title: Loss of somatostatin receptor subtype 2 in prostate cancer is linked to an aggressive cancer phenotype, high tumor cell proliferation and predicts early metastatic and biochemical relapse.
abstract: Somatostatin receptor subtype 2 (SSTR2) is the most frequently expressed SSTR subtype in normal human tissues. SSTR2 expression is differentially regulated in various tumor types and therapeutic somatostatin analogs binding to SSTR2 are in clinical use. In prostate cancers highly contradictory results in terms of SSTR2 expression and its consequences have been published over the past years. The aim of this study was to clarify prevalence and clinical significance of SSTR2 expression in prostate cancer. Therefore, quantitative immunohistochemistry (IHC) using a tissue microarray containing samples from 3,261 prostate cancer patients with extensive clinical and molecular cancer characteristics and oncological follow-up data was performed. IHC data was compared to publicly available Gene Expression Omnibus datasets of human prostate cancer gene expression arrays. While membranous SSTR2 staining was always seen in normal prostate epithelium, SSTR2 staining was absent in more than half (56.1%) of 2,195 interpretable prostate cancer samples. About 13% of all analyzed prostate cancers showed moderate to strong cytoplasmic and membranous SSTR2 staining. Staining intensities were inversely correlated with high Gleason grade, advanced pT category, high tumor cell proliferation (p<0.0001 each), high pre-operative PSA levels, (p = 0.0011) and positive surgical margins (p = 0.006). In silico analysis confirmed lower SSTR2 gene expression in prostate cancers vs. normal adjacent tissue (p = 0.0424), prostate cancer metastases vs. primary cancers (p = 0.0011) and recurrent vs. non-recurrent prostate cancers (p = 0.0438). PSA-free survival gradually declined with SSTR2 staining intensity (p<0.0001). SSTR2-negative cancers were more likely to develop metastases over time (p<0.05). In conclusion, most prostate cancers are indeed SSTR2-negative and loss of SSTR2 strongly predicts an unfavorable tumor phenotype and poor prognosis. Therefore, SSTR2 expression seems an important factor in the pathogenesis of prostate cancer and re-introduction of the receptor in SSTR2-negative prostate cancers may feature a promising target for novel gene therapy approaches.
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Internal Medicine II - Oncology, Hematology, BMT with Section Pneumology, Hubertus-Wald-Tumorzentrum/University Cancer Center Hamburg (UCCH) University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hennigs
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University - School of Medicine, Stanford, California, United States of America.
authors.forename: Matti
authors.initials: M
authors.lastname: Adam
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University - School of Medicine, Stanford, California, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Emilia
authors.initials: E
authors.lastname: Riedel
authors.affiliation: Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.affiliation: Department of Internal Medicine II - Oncology, Hematology, BMT with Section Pneumology, Hubertus-Wald-Tumorzentrum/University Cancer Center Hamburg (UCCH) University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.affiliation: Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
mesh_terms: D000368:Aged; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D017481:Receptors, Somatostatin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012008:Recurrence
chemical_list: D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2