of paragangliomas. Oncotarget 8:89958–89969
Lambertini C, Barzaghi-Rinaudo P, D’Amato L, Schulz S, Nuciforo P, Schmid HA (2013) Evaluation of somatostatin receptor subtype expression in human neuroendocrine tumors using two sets of new monoclonal antibodies. Regul Pept 187:35–41
Lapa C, Hänscheid H, Wild V, Pelzer T, Schirbel A, Werner RA, Droll S, Herrmann K, Buck AK, Lückerath K (2016a) Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget 7:20033–20040
Lapa C, Lückerath K, Rudelius M, Schmid JS, Schoene A, Schirbel A, Samnick S, Pelzer T, Buck AK, Kropf S, Wester HJ, Herrmann K (2016b) [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer—initial experience. Oncotarget 7:9288–9295
Lehmann J, Hoeksma M, Chen H, Shi C, Eisenberg R (2015) Loss of somatostatin receptor 2 expression and lung cancer growth. J Clin Oncol 33(Suppl):7569–7569
Lemjabbar-Alaoui H, Hassan OU, Yang YW, Buchanan P (2015) Lung cancer: biology and treatment options. Biochim Biophys Acta 1856:189–210
Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS (2014) US lung cancer trends by histologic type. Cancer 120:2883–2892
Li Y, Shen Y, Miao Y, Luan Y, Sun B, Qiu X (2014) Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in small cell lung cancer. Int J Clin Exp Pathol 7:3771–3780
Lortet-Tieulent J, Soerjomataram I, Ferlay J, Rutherford M, Weiderpass E, Bray F (2014) International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer 84:13–22
Lupp A, Hunder A, Petrich A, Nagel F, Doll C, Schulz S (2011) Reassessment of sst5 somatostatin receptor expression in normal and neoplastic human tissues using the novel rabbit monoclonal antibody UMB-4. Neuroendocrinol 94:255–264
Lupp A, Nagel F, Doll C, Röcken C, Evert M, Mawrin C, Saeger W, Schulz S (2012) Reassessment of sst3 somatostatin receptor expression in normal and neoplastic human tissues using the novel rabbit monoclonal antibody UMB-4. Neuroendocrinol 96:301–310
Lupp A, Nagel F, Schulz S (2013) Reevaluation of sst1 somatostatin receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-7. Regul Pept 183:1–6
Macaulay VM, Smith IE, Everard MJ, Teale JD, Reubi JC, Millar JL (1991) Experimental and clinical studies with somatostatin analogue in small cell lung cancer. Br J Cancer 64:451–456
Malvezzi M, Bertuccio P, Rosso T, Rota M, Levi F, La Vecchia C, Negri E (2015) European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann Oncol 26:779–786
Marschke RF, Grill JP, Sloan JA (1999) Phase II study of high-dose somatostatin analogue in patients either previously treated or untreated who have extensive-stage small cell lung cancer. Am J Clin Oncol 22:15–17
Mehta S, de Reuver PR, Gill P, Andrici J, D’Urso L, Mittal A, Pavlakis N, Clarke S, Samra JS, Gill AJ (2015) Somatostatin receptor SSTR-2a expression is a stronger predictor for survival than Ki-67 in pancreatic neuroendocrine tumors. Medicine 94:1–6
Minamiya YY, Saito H, Takahashi N, Ito M, Imai K, Ono T, Motoyama S, Ogawa J (2010) Expression of the chemokine receptor CXCR4 correlates with a favorable prognosis in patients with adenocarcinoma of the lung. Lung Cancer 3:466–471
Na IK, Scheibenbogen C, Adam C, Stroux A, Ghadjar P, Thiel E, Keilholz U, Coupland SE (2008) Nuclear expression of CXCR4 in tumor cells of non-small cell lung cancer is correlated with lymph node metastasis. Hum Pathol 39:1751–1755
Okuwaki K, Kida M, Mikami T, Yamauchi H, Imaizumi H, Miyazawa S, Iwai T, Takezawa M, Saegusa M, Watanabe M, Koizumi W (2013) Clinicopathologic characteristics of pancreatic neuroendocrine tumors and relation of somatostatin receptor 2A to outcomes. Cancer 119:4094–4102
Otsuka S, Klimowicz AC, Kopciuk K, Petrillo SK, Konno M, Hao D, Muzik H, Stolte E, Boland W, Morris D, Magliocco AM, Bebb G (2011) CXCR4 overexpression is associated with poor outcome in females diagnosed with stage IV non-small cell lung cancer. J Thorac Oncol 6:1169–1178
