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Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors

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Abstract

Purpose

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a heterogeneous group of malignancies often presenting with metastasis at diagnosis and whose clinical outcome is difficult to predict. Somatostatin (SST) analogs (SSAs) provide a valuable pharmacological tool to palliate hormonal symptoms, and control progression in some NETs. However, many patients do not respond to SSAs or develop resistance, and there are many uncertainties regarding pathophysiology of SST and its receptors (sst1–sst5) in GEP-NETs.

Methods

The expression of SST system components in GEP-NETs was determined, compared with that of non-tumor adjacent and normal tissues and correlated with clinical and histological characteristics. Specifically, 58 patients with GEP-NETs and 14 normal samples were included. Cell viability in NET cell lines was determined in response to specific SSAs.

Results

Normal samples and non-tumor adjacent tissues presented a similar expression profile, with appreciable expression of sst2 and sst3, and a lower expression of the other receptors. In contrast, cortistatin, sst1, sst4, and sst5 were overexpressed in tumors, while sst3 and sst4 seemed overexpressed in less differentiated tumors. Some SST system components were related to vascular/nerve invasion and metastasis. In vitro, sst1 and sst3 agonists reduced viability in BON-1 cells, while they, similar to octreotide and pasireotide, increased viability in QGP-1 cells.

Conclusions

These results provide novel information on SST system pathophysiology in GEP-NETs, including relevant associations with clinical-histological parameters, which might help to better understand the intrinsic heterogeneity of NETs and to identify novel biomarkers and/or targets with potential prognostic and/or therapeutic value for GEP-NETs patients.

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References

  1. A. Dasari et al., Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 3(10), 1335–1342 (2017)

  2. V.L. Tsikitis, B.C. Wertheim, M.A. Guerrero, Trends of incidence and survival of gastrointestinal neuroendocrine tumors in the United States: a SEER analysis. J. Cancer 3, 292–302 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  3. S. Massironi, D. Conte, R.E. Rossi, Somatostatin analogues in functioning gastroenteropancreatic neuroendocrine tumours: literature review, clinical recommendations and schedules. Scand J. Gastroenterol. 51(5), 513–523 (2016)

  4. I.M. Modlin, K.D. Lye, M. Kidd, A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97(4), 934–959 (2003)

    Article  PubMed  Google Scholar 

  5. R. Garcia-Carbonero et al., SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) 2014. Clin. Transl. Oncol. 16(12), 1025–1034 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. H. Sorbye et al., Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann. Oncol. 24(1), 152–160 (2013)

    Article  CAS  PubMed  Google Scholar 

  7. R. Garcia-Carbonero et al., Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann. Oncol. 21(9), 1794–1803 (2010)

    Article  CAS  PubMed  Google Scholar 

  8. B. Lawrence et al., The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol. Metab. Clin. North Am. 40(1), 1–18, vii (2011).

  9. J. Capdevila et al., Translational research in neuroendocrine tumors: pitfalls and opportunities. Oncogene 36(14), 1899–1907 (2017)

    Article  CAS  PubMed  Google Scholar 

  10. M. Volante et al., Somatostatin, cortistatin and their receptors in tumours. Mol. Cell Endocrinol. 286(1-2), 219–229 (2008)

    Article  CAS  PubMed  Google Scholar 

  11. M. Korner, Specific biology of neuroendocrine tumors: peptide receptors as molecular targets. Best Pract. Res. Clin. Endocrinol. Metab. 30(1), 19–31 (2016)

    Article  CAS  PubMed  Google Scholar 

  12. V.K. Pokuri, M.K. Fong, R. Iyer, Octreotide and lanreotide in gastroenteropancreatic neuroendocrine tumors. Curr. Oncol. Rep. 18(1), 7 (2016)

    Article  PubMed  Google Scholar 

  13. A. Rinke 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. 27(28), 4656–4663 (2009)

    Article  CAS  PubMed  Google Scholar 

  14. M.E. Caplin et al., Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N. Engl. J. Med. 371(3), 224–233 (2014)

    Article  PubMed  Google Scholar 

  15. W.W. de Herder et al., Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocr. Relat. Cancer 10(4), 451–458 (2003)

    Article  PubMed  Google Scholar 

  16. D. Kaemmerer et al., Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers. J. Clin. Endocrinol. Metab. 100(3), 831–840 (2015)

