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. Keywords: PSCA,ERG,Tissuemicroarray, Prostate cancer, Immunohistochemistry Background Prostate stem cell antigen (PSCA) is a protein of unknown While most prostate cancers have an indolent clinical function anchored to the cell surface. It was discovered in an course, the disease represents the third most common attempt to identify genes up regulated in human prostate cause of cancer related death in men in Western societies cancer . Though the nameimplies specificityfor thepros- . Gleason grade and tumor extent on biopsies, pre- tate, PSCA is expressed in several tissues: Placenta, kidney, operative prostate-specific antigen (PSA), and clinical pancreas, and bladder [3–5]. The function of PSCA has not stage are the currently established pretreatment prognos- been fully elucidated [6–9]. Experiments suggest a possible tic parameters. Although these parameters are linked to role in cell adhesion, proliferation control and cell survival [2, cancer aggressiveness, the distinction between indolent 10]. Evidence is accumulating that – depending on the cell and aggressive prostate cancer is difficult for the individual type involved – PSCA can have a tumor promoting or a patient. Molecular marker may enable a better prediction tumor suppressive effect [11–15]. For example, loss of PSCA of prostate cancer aggressiveness in the future. was associated with poor outcome in cancer of the gallblad- der and stomach [12, 16], but with improved prognosis in pancreatic adenocarcinoma, renal cell carcinoma and non-small lung cancer [17–20]. The part of PSCA in prostate * Correspondence: firstname.lastname@example.org † cancer remains unclear. Even if most available data suggest Marie-Christine Heinrich and Cosima Göbel contributed equally to this work. Institute of Pathology, University Medical Center Hamburg-Eppendorf, that prostate cancer may belong to the tumors with an onco- Martinistrasse 52, D-20246 Hamburg, Germany genic function of PSCA overexpression [21–24], there are Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Heinrich et al. BMC Cancer (2018) 18:612 Page 2 of 9 also studies that do not support such a conclusion or Table 1 Pathological and clinical data of the arrayed prostate cancers suggest the opposite that prostate cancer aggressiveness and metastasis is driven by PSCA down regulation [26–29]. Study cohort on Biochemical relapse TMA (n = 13,660) among category To clarify the prognostic role of PSCA expression in pros- Follow-up tate cancer, we analyzed PSCA expression by immunohisto- chemistry on a large preexisting tissue micro array (TMA). n 12,208 3017 (25%) Mean / median 58.8 / 48.5 months – Methods Age (y) Patients ≤50 352 61 (17%) Radical prostatectomy specimens were from 13,660 consecu- 51–59 3335 701 (21%) tive patients operated between 1992 and 2014 at the 60–69 7827 1747 (22%) University Medical Center Hamburg-Eppendorf (Depart- ment of Urology and Martini Clinic). In addition to the clas- ≥70 2093 508 (24%) sical Gleason categories, “quantitative” Gleason grading was Pretreatment PSA (ng/ml) performed as described elsewhere . Follow-up was avail- < 4 1694 252 (15%) able for 12,208 patients (Table 1). In Kaplan-Meier analysis 4–10 8195 1464 (18%) prostate specific antigen (PSA) recurrence was defined as the 10–20 2763 847 (31%) time point when postoperative PSA was at least 0.2 ng/ml. > 20 922 442 (48%) Immunochemistry pT stage (AJCC 2002) TMAs were manufactured as described . Rabbit poly- pT2 8861 1030 (12%) clonal antibody specific for PSCA (cat#PA1–38516, pT3a 2984 958 (32%) Thermo scientific, dilution 1:150) was applied at 37 °C for pT3b 1696 976 (58%) 60 min. Bound antibody was visualized with the EnVision pT4 71 53 (75%) Kit (Dako, Glostrup, Denmark). Staining was membranous Gleason grade and cytoplasmic in cancer and negative in normal tissue (Fig. 1). PSCA staining was typically found in either all ≤3 + 3 2888 236 (8%) (100%) or none (0%) of the cells in a cancer spot. Staining 3 + 4 7286 1269 (17%) intensity was semi-quantitatively assessed by visual exam- 3 + 4 Tertiary 5 573 133 (23%) ination of the stained slides under a microscope and 4 + 3 1301 594 (46%) grouped into four categories: Examples of negative, weak, 4 + 3 Tertiary 5 868 380 (44%) moderate and strong staining are in Fig. 1. ≥4 + 4 733 404 (55%) Statistics Nodal (pN) stage To study association between PSCA expression and pN0 7904 1896 (24%) clinico-pathological variables, contingency tables were cal- pN+ 856 524 (61%) culated and tested with the chi-square (likelihood) Surgical margin (R) status method. Analysis of variance and F-test was applied to Negative 10,962 1939 (18%) find associations between PSCA expression and tumor cell Positive 2649 1078 (41%) proliferation. Kaplan-Meier curves were generated for NOTE: Numbers do not always add up to 13,660 in the different categories PSA recurrence-free survival. Differences were checked by because of cases with missing data. Abbreviation: AJCC American Joint the log-rank test. Cox proportional hazards regression Committee on Cancer analysis was performed to test for independence and sig- nificance between pathological, molecular, and clinical variables. All calculations were done with JMP 11 (SAS In- stitute Inc., NC, USA). and was considered weak in 22.4%, moderate in 24.5% and strong in 6.8% of cancers. 4461 tumors (46.3%) showed no Results PSCA staining. A total of 9642 (70.6%) of TMA spots were interpretable. Non-informative cases (4023 spots; 29.4%) lacked tissue samples or unequivocal cancer tissue spots. PSCA staining PSCA expression and tumor phenotype was absent in glands, stromal tissue and inflammatory cells Absence of PSCA expression was linked to advanced of the normal prostate. In cancers, positive PSCA staining pathological tumor stage (p < 0.0001), high Gleason was seen in 5581 of our 9642 (53.7%) interpretable tumors grade (p < 0.0001), lymph node metastases (p < 0.0001), Heinrich et al. BMC Cancer (2018) 18:612 Page 3 of 9 Fig. 1 Representative images of (a) negative, (b) weak, (c) moderate and (d) strong PCSA staining in prostate cancer and (e) normal prostate at 100× and 400× (inset) magnification preoperative PSA level (p = 0.0118) and positive surgical 95% cancers. PSCA staining did not differ significantly margin (p < 0.0001). Data are summarized in Table 2. between ERG positive and ERG negative cancers (Fig. 2). PSCA expression and TMPRSS2:ERG fusion Association with other key genomic deletion Because TMPRSS2:ERG fusion is the predominant gen- Earlier studies had provided evidence for distinct etic marker in prostate cancer we analyzed its relation to molecular subgroups of prostate cancer defined by PSCA expression . Data on TMPRSS2:ERG fusion TMPRSS2:ERG fusion and several genomic deletions status obtained by FISH were available from 5241 and [32–37]. Therefore PSCA expression was compared by immunohistochemistry (IHC) from 7762 tumors with with preexisting data on 10q23 (PTEN), 3p13 evaluable PSCA staining. Data on both ERG FISH and (FOXP1), 6q15 (MAP3K7), and 5q21 (CHD1) dele- IHC were available from 5042 cancers, and an identical tion. PSCA expression did not differ notably between result (ERG IHC positive and break by FISH or ERG cancers with and without these deletions with the IHC negative and missing break by FISH) was found in exception of marginal association of positive PSCA Heinrich et al. BMC Cancer (2018) 18:612 Page 4 of 9 Table 2 Association between PSCA staining and prostate cancer phenotype Evaluable PSCA staining (%) Parameter (N) Negative Weak Moderate Strong P Total 9642 46.3 22.4 24.5 6.8 Tumor stage pT2 6003 41.5 23.6 26.9 8.0 < 0.0001 pT3a 2269 51.1 20.9 22.5 5.5 pT3b-pT4 1326 59.7 19.5 17.0 3.8 Gleason grade ≤3 + 3 1713 47.0 23.0 22.8 7.2 < 0.0001 3 + 4 5275 43.4 22.8 26.5 7.4 3 + 4 Tertiary 5 441 46.3 23.6 23.8 6.3 4 + 3 977 50.2 21.2 21.8 6.9 4 + 3 Tertiary 5 666 48.6 22.8 23.7 4.8 ≥4 + 4 562 61.6 17.4 17.8 3.2 Lymph node metastasis N0 5873 46.0 22.4 24.4 7.2 < 0.0001 N+ 674 59.9 19.1 17.7 3.3 Preoperative PSA level (ng/ml) < 4 1099 48.6 19.7 25.3 6.4 0.0118 4–10 5715 44.9 23.4 24.7 7.0 10–20 1995 46.9 21.8 24.1 7.3 > 20 724 51.2 20.0 23.6 5.1 Surgical margin Negative 7544 45.1 22.8 24.8 7.3 < 0.0001 Positive 1882 51.3 20.8 22.6 5.3 expression and 6q15- (p = 0.0318) respective 3p13- de- expression was lost in subgroups with comparable quantita- letion (p = 0.0019, Fig. 3). tive Gleason scores (Additional file 1:FigureS1). Tumor cell proliferation Multivariate analysis No association was found between PSCA staining and Four different multivariate scenarios were used to simulate tumor cell proliferation as measured by Ki67 labeling clinical decisions (Table 3). Scenario 1 evaluated the pre- index (p = 0.2211), neither in all cancers nor in subsets of operatively available parameters: Preoperative Gleason grade ERG negative