title: Survivin in adrenocortical tumors - pathophysiological implications and therapeutic potential.
abstract: Treatment options for adrenocortical carcinoma (ACC) are very limited. In other solid tumors, small vaccination trials targeting the anti-apoptotic molecule survivin suggested immunological and clinical benefit in selected patients. Therefore, we investigated whether survivin might be a suitable target for immunotherapy in ACC. Survivin mRNA and protein expression was assessed in adrenal tissue specimens [by real-time-PCR in 29 ACC, 24 adrenocortical adenomas (ACA) and 12 normal adrenal glands; by immunohistochemistry in 167 ACCs, 15 ACA, and 5 normal adrenal glands]. Expression was correlated with clinical outcome using Kaplan-Meier and Cox regression analyses. The anti-apoptotic role of survivin was investigated in the SW13 ACC cell line using survivin siRNA. The presence of spontaneous survivin specific T-cells in peripheral blood was assessed by FACS dextramere staining in 29 ACC patients in comparison to healthy controls. Survivin mRNA in ACC was significantly overexpressed when compared with ACA or normal adrenal glands. Immunohistochemistry confirmed survivin protein expression in 97% of the ACCs. In 83% of samples, staining was moderate or high and clinical outcome in this subgroup showed a trend towards poorer prognosis [hazard ratio for death 2.28 (95% CI 0.99-5.28); p=0.053]. Survivin knockdown in SW-13 cell significantly increased the rate of apoptosis. Finally, spontaneous survivin-reactive T cells were detectable in 3 of 29 ACC patients. In conclusion, our data suggest that survivin could play an important role in the anti-apoptotic mechanisms in ACC and provide first hints that targeting survivin might be an interesting new therapeutic approach in this rare disease.
authors.affiliation: Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sbiera
authors.forename: M
authors.initials: M
authors.lastname: Kroiss
authors.forename: T
authors.initials: T
authors.lastname: Thamm
authors.forename: M
authors.initials: M
authors.lastname: Beyer
authors.forename: F
authors.initials: F
authors.lastname: Majidi
authors.forename: D
authors.initials: D
authors.lastname: Kuehner
authors.forename: M
authors.initials: M
authors.lastname: Wobser
authors.forename: J C
authors.initials: JC
authors.lastname: Becker
authors.forename: P
authors.initials: P
authors.lastname: Adam
authors.forename: C
authors.initials: C
authors.lastname: Ronchi
authors.forename: B
authors.initials: B
authors.lastname: Allolio
authors.forename: M
authors.initials: M
authors.lastname: Fassnacht
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018268:Adrenocortical Carcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D034622:RNA Interference; D016019:Survival Analysis; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D000077022:Survivin