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01.12.2017 | Original Article

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

verfasst von: 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

Erschienen in: Endocrine | Ausgabe 2/2018

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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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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)

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)CrossRefPubMedPubMedCentral

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)

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

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)CrossRefPubMedPubMedCentral

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)CrossRefPubMed

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)CrossRefPubMed

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

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

10.

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

11.

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

12.

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

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)CrossRefPubMed

14.

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

15.

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

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)CrossRefPubMed

17.

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

18.

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

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)CrossRefPubMed

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)CrossRefPubMedPubMedCentral

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)CrossRefPubMedPubMedCentral

23.

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

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)CrossRefPubMed

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)CrossRefPubMedPubMedCentral

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMed

30.

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

31.

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

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)CrossRefPubMedPubMedCentral

33.

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

34.

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

35.

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

36.

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

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMed

40.

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

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMed

44.

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

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)CrossRefPubMed

46.

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

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)CrossRef

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)CrossRefPubMedPubMedCentral

49.

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

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)CrossRefPubMed

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)CrossRefPubMedPubMedCentral

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)PubMedPubMedCentral

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)CrossRefPubMed

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)PubMed

55.

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

56.

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

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)CrossRefPubMed

58.

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

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)CrossRefPubMed

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)CrossRefPubMed

61.

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

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMedPubMedCentral

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)CrossRefPubMed

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)CrossRefPubMed

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)CrossRefPubMedPubMedCentral

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)CrossRefPubMed

Titel: Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors
verfasst von: 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
Publikationsdatum: 01.12.2017
Verlag: Springer US
Erschienen in: Endocrine / Ausgabe 2/2018
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-017-1482-3

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

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