Somatostatin analogs mantain their major role in the treatment of patients with advanced neuroendocrine tumors (NETs) and have multiple modulatory effects on the immune system. Here, we evaluated the effects of lanreotide treatment on expression of Th1, Th2 cytokine patterns in serum of patients with NETs and in bronchial and pancreatic NET cell lines. Our results showed that lanreotide treatment promoted a Th1 cytotoxic immune-phenotype in patients with NETs originated by intestinal sites. Similar results were obtained also in vitro where lanreotide induced expression of Th1 cytokines only in pancreatic and not in bronchial-derived NET cell lines. It seems, therefore, that cytokinomics can represent a useful tool for the identification of tumor biomarkers for the early diagnosis and evaluation of the response to therapy in NET patients. To avoid the drug-resistance induced by everolimus (mTOR inhibitor), we made the pancreatic NET cell line resistant to this drug. After treatment with lanreotide we found that the drug reduced its viability compared to that of sensitive cells. These data may have direct implications in design of future translation combination trial on NET patients.

1st Department of Internal Medicine Centre of Excellency for Atherosclerosis Research University of Pavol Jozef Safarik Košice Slovakia

CEITEC Central European Institute of Technology University of Veterinary and Pharmaceutical Sciences Brno Brno Czechia

Department of Clinical Medicine and Surgery University Federico 2 of Naples Naples Italy

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Experimental Medicine Division of Endocrinology Sapienza University of Rome Rome Italy

Department of Experimental Medicine University of Campania Luigi Vanvitelli Naples Italy

Department of Medical Oncology Centro di Riferimento Oncologico Istituto Nazionale Tumori CRO Aviano Italy

Department of Oncology Livestrong Cancer Institutes Dell Medical School The University of Texas Austin TX United States

Department of Precision Medicine University of Campania Luigi Vanvitelli Naples Italy

Laboratory of Geriatric and Oncologic Neuroendocrinology Research Istituto Auxologico Italiano IRCCS Milan Italy

Laboratory of Precision and Molecular Oncology Institute of Genetic Research Biogem Scarl Avellino Italy

Medical Oncology Unit Bianchi Melacrino Morelli Grand Metropolitan Hospital Reggio Calabria Italy

Oncology Unit AORN Cardarelli Naples Italy

Zobrazit více v PubMed

Kloppel G. Neuroendocrine neoplasms: dichotomy, origin and classifications. Visc Med. (2017) 33:324–30. 10.1159/000481390 PubMed DOI PMC

Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD, Knowledge N. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer. (2014) 21:R153–63. 10.1530/ERC-13-0125 PubMed DOI

Bhate K, Mok WY, Tran K, Khan S, Al-Nahhas A. Functional assessment in the multimodality imaging of pancreatic neuro-endocrine tumours. Minerva Endocrinol. (2010) 35:17–25. PubMed

Scherubl H, Streller B, Stabenow R, Herbst H, Hopfner M, Schwertner C, et al. . Clinically detected gastroenteropancreatic neuroendocrine tumors are on the rise: epidemiological changes in Germany. World J Gastroenterol. (2013) 19:9012–9. 10.3748/wjg.v19.i47.9012 PubMed DOI PMC

Plockinger U, Wiedenmann B. Treatment of gastroenteropancreatic neuroendocrine tumors. Virchows Arch. (2007) 451 Suppl 1:S71–80. 10.1007/s00428-007-0446-z PubMed DOI

Faggiano A, Lo Calzo F, Pizza G, Modica R, Colao A. The safety of available treatments options for neuroendocrine tumors. Expert Opin Drug Saf. (2017) 16:1149–61. 10.1080/14740338.2017.1354984 PubMed DOI

Arnold R, Trautmann ME, Creutzfeldt W, Benning R, Benning M, Neuhaus C, et al. . Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut. (1996) 38:430–8. 10.1136/gut.38.3.430 PubMed DOI PMC

Zaytseva YY, Valentino JD, Gulhati P, Evers BM. mTOR inhibitors in cancer therapy. Cancer Lett. (2012) 319:1–7. 10.1016/j.canlet.2012.01.005 PubMed DOI

Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. (1996) 334:246–54. 10.1056/NEJM199601253340408 PubMed DOI

Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. (1999) 20:157–98. 10.1006/frne.1999.0183 PubMed DOI

Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. (2010) 31:169–88. 10.1111/j.1365-2036.2009.04174.x PubMed DOI

Rai U, Thrimawithana TR, Valery C, Young SA. Therapeutic uses of somatostatin and its analogues: Current view and potential applications. Pharmacol Ther. (2015) 152:98–110. 10.1016/j.pharmthera.2015.05.007 PubMed DOI

Msaouel P, Galanis E, Koutsilieris M. Somatostatin and somatostatin receptors: implications for neoplastic growth and cancer biology. Expert Opin Investig Drugs. (2009) 18:1297–316. 10.1517/13543780903176399 PubMed DOI

Hankus J, Tomaszewska R. Neuroendocrine neoplasms and somatostatin receptor subtypes expression. Nucl Med Rev Cent East Eur. (2016) 19:111–7. 10.5603/NMR.2016.0022 PubMed DOI

Gatto F, Barbieri F, Arvigo M, Thellung S, Amaru J, Albertelli M, et al. . Biological and biochemical basis of the differential efficacy of first and second generation somatostatin receptor ligands in neuroendocrine neoplasms. Int J Mol Sci. (2019) 20:16. 10.3390/ijms20163940 PubMed DOI PMC

Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. (2009) 27:4656–63. 10.1200/JCO.2009.22.8510 PubMed DOI

Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. (2014) 371:224–33. 10.1056/NEJMoa1316158 PubMed DOI