or ERG positive cancer, or in tumor subsets obtained on the original biopsy, clinical tumor stage (cT with identical Gleason score (p > 0.05; data not shown). stage) and preoperative PSA together with the postopera- tively obtained PSCA expression. In scenario 2, the radical Association with PSA recurrence prostatectomy Gleason grade replaced the biopsy Gleason Follow-up data were available from 8410 patients with grade, while in scenario 3 pathological (pT) stage and interpretable PSCA staining. Tumors with negative PSCA surgical margin (R) status replaced cT stage. In scenario 4, staining showed a significantly shortened PSA the lymph node (pN) stage is added. Overall, PSCA recurrence-free interval compared with positively stained expression proved to be an independent favorable cancers (p < 0.0001, Fig. 4). This holds true for the subgroup prognostic parameter. The Cox hazard ratio for PSA of ERG fusion negative and positive cancer (data not shown). recurrence-free survival after radical prostatectomy between In further analysis weak, moderate and strong stained tu- weak and negative PSCA expression varied from 0.84 to mors were grouped as positive. PSCA expression provided 0.93 and was significant in scenario 1 and 2 (Table 3). additional prognostic impact in most subsets of cancer with identical classical Gleason grade group (p = 0.0346 for ≤3+ Discussion 3, p=0.0206 for 3+4, p=0.0092for 4+3and p =0.4423 for This study demonstrates that PSCA expression is signifi- ≥4+4, Fig. 5). However, the prognostic impact of PSCA cantly associated with favorable tumor phenotype and a Heinrich et al. BMC Cancer (2018) 18:612 Page 5 of 9 Fig. 2 No association between PSCA staining and ERG status neither when the latter was determined by immunohistochemistry nor by fluorescence in-situ hybridization; Breakage indicates rearrangement of the ERG gene reduced risk for PSA recurrence. A total of 54% of prostate expression but rather that a certain threshold for detection is cancers showed detectable PSCA expression in our IHC not reached. The threshold of detection is greatly influenced study. This is in the range of two other studies reporting in by the IHC protocol . Although Ross et al. and Reiter 88% of 126  or 48% of 233 patients  IHC positivity. et al.  used different antibodies and protocols; they obvi- These IHC findings are not contradictory to further studies ously resulted in a comparable sensitivity as in our study. describing at least a low level PSCA expression in all prostate We consider our protocol suited for studying the prognostic cancers utilizing polymerase chain reaction [5, 23]. It is well impact of PSCA expression as the selected conditions enable known that IHC negativity does not reflect the absence of a distinction of cancers with high and low levels of PSCA Fig. 3 Association analysis between negative versus positive (weak + moderate + strong) PSCA expression and deletion of 10q23 (PTEN), 6q15 (MAP3K7), 5q21 (CHD1) and 3p13 (FOXP1). *Asterisk denotes significant p-value Heinrich et al. BMC Cancer (2018) 18:612 Page 6 of 9 Fig. 4 Kaplan-Meier analysis of prostate specific antigen (PSA) recurrence after radical prostatectomy and negative versus weak, moderate and strong PSCA expression. *Asterisk denotes significant p-value expression. Given that normal prostate epithelial cells usually It is noteworthy that several investigators reported did not stain for PSCA, we assume that PSCA up-regulation contrary results. IHC with various and partly custom had occurred in a fraction of prostate cancers. The link be- made antibodies to conventional large sections of 40 tween cancer specific up-regulation of a protein and better  and 112  prostate cancers revealed associations prognosisisuncommon and arguesfora “protective” or with high Gleason score, advanced stage and castration tumor suppressive role. Our outcomes are in concordance resistant disease. Also in TMA studies including 114 with data from Larkin et al. , also reporting a link be-  and 246  prostate cancers the authors reported tween elevated PSCA expression and favorable clinical associations between strong PSCA expression and high course. A tumor suppressive role of high level PSCA expres- Gleason score. However, another TMA study on 64 sion is also supported from cell line models. For example, prostate cancers could not confirm these findings . functional analysis of cell lines from gastric and gallbladder We cannot