    Article  CAS  PubMed  Google Scholar 

  17. M. Volante, F. Bozzalla-Cassione, M. Papotti, Somatostatin receptors and their interest in diagnostic pathology. Endocr. Pathol. 15(4), 275–291 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. M. Theodoropoulou, G.K. Stalla, Somatostatin receptors: from signaling to clinical practice. Front. Neuroendocrinol. 34(3), 228–252 (2013)

    Article  CAS  PubMed  Google Scholar 

  19. S.W. Lamberts, W.W. de Herder, L.J. Hofland, Somatostatin analogs in the diagnosis and treatment of cancer. Trends Endocrinol. Metab. 13(10), 451–457 (2002)

    Article  CAS  PubMed  Google Scholar 

  20. M. Sampedro-Nunez et al., Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors. Oncotarget. 7(6), 6593–6608 (2016)

  21. R.M. Luque et al., Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas. Cancer Lett. 359(2), 299–306 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. G. Mizutani et al., Expression of somatostatin receptor (SSTR) subtypes (SSTR-1, 2A, 3, 4 and 5) in neuroendocrine tumors using real-time RT-PCR method and immunohistochemistry. Acta Histochem. Cytochem. 45(3), 167–176 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. L.J. Hofland, S.W. Lamberts, Somatostatin receptor subtype expression in human tumors. Ann. Oncol. 12 (Suppl 2), S31–S36 (2001)

    Article  PubMed  Google Scholar 

  24. A.D. Herrera-Martinez et al., The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features. Lung Cancer 109, 128–136 (2017)

    Article  PubMed  Google Scholar 

  25. G. Rindi et al., TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 449(4), 395–401 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. M. Duran-Prado et al., Identification and characterization of two novel truncated but functional isoforms of the somatostatin receptor subtype 5 differentially present in pituitary tumors. J. Clin. Endocrinol. Metab. 94(7), 2634–2643 (2009)

    Article  CAS  PubMed  Google Scholar 

  27. A.J. Martinez-Fuentes et al., Ghrelin is produced by and directly activates corticotrope cells from adrenocorticotropin-secreting adenomas. J. Clin. Endocrinol. Metab. 91(6), 2225–2231 (2006)

    Article  CAS  PubMed  Google Scholar 

  28. M.D. Gahete et al., Expression of somatostatin, cortistatin, and their receptors, as well as dopamine receptors, but not of neprilysin, are reduced in the temporal lobe of Alzheimer’s disease patients. J. Alzheimers Dis. 20(2), 465–475 (2010)

    Article  CAS  PubMed  Google Scholar 

  29. G.F. Taboada et al., Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur. J. Endocrinol. 156(1), 65–74 (2007)

    Article  CAS  PubMed  Google Scholar 

  30. U. Kumar, Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer’s disease brain: an immunohistochemical analysis. Neuroscience 134(2), 525–538 (2005)

    Article  CAS  PubMed  Google Scholar 

  31. C.D. Breder et al., Differential expression of somatostatin receptor subtypes in brain. J. Neurosci. 12(10), 3920–3934 (1992)

    CAS  PubMed  Google Scholar 

  32. R.M. Luque et al., In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: evidence from clinical, cellular and molecular parameters. Oncotarget 6(23), 19619–19633 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  33. M. Kaku et al., Establishment of a carcinoembryonic antigen-producing cell line from human pancreatic carcinoma. Gan 71(5), 596–601 (1980)

    CAS  PubMed  Google Scholar 

  34. C.C. Uphoff, H.G. Drexler, Detection of mycoplasma contaminations. Methods Mol. Biol. 946, 1–13 (2013)

    Article  CAS  PubMed  Google Scholar 

  35. R. Baldelli et al., Somatostatin analogs therapy in gastroenteropancreatic neuroendocrine tumors: current aspects and new perspectives. Front. Endocrinol. 5, 7 (2014)

    Article  Google Scholar 

  36. J.C. Reubi et al., SST3-selective potent peptidic somatostatin receptor antagonists. Proc. Natl. Acad. Sci. USA 97(25), 13973–13978 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. J. Cordoba-Chacon et al., Somatostatin dramatically stimulates growth hormone release from primate somatotrophs acting at low doses via somatostatin receptor 5 and cyclic AMP. J. Neuroendocrinol. 24(3), 453–463 (2012)

    Article  CAS  PubMed  Google Scholar 

  38. M. van Hoek et al., Effects of somatostatin analogs on a growth hormone-releasing hormone secreting bronchial carcinoid, in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 94(2), 428–433 (2009)

