title: Oncogene-Induced Senescence in Pituitary Adenomas--an Immunohistochemical Study.
abstract: Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.
authors.affiliation: Institute of Pathology, Medical Faculty, University of Belgrade, Dr Subotica 1, Belgrade, Serbia. emanojlovicgacic@gmail.com.
authors.forename: Emilija
authors.initials: E
authors.lastname: Manojlovic-Gacic
authors.affiliation: Institute of Pathology, Medical Faculty, University of Belgrade, Dr Subotica 1, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Skender-Gazibara
authors.affiliation: Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, Belgrade, Serbia.|Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, Serbia.
authors.forename: Vera
authors.initials: V
authors.lastname: Popovic
authors.affiliation: Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Soldatovic
authors.affiliation: Institute of Pathology, Medical Faculty, University of Belgrade, Dr Subotica 1, Belgrade, Serbia.
authors.forename: Novica
authors.initials: N
authors.lastname: Boricic
authors.affiliation: Neurosurgery Clinic, Clinical Center of Serbia, Koste Todorovica 4, Belgrade, Serbia.
authors.forename: Savo
authors.initials: S
authors.lastname: Raicevic
authors.affiliation: Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, Belgrade, Serbia.|Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, Serbia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pekic
authors.affiliation: Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, Belgrade, Serbia.|Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Doknic
authors.affiliation: Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, Belgrade, Serbia.|Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Miljic
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, Sweden.|Department of Clinical Pathology and Cytology, Uppsala University Hospital, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, Sweden.|Department of Clinical Pathology and Cytology, Uppsala University Hospital, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, Sweden.
authors.forename: Olivera
authors.initials: O
authors.lastname: Casar-Borota
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009857:Oncogenes; D010911:Pituitary Neoplasms / Q000473:pathology*; D046888:Tissue Array Analysis; D055815:Young Adult; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D001616:beta-Galactosidase
keywords: GH adenomas granulation pattern; Immunohistochemistry; Oncogene-induced senescence; Pituitary adenoma