title: Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas.
abstract: The GH/IGF1 response of somatotropinomas to somatostatin analogues (SSA) is associated with their pattern of somatostatin receptor (sst1-sst5) expression. Recently, we demonstrated that expression of a truncated sst5-variant (sst5TMD4) can influence the secretory response of somatotropinomas to SSA-therapy; however, its potential relationship with aggressive features (e.g. invasion/proliferation) is still unknown. Here, we show that sst5TMD4 is present in 50% of non-functioning pituitary-adenomas (NFPA) (n = 30) and 89% of somatotropinomas (n = 36), its expression levels being highest in somatotropinomas > > NFPAs > > > normal pituitaries (negligible expression; n = 8). In somatotropinomas, sst5TMD4 mRNA and protein levels correlated positively, and its expression was directly associated with tumor invasiveness (cavernous/sphenoid sinus), and inversely correlated with age and GH/IGF1 reduction after 3-6 months with octreotide-LAR therapy. GNAS+ somatotropinomas expressed lower sst5TMD4 levels. ROC analysis revealed sst5TMD4 expression as the only marker, within all sst-subtypes, capable to predict tumor invasiveness in somatotropinomas. sst5TMD4 overexpression increased cell viability in cultured somatotropinoma (n = 5). Hence, presence of sst5TMD4 associates with increased aggressive features and worse prognosis in somatotropinomas, thereby providing a potentially useful tool to refine somatotropinoma diagnosis, predict outcome of clinical response to SSA-therapy and develop new therapeutic targets.
authors: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and Hospital Universitario Reina Sofia.; CIBER Fisiopatología de la Obesidad y Nutrición; Campus de Excelencia Internacional Agroalimentario (ceiA3), 14014, Córdoba, Spain. Electronic address: raul.luque@uco.es.
authors: Raúl M
authors: RM
authors: Luque
authors: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and Hospital Universitario Reina Sofia.; CIBER Fisiopatología de la Obesidad y Nutrición; Campus de Excelencia Internacional Agroalimentario (ceiA3), 14014, Córdoba, Spain.
authors: Alejandro
authors: A
authors: Ibáñez-Costa
authors: Endocrinology Unit, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Endocrinology Section, Federal Hospital of Lagoa, Rio de Janeiro, Brazil.
authors: Leonardo Vieira
authors: LV
authors: Neto
authors: Endocrinology Section, Hospital Universitario Antônio Pedro, Universidade Federal Fluminense, Rio de Janeiro, Brazil.
authors: Giselle F
authors: GF
authors: Taboada
authors: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and Hospital Universitario Reina Sofia.; CIBER Fisiopatología de la Obesidad y Nutrición; Campus de Excelencia Internacional Agroalimentario (ceiA3), 14014, Córdoba, Spain.
authors: Daniel
authors: D
authors: Hormaechea-Agulla
authors: Endocrinology Unit, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Leandro
authors: L
authors: Kasuki
authors: Metabolism and Nutrition Unit, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Seville 41013, Spain.
authors: Eva
authors: E
authors: Venegas-Moreno
authors: Endocrinology and Nutrition Unit, Complejo Hospitalario de Jaén, Jaén 23007, Spain.
authors: Alberto
authors: A
authors: Moreno-Carazo
authors: Service of Endocrinology and Nutrition, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, Córdoba 14004, Spain.
authors: María Ángeles
authors: MÁ
authors: Gálvez
authors: Metabolism and Nutrition Unit, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Seville 41013, Spain.
authors: Alfonso
authors: A
authors: Soto-Moreno
authors: Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Research and Development Division, University of Illinois at Chicago, Chicago, IL, USA.
authors: Rhonda D
authors: RD
authors: Kineman
authors: IPSEN Bioscience, Cambridge, MA 02142, USA.
authors: Michael D
authors: MD
authors: Culler
authors: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and Hospital Universitario Reina Sofia.; CIBER Fisiopatología de la Obesidad y Nutrición; Campus de Excelencia Internacional Agroalimentario (ceiA3), 14014, Córdoba, Spain.
authors: Manuel D
authors: MD
authors: Gahete
authors: Endocrinology Unit, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Mônica R
authors: MR
authors: Gadelha
authors: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and Hospital Universitario Reina Sofia.; CIBER Fisiopatología de la Obesidad y Nutrición; Campus de Excelencia Internacional Agroalimentario (ceiA3), 14014, Córdoba, Spain. Electronic address: justo@uco.es.
authors: Justo P
authors: JP
authors: Castaño
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D049109:Cell Proliferation; D002470:Cell Survival; D018389:Codon, Nonsense; D019008:Drug Resistance, Neoplasm; D005260:Female; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D015282:Octreotide / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018389:Codon, Nonsense; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D019382:Human Growth Hormone; C094573:somatostatin receptor 5; D015282:Octreotide
keywords: Acromegaly; Invasion; Proliferation; sst5TMD4
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