Stueven AK, Kayser A, Wetz C, Amthauer H, Wree A, Tacke F, et al. . Somatostatin analogues in the treatment of neuroendocrine tumors: past, present and future. Int J Mol Sci. (2019) 20:12. 10.3390/ijms20123049 PubMed DOI PMC

Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. (2012) 149:274–93. 10.1016/j.cell.2012.03.017 PubMed DOI PMC

Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans. (2009) 37(Pt 1):217–22. 10.1042/BST0370217 PubMed DOI PMC

Lamberti G, Brighi N, Maggio I, Manuzzi L, Peterle C, Ambrosini V, et al. . The role of mtor in neuroendocrine tumors: future cornerstone of a winning strategy? Int J Mol Sci. (2018) 19:3. 10.3390/ijms19030747 PubMed DOI PMC

Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, et al. . Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. (2016) 34:3906–13. 10.1200/JCO.2016.68.0702 PubMed DOI PMC

Gallo M, Malandrino P, Fanciulli G, Rota F, Faggiano A, Colao A, et al. . Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives. J Cancer Res Clin Oncol. (2017) 143:1209–24. 10.1007/s00432-017-2407-5 PubMed DOI PMC

Faggiano A, Malandrino P, Modica R, Agrimi D, Aversano M, Bassi V, et al. . Efficacy and safety of everolimus in extrapancreatic neuroendocrine tumor: a comprehensive review of literature. Oncologist. (2016) 21:875–86. 10.1634/theoncologist.2015-0420 PubMed DOI PMC

Gagliano T, Bellio M, Gentilin E, Mole D, Tagliati F, Schiavon M, et al. . mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids. Endocr Relat Cancer. (2013) 20:463–75. 10.1530/ERC-13-0042 PubMed DOI

Pivonello C, Rousaki P, Negri M, Sarnataro M, Napolitano M, Marino FZ, et al. . Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study. Endocrine. (2017) 56:603–20. 10.1007/s12020-016-1079-2 PubMed DOI

Ferolla P, Brizzi MP, Meyer T, Mansoor W, Mazieres J, Do Cao C, et al. Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. (2017) 18:1652–64. 10.1016/S1470-2045(17)30681-2 PubMed DOI

Yaguchi T, Kawakami Y. Cancer-induced heterogeneous immunosuppressive tumor microenvironments and their personalized modulation. Int Immunol. (2016) 28:393–9. 10.1093/intimm/dxw030 PubMed DOI PMC

Wojtowicz-Praga S. Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. J Immunother. (1997) 20:165–77. 10.1097/00002371-199705000-00001 PubMed DOI

Hofsli E, Thommesen L, Yadetie F, Langaas M, Kusnierczyk W, Falkmer U, et al. . Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells. Br J Cancer. (2005) 92:1506–16. 10.1038/sj.bjc.6602535 PubMed DOI PMC

Lamrani A, Tulliez M, Chauvelot-Moachon L, Chaussade S, Mauprivez C, Hagnere AM, et al. . Effects of octreotide treatment on early TNF-alpha production and localization in experimental chronic colitis. Aliment Pharmacol Ther. (1999) 13:583–94. 10.1046/j.1365-2036.1999.00515.x PubMed DOI

Casnici C, Lattuada D, Franco P, Cattaneo L, Marelli O. Regulation of human peripheral blood lymphocytes IL-10 BY SMS 201-995. J Neuroimmunol. (2004) 149:210–6. 10.1016/j.jneuroim.2003.12.020 PubMed DOI

Lattuada D, Casnici C, Crotta K, Mastrotto C, Franco P, Schmid HA, et al. . Inhibitory effect of pasireotide and octreotide on lymphocyte activation. J Neuroimmunol. (2007) 182:153–9. 10.1016/j.jneuroim.2006.10.007 PubMed DOI

Hayry P, Raisanen A, Ustinov J, Mennander A, Paavonen T. Somatostatin analog lanreotide inhibits myocyte replication and several growth factors in allograft arteriosclerosis. FASEB J. (1993) 7:1055–60. 10.1096/fasebj.7.11.8370476 PubMed DOI

Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. . RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. (2016) 62:132–7. 10.1016/j.ejca.2016.03.081 PubMed DOI PMC

Datta J, Fracol M, McMillan MT, Berk E, Xu S, Goodman N, et al. . Association of depressed anti-HER2 T-helper type 1 response with recurrence in patients with completely treated her2-positive breast cancer: role for immune monitoring. JAMA Oncol. (2016) 2:242–6. 10.1001/jamaoncol.2015.5482 PubMed DOI

Cintolo JA, Datta J, Mathew SJ, Czerniecki BJ. Dendritic cell-based vaccines: barriers and opportunities. Future Oncol. (2012) 8:1273–99. 10.2217/fon.12.125 PubMed DOI PMC

Vitale G, Lupoli G, Guarrasi R, Colao A, Dicitore A, Gaudenzi G, et al. . Interleukin-2 and lanreotide in the treatment of medullary thyroid cancer: in vitro and in vivo studies. J Clin Endocrinol Metab. (2013) 98:E1567–74. 10.1210/jc.2013-1443 PubMed DOI

Vitale G, Tagliaferri P, Caraglia M, Rampone E, Ciccarelli A, Bianco AR, et al. . Slow release lanreotide in combination with interferon-alpha2b in the treatment of symptomatic advanced medullary thyroid carcinoma. J Clin Endocrinol Metab. (2000) 85:983–8. 10.1210/jcem.85.3.6435 PubMed DOI

Stassi G, Todaro M, Zerilli M, Ricci-Vitiani L, Di Liberto D, Patti M, et al. . Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res. (2003) 63:6784–90. PubMed