    Article  PubMed  Google Scholar 

  39. L.J. Hofland et al., The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur. J. Endocrinol. 152(4), 645–654 (2005)

    Article  CAS  PubMed  Google Scholar 

  40. A. Ibanez-Costa et al., Octreotide and pasireotide (dis)similarly inhibit pituitary tumor cells in vitro. J. Endocrinol. 231(2), 135–145 (2016)

    Article  CAS  PubMed  Google Scholar 

  41. T. Cuny et al., Somatostatin receptor sst2 gene transfer in human prolactinomas in vitro: impact on sensitivity to dopamine, somatostatin and dopastatin, in the control of prolactin secretion. Mol. Cell Endocrinol. 355(1), 106–113 (2012)

    Article  CAS  PubMed  Google Scholar 

  42. G. Kanakis et al., Expression of somatostatin receptors 1-5 and dopamine receptor 2 in lung carcinoids: implications for a therapeutic role. Neuroendocrinology 101(3), 211–222 (2015)

    Article  CAS  PubMed  Google Scholar 

  43. A. Nasir et al., Somatostatin receptor profiling in hepatic metastases from small intestinal and pancreatic neuroendocrine neoplasms: immunohistochemical approach with potential clinical utility. Cancer Control 13(1), 52–60 (2006)

    Article  PubMed  Google Scholar 

  44. M. Diez, A. Teule, R. Salazar, Gastroenteropancreatic neuroendocrine tumors: diagnosis and treatment. Ann. Gastroenterol. 26(1), 29–36 (2013)

    PubMed  PubMed Central  Google Scholar 

  45. M. Li et al., Characterization of somatostatin receptor expression in human pancreatic cancer using real-time RT-PCR. J. Surg. Res. 119(2), 130–137 (2004)

    Article  CAS  PubMed  Google Scholar 

  46. J.C. Yao et al., Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364(6), 514–523 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. E. Liu, P. Marincola, K. Oberg, Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations. Ther. Adv. Gastroenterol. 6(5), 412–419 (2013)

    Article  CAS  Google Scholar 

  48. A.K. Clift et al., Predicting the survival of patients with small bowel neuroendocrine tumours: comparison of 3 systems. Endocr. Connect. 6(2), 71–81 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  49. J. Strosberg, L. Kvols, Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J. Gastroenterol. 16(24), 2963–2970 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. J.C. Schaer et al., Somatostatin receptor subtypessst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography. Int. J. Cancer 70(5), 530–537 (1997)

    Article  CAS  PubMed  Google Scholar 

  51. B. Waser et al., Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients. Am. J. Pathol. 180(5), 1942–1949 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. A. Mojtahedi et al., The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature. Am. J. Nucl. Med. Mol. Imaging 4(5), 426–434 (2014)

    PubMed  PubMed Central  Google Scholar 

  53. G.D. Slooter et al., Somatostatin receptor imaging, therapy and new strategies in patients with neuroendocrine tumours. Br. J. Surg. 88(1), 31–40 (2001)

    Article  CAS  PubMed  Google Scholar 

  54. L. Bodei, G. Pepe, G. Paganelli, Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors with somatostatin analogues. Eur. Rev. Med. Pharmacol. Sci. 14(4), 347–351 (2010)

    CAS  PubMed  Google Scholar 

  55. A. Benevento et al., Result of liver resection as treatment for metastases from noncolorectal cancer. J. Surg. Oncol. 74(1), 24–29 (2000)

    Article  CAS  PubMed  Google Scholar 

  56. J.D. Godwin, 2nd, Carcinoid tumors. An analysis of 2,837 cases. Cancer 36(2), 560–569 (1975)

    Article  PubMed  Google Scholar 

  57. E.W. McDermott, B. Guduric, M.F. Brennan, Prognostic variables in patients with gastrointestinal carcinoid tumours. Br. J. Surg. 81(7), 1007–1009 (1994)

    Article  CAS  PubMed  Google Scholar 

  58. J. Zeitels et al., Carcinoid tumors: a 37-year experience. Arch. Surg. 117(5), 732–737 (1982)

    Article  CAS  PubMed  Google Scholar 

  59. M. Duran-Prado et al., The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells. Oncogene 31(16), 2049–2061 (2012)

