Aura D Herrera-Martínez1,2, Manuel D Gahete1,3,4,5,6, Sergio Pedraza-Arevalo1,3,4,5,6, Rafael Sánchez-Sánchez1,7, Rosa Ortega-Salas1,7, Raquel Serrano-Blanch1,8, Raúl M Luque9,10,11,12,13, María A Gálvez-Moreno14,15, Justo P Castaño16,17,18,19,20. 1. Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain. 2. Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain. 3. Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain. 4. Reina Sofia University Hospital, Córdoba, Spain. 5. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. 6. Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain. 7. Pathology Service, Reina Sofia University Hospital, Córdoba, Spain. 8. Medical Oncology Service, Reina Sofia University Hospital, Córdoba, Spain. 9. Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain. raul.luque@uco.es. 10. Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain. raul.luque@uco.es. 11. Reina Sofia University Hospital, Córdoba, Spain. raul.luque@uco.es. 12. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. raul.luque@uco.es. 13. Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain. raul.luque@uco.es. 14. Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain. mamolag@yahoo.es. 15. Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain. mamolag@yahoo.es. 16. Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain. justo@uco.es. 17. Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain. justo@uco.es. 18. Reina Sofia University Hospital, Córdoba, Spain. justo@uco.es. 19. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. justo@uco.es. 20. Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain. justo@uco.es.
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.
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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