Abstract
Background
Prostate Stem Cell Antigen (PSCA) is frequently expressed in prostate cancer but its exact function is unclear.
Methods
To clarify contradictory findings on the prognostic role of PSCA expression, a tissue microarray containing 13,665 prostate cancers was analyzed by immunohistochemistry.
Results
PSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: Early pathological tumor stage (p < 0.0001), low Gleason grade (p < 0.0001), absence of lymph node metastasis (p < 0.0001), low pre-operative PSA level (p = 0.0118), negative surgical margin (p < 0.0001) and reduced PSA recurrence (p < 0.0001). PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001).
Conclusions
The absence of statistical relationship to TMPRSS2:ERG fusion status, chromosomal deletion or high tumor cell proliferation argues against a major role of PSCA for regulation of cell cycle or genomic integrity. PSCA expression is linked to favorable prognosis. PSCA measurement is a candidate for inclusion in multi-parametric prognostic prostate cancer tests.
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Background
While most prostate cancers have an indolent clinical course, the disease represents the third most common cause of cancer related death in men in Western societies [1]. Gleason grade and tumor extent on biopsies, preoperative prostate-specific antigen (PSA), and clinical stage are the currently established pretreatment prognostic parameters. Although these parameters are linked to cancer aggressiveness, the distinction between indolent and aggressive prostate cancer is difficult for the individual patient. Molecular marker may enable a better prediction of prostate cancer aggressiveness in the future.
Prostate stem cell antigen (PSCA) is a protein of unknown function anchored to the cell surface. It was discovered in an attempt to identify genes up regulated in human prostate cancer [2]. Though the name implies specificity for the prostate, PSCA is expressed in several tissues: Placenta, kidney, pancreas, and bladder [3,4,5]. The function of PSCA has not been fully elucidated [6,7,8,9]. Experiments suggest a possible role in cell adhesion, proliferation control and cell survival [2, 10]. Evidence is accumulating that – depending on the cell type involved – PSCA can have a tumor promoting or a tumor suppressive effect [11,12,13,14,15]. For example, loss of PSCA was associated with poor outcome in cancer of the gallbladder and stomach [12, 16], but with improved prognosis in pancreatic adenocarcinoma, renal cell carcinoma and non-small lung cancer [17,18,19,20]. The part of PSCA in prostate cancer remains unclear. Even if most available data suggest that prostate cancer may belong to the tumors with an oncogenic function of PSCA overexpression [46,47].
PSCA expression was significantly associated with favorable patient outcome in our cohort. A possible clinical relevance of this finding is supported by its statistical independence of classical prognostic markers, especially in a pre-operative disease state. However, in comparison with established features such as the Gleason score, the impact of PSCA expression on patient outcome was rather small. If traditional prognostic Gleason groups were used, a small prognostic impact was still found in Gleason 3 + 4 (p = 0.0206) or Gleason 4 + 3 (p = 0.0092). However, if these subgroups were further differentiated according to the fraction of Gleason 4 (quantitative Gleason grading [30]) these PSCA associated prognostic differences vanished. This further illustrates the high bar that molecular characteristics have to overcome if compared with optimized morphologic analysis.
Conclusions
PSCA expression is a statistically independent predictor of favorable prognosis in prostate cancer. Although its prognostic impact per se is not very strong, PSCA expression analysis could be considered for inclusion in multi-parametric prognostic tests to distinguish prostate cancers with need for radical therapy.
Abbreviations
- AR:
-
Androgen receptor
- CHD1:
-
Chromodomain-Helicase-DNA-Binding Protein 1
- ELAV1:
-
Embryonic Lethal, Abnormal Vision, Drosophila)-Like 1
- FISH:
-
Fluorescence in-situ hybridization
- FOXP1:
-
Forkhead box protein P1
- HOOK3:
-
Hook Microtubule Tethering Protein 3
- IHC:
-
Immunohistochemistry
- MAP3K:
-
Mitogen-Activated Protein Kinase Kinase Kinase 7
- PSCA:
-
Prostate stem cell antigen
- PSA:
-
Prostate specific antigen
- PTEN:
-
Phosphatase and tensin homolog
- RPE:
-
Radical prostatectomy
- TMPRSS2:
-
Transmembrane protease, serine 2
- ERG:
-
ETS-related gene fusion
- TMA:
-
Tissue microarray
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Acknowledgements
We thank Julia Schumann, Sünje Seekamp and Inge Brandt for excellent technical assistance.
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All data generated or analyzed during this study are included in this published article [and its Additional file 1].
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MCH, AH, RS, and GS designed the study, and drafted the manuscript. HH1, MG, CB and TS participated in study design. MCH, AH, CG, CS1, CS2 performed IHC analysis and scoring. PL and EB participated in pathology data analysis. CH-M and RS performed statistical analysis. TS, CK, MK, MCH, HH2 and AH participated in data interpretation, and helped to draft the manuscript. All authors read and approved the final manuscript.
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The ethics committee of the Ärztekammer Hamburg approved this study (WF-049/09 and PV3652). According to local laws (HmbKHG, §12,1) informed consent was not required for this study.
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Additional file 1:
Figure S1. Kaplan-Meier plot of prostate specific antigen (PSA) recurrence and PSCA expression stratified for quantitative Gleason grade. Note the different time scale for Gleason Tertiary 5 grades. (DOC 2467 kb)
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Heinrich, MC., Göbel, C., Kluth, M. et al. PSCA expression is associated with favorable tumor features and reduced PSA recurrence in operated prostate cancer. BMC Cancer 18, 612 (2018). https://doi.org/10.1186/s12885-018-4547-7
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DOI: https://doi.org/10.1186/s12885-018-4547-7