Pless M, Waldherr C, Maecke H, Buitrago C, Herrmann R, Mueller-Brand J (2004) Targeted radiotherapy for small cell lung cancer using 90Yttrium-DOTATOC, an Yttrium-labelled somatostatin analogue: a pilot trial. Lung Cancer 45:365–371
Qian ZR, Li T, Ter-Minassian M, Yan J, Chan JA, Brais LK, Masugi Y, Thiaglingam A, Brooks N, Nishihara R, Bonnemarie M, Masuda A, Inamura K, Kim SA, Mima K, Sukawa Y, Dou R, Lin X, Christiani DC, Schmidlin F, Fuchs CS, Mahmood U, Ogino S, Kulke MH (2016) Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors. Pancreas 45:1386–1393
Reck M, Heigener DF, Mok T, Soria JC, Rabe KF (2013) Management of non-small-cell lung cancer: recent developments. Lancet 382:709–719
Reckamp KL, Figlin RA, Burdick MD, Dubinett SM, Elashoff RM, Strieter LW (2009) CXCR4 expression on circulating pan-cytokeratin positive cells is associated with survival in patients with advanced non-small cell lung cancer. BMC Cancer 9:213
Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140
Ridge CA, McErlean AM, Ginsberg MS (2013) Epidemiology of lung cancer. Semin Intervent Radiol 30:93–98
Righi L, Volante M, Tavaglione V, Billè A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M (2010) Somatostatin receptor tissue distribution in lung neuroendocrine tumors: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol 21:548–555
Schottelius M, Osl T, Poschenrieder A, Hoffmann F, Beykan S, Hänscheid H, Schirbel A, Buck AK, Kropf S, Schwaiger M, Keller U, Lassmann M, Wester HJ (2017) [177Lu]pentixather: comprehensive preclinical characterization of a first CXCR4-directed endoradiotherapeutic agent. Theranostics 7:2350–2362
Singh SP, Han L, Murali R, Solis L, Roth J, Ji L, Wistuba I, Kundra V (2011) SSTR2-based reporters for assessing gene transfer into non-small cell lung cancer: evaluation using an intrathoracic mouse model. Hum Gene Ther 22:55–64
Sollini M, Farioli D, Froio A, Chella A, Asti M, Boni R, Grassi E, Roncali M, Versari A, Erba PA (2013) Brief report on the use of radiolabeled somatostatin analogs for the diagnosis and treatment of metastatic small-cell lung cancer patients. J Thorac Oncol 8:1095–1101
Song KB, Kim SC, Kim JH, Seo DW, Hong SM, Park KM, Hwang DW, Lee JH, Lee YJ (2016) Prognostic value of somatostatin receptor subtypes in pancreatic neuroendocrine tumors. Pancreas 45:187–192
Spano JP, Andre F, Morat L, Sabatier L, Besse B, Combatiere C, Deterre P, Martin A, Azorin J, Valeyre D, Khayat D, Le Chevalier T, Soria JC (2004) Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome. Ann Oncol 15:613–617
Suzuki M, Mohamed S, Nakajima T, Kubo R, Tian L, Fujiwara T, Suzuki H, Nagato K, Chiyo M, Motohashi S, Yasufuku K, Iyoda A, Yoshida S, Sekine Y, Shibuya K, Hiroshima K, Nakatani Y, Yoshino I, Fujisawa T (2008) Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis. Int J Oncol 1:113–119
Taromi S, Kayser G, Catusse J, von Elverfeldt D, Reichardt W, Braun F, Weber WA, Zeiser R, Burger M (2016) CXCR4 antagonists suppress small cell lung cancer progression. Oncotarget 7:85185–85195
Tartarone A, Lerose R, Ardito R, Troiani L, Tedesco B, Bozza G, Cangiano R, Aieta M (2014) Long-term survival in small cell lung cancer: a case report and review of the literature. Future Oncol 10:523–528
Tartarone A, Lerose R, Aieta M (2016) Somatostatin analog therapy in small cell lung cancer. Sem Nucl Med 46:239–242
Traub T, Petkov V, Ofluoglu S, Pangerl T, Raderer M, Fueger B, Schima W, Kurtaran A, Dudczak R, Virgolini I (2001) 111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung. J Nucl Med 42:1309–1315
Tsuta K, Wistuba II, Moran CA (2012) Differential expression of somatostatin receptors 1–5 in neuroendocrine carcinoma of the lung. Pathol Res Practice 208:470–474
