title: Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas.
abstract: OBJECTIVE
  GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level.
  
  
  METHODS
  In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.
  
  
  RESULTS
  The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%).
  
  
  CONCLUSIONS
  Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.
authors.affiliation: Division of Endocrinology and Diabetes, Department of Medicine I.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mayr
authors.forename: Rolf
authors.initials: R
authors.lastname: Buslei
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.forename: Christof
authors.initials: C
authors.lastname: Schöfl
mesh_terms: D000172:Acromegaly / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002864:Chromogranins; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000473:pathology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology; D061251:Primary Cell Culture; D017481:Receptors, Somatostatin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; C497410:CREM protein, human; D018797:Cell Cycle Proteins; D002864:Chromogranins; C106464:PLAGL1 protein, human; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C101130:somatostatin receptor type 1; D051786:Cyclic AMP Response Element Modulator; C094573:somatostatin receptor 5; D000242:Cyclic AMP; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D015282:Octreotide