    Article  CAS  PubMed  Google Scholar 

  60. D. Mole et al., The expression of the truncated isoform of somatostatin receptor subtype 5 associates with aggressiveness in medullary thyroid carcinoma cells. Endocrine 50(2), 442–452 (2015)

    Article  CAS  PubMed  Google Scholar 

  61. S. Pusceddu et al., Everolimus treatment for neuroendocrine tumors: latest results and clinical potential. Ther. Adv. Med. Oncol. 9(3), 183–188 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. S. Faivre et al., Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann. Oncol. 28(2), 339–343 (2017)

  63. E. Raymond et al., Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364(6), 501–513 (2011)

    Article  CAS  PubMed  Google Scholar 

  64. L.J. Hofland et al., Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors. J. Clin. Endocrinol. Metab. 84(2), 775–780 (1999)

    Article  CAS  PubMed  Google Scholar 

  65. R.C. van Adrichem et al., Effects of somatostatin analogs and dopamine agonists on insulin-like growth factor 2-induced insulin receptor isoform-A activation by gastroenteropancreatic neuroendocrine tumor cells. Neuroendocrinology 103(6), 815–825 (2016)

    Article  PubMed  Google Scholar 

  66. P. Cordelier et al., Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. Proc. Natl. Acad. Sci. USA 94(17), 9343–9348 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. M. Filopanti et al., Loss of heterozygosity at the SS receptor type 5 locus in human GH- and TSH-secreting pituitary adenomas. J. Endocrinol. Invest. 27(10), 937–942 (2004)

    Article  CAS  PubMed  Google Scholar 

  68. D. O’Toole et al., The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies. Eur. J. Endocrinol. 155(6), 849–857 (2006)

    Article  PubMed  Google Scholar 

  69. E. Cortez et al., Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD. Proc. Natl. Acad. Sci. USA 113(7), E864–E873 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. C. Lapa, R.A. Werner, K. Herrmann, Visualization of tumor heterogeneity in neuroendocrine tumors by positron emission tomography. Endocrine 51(3), 556–557 (2016)

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was funded by Instituto de Salud Carlos III, co-funded by European Union (ERDF/ESF, “Investing in your future”) [PI16/00264 to R.M.L., Miguel Servet grant (CP15/00156) to M.D.G.], MINECO (BFU2016-80360-R to J.P.C.), Junta de Andalucía (BIO-0139, CTS-1406, PI-0541-2013 to R.M.L., J.P.C., and M.D.G.), GETNE Grant 2014 and CIBERobn. CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain.

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Authors and Affiliations

  1. Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain

    Aura D. Herrera-Martínez, Manuel D. Gahete, Sergio Pedraza-Arevalo, Rafael Sánchez-Sánchez, Rosa Ortega-Salas, Raquel Serrano-Blanch, Raúl M. Luque, María A. Gálvez-Moreno & Justo P. Castaño

  2. Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain

    Aura D. Herrera-Martínez & María A. Gálvez-Moreno

  3. Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain

    Manuel D. Gahete, Sergio Pedraza-Arevalo, Raúl M. Luque & Justo P. Castaño

  4. Reina Sofia University Hospital, Córdoba, Spain

    Manuel D. Gahete, Sergio Pedraza-Arevalo, Raúl M. Luque & Justo P. Castaño

  5. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain

    Manuel D. Gahete, Sergio Pedraza-Arevalo, Raúl M. Luque & Justo P. Castaño

  6. Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain

    Manuel D. Gahete, Sergio Pedraza-Arevalo, Raúl M. Luque & Justo P. Castaño

  7. Pathology Service, Reina Sofia University Hospital, Córdoba, Spain

    Rafael Sánchez-Sánchez & Rosa Ortega-Salas

  8. Medical Oncology Service, Reina Sofia University Hospital, Córdoba, Spain

    Raquel Serrano-Blanch

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  1. Aura D. Herrera-Martínez
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  2. Manuel D. Gahete
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  4. Rafael Sánchez-Sánchez
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Correspondence to Raúl M. Luque, María A. Gálvez-Moreno or Justo P. Castaño.

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Aura D. Herrera-Martínez and Manuel D. Gahete contributed equally to this work.

Raúl M. Luque, María A. Gálvez-Moreno, Justo P. Castaño contributed equally to this work.

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Herrera-Martínez, A.D., Gahete, M.D., Pedraza-Arevalo, S. et al. Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors. Endocrine 59, 426–437 (2018). https://doi.org/10.1007/s12020-017-1482-3

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