Virgolini I, Britton K, Buscombe J, Moncayo R, Paganelli G, Riva P (2002) In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Semin Nucl Med 32:148–155
Wagner P, Hyjek E, Vazquez MF, Meherally D, Liu YF, Chadwick PA, Rengifo T, Sica GL, Port JL, Lee PC, Paul S, Altorki NK, Saqi A (2009) CXCL12 and CXCR4 in adenocarcinoma of the lung: association with metastasis and survival. J Thorac Cardiovasc Surg 137:615–621
Walker R, Deppen S, Smith G, Shi C, Lehman J, Clanton J, Moore B, Burns R, Grogan EL, Massion PP (2017) 68 Ga-DOTATATE PET/CT imaging of indeterminate pulmonary nodules and lung cancer. PLoS One 12:e0171301. https://doi.org/10.1371/journal.pone.0171301 (eCollection 2017)
Wang M, Chen GY, Song HT, Hong X, Yang ZY, Sui GJ (2011) Significance of CXCR4, phosphorylated STAT3 and VEGF-A expression in resected non-small cell lung cancer. Exp Ther Med 3:517–522
Zarogoulidis K, Eleftheriadou E, Kontakiotis T, Gerasimou G, Zarogoulidis P, Sapardianis I, Galaktidou G, Sakkas L, Gotzamani-Psarrakou A, Karatzas N (2012) Long acting somatostatin analogues in combination to antineoplastic agents in the treatment of small cell lung cancer patients. Lung Cancer 76:84–88
Zhao H, Guo L, Zhao H, Zhao J, Weng H, Zhao B (2015) CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget 6:5022–5040
Zobair AA, Obeidy BF, Yang L, Yang C, Hui Y, Yu H, Zheng F, Yang G, Xie C, Zhou F, Zhou Y (2013) Concomitant overexpression of EGFR and CXCR4 is associated with worse prognosis in a new molecular subtype of non-small cell lung cancer. Oncol Rep 4:1524–1532
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The Theranostic Research Center, Zentralklinik Bad Berka, 99437 Bad Berka, Germany, provided funding for this research.
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Conceived and designed the experiments: DK, AL. Provided the tumor samples: JS. Provided the antibodies: SS. Acquired the clinical data: DK. Performed the experiments: CS, EN, AL. Analyzed the data: CS, AL. Interpreted the data: AL. Wrote the paper: AL. Revised critically the manuscript: CS, DK, EN, JS, SS, AL. Each of the authors has approved the manuscript and acknowledges that he or she participated sufficiently in the work to take public responsibility for its content.
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Daniel Kaemmerer received funding and support for travelling to meetings by the companies IPSEN and PFIZER. All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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All procedures performed in this study 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. Permission was gained from the local ethics committee (Ethikkommission der Landesärztekammer Thüringen) for this retrospective analysis. For this type of study formal consent is not required. All data were recorded and analyzed anonymously.
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432_2018_2722_MOESM1_ESM.tif
Supplemental Figure 1: Typical examples for positive control immunostainings for somatostatin receptors (SST) and CXCR4 and for CXCR4 positivity of tumor vessels. SST1, SST2, SST3 and SST5: pancreatic islets; CXCR4: germinal center of a lymph follicle and CXCR4-positive tumor vessels (arrows). Immunohistochemistry (red-brown color), counterstaining with hematoxylin; original magnification: x400. (TIF 17763 KB)
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Stumpf, C., Kaemmerer, D., Neubauer, E. et al. Somatostatin and CXCR4 expression patterns in adenocarcinoma and squamous cell carcinoma of the lung relative to small cell lung cancer. J Cancer Res Clin Oncol 144, 1921–1932 (2018). https://doi.org/10.1007/s00432-018-2722-5
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DOI: https://doi.org/10.1007/s00432-018-2722-5