explain the discrepancy between these stud- cancer demonstrated that forced overexpression of PSCA ies and our data obtained on almost 10,000 successfully hampered cell proliferation [12, 16]. analyzed carcinoma. Fig. 5 Kaplan-Meier plot of PSA recurrence-free survival and negative or positive (weak + moderate + strong) PSCA expression stratified for Gleason grade (≤3+ 3, n = 1535; 3 + 4, n = 3430; 4 + 3, n = 984; ≥4+4, n = 323). *Asterisk denotes significant p-value Heinrich et al. BMC Cancer (2018) 18:612 Page 7 of 9 Table 3 Hazard ratios of established prognostic parameters and control and development of deletion in prostate cancer. PSCA expression in prostate cancer This is in contrast to one experimental study, suggesting Scenario 1 2 3 4 an accelerating effect of PSCA loss on cell proliferation in a gastric cancer cell line . That PSCA expression was Analyzable (N) 8334 8454 8570 5801 completely unrelated to TMPRSS2:ERG fusion further Gleason grade biopsy demonstrates that PSCA is not significantly affected by 3 + 4 vs. ≤3 + 3 1.94*** any of the hundreds of genes that are deregulated in ERG 4 + 3 vs. 3 + 4 1.63*** fusion positive prostate cancer [44–47]. ≥4 + 4 vs. 4 + 3 1.39*** PSCA expression was significantly associated with favor- cT stage able patient outcome in our cohort. A possible clinical T2a vs. T1c 1.53*** 1.47*** relevance of this finding is supported by its statistical inde- pendence of classical prognostic markers, especially in a T3a vs. T2c 0.65* 1.07 pre-operative disease state. However, in comparison with Preoperative PSA level established features such as the Gleason score, the impact 4–10 vs. < 4 1.25* 1.21* 1.11 1.14 of PSCA expression on patient outcome was rather small. 10–20 vs. 4–10 1.58*** 1.41*** 1.25*** 1.16* If traditional prognostic Gleason groups were used, a > 20 vs. 10–20 1.67*** 1.47*** 1.23* 1.22* small prognostic impact was still found in Gleason 3 + 4 PSCA expression (p = 0.0206) or Gleason 4 + 3 (p = 0.0092). However, if these subgroups were further differentiated according to Positive vs. negative 0.84*** 0.86** 0.93 0.93 the fraction of Gleason 4 (quantitative Gleason grading Gleason grade ) these PSCA associated prognostic differences prostatectomy vanished. This further illustrates the high bar that molecu- 3 + 4 vs. ≤3 + 3 2.91*** 2.39*** 2.30*** lar characteristics have to overcome if compared with 4 + 3 vs. 3 + 4 2.72*** 2.24*** 2.05*** optimized morphologic analysis. ≥4 + 4 vs. 4 + 3 1.75*** 1.25* 1.21* pT stage Conclusions T3a vs. T2 1.94*** 1.94*** PSCA expression is a statistically independent predictor T3b vs. T3a 1.73*** 1.52*** of favorable prognosis in prostate cancer. Although its T4 vs. T3b 1.20 1.24 prognostic impact per se is not very strong, PSCA ex- Surgical margin pression analysis could be considered for inclusion in (R) status multi-parametric prognostic tests to distinguish prostate R1 vs. R0 1.40*** 1.18* cancers with need for radical therapy. Nodal (pN) stage N+ vs. N0 1.56*** Additional file Scenario 1 combines preoperatively available parameter (preoperative Gleason grade obtained on the original biopsy, clinical tumor (cT) stage, and Additional file 1: Figure S1. Kaplan-Meier plot of prostate specific preoperative PSA) with the postoperative PSCA expression. In scenario 2 the antigen (PSA) recurrence and PSCA expression stratified for quantitative biopsy Gleason is replaced by the Gleason grade obtained on radical Gleason grade. Note the different time scale for Gleason Tertiary 5 grades. prostatectomy. In scenario 3 cT stage is superseded by pathological tumor (pT) (DOC 2467 kb) stage and surgical margin (R) status. In scenario 4 the lymph node (pN) stage is added. Asterisk indicate significance level: * p ≤ 0.05, ** p ≤ 0.001, and *** p ≤ 0.0001 Abbreviations AR: Androgen receptor; CHD1: Chromodomain-Helicase-DNA-Binding Protein 1; ELAV1: Embryonic Lethal, Abnormal Vision, Drosophila)-Like 1; The mechanism for a tumor suppressive function of FISH: Fluorescence in-situ hybridization; FOXP1: Forkhead box protein P1; PSCA is unknown. In our study, we compared the expres- HOOK3: Hook Microtubule Tethering Protein 3; IHC: Immunohistochemistry; sion of PSCA with molecular attributes associated with MAP3K: Mitogen-Activated Protein Kinase Kinase Kinase 7; PSCA: Prostate stem cell antigen; PSA: Prostate specific antigen; PTEN: Phosphatase and genomic instability, chromosomal deletion and tumor cell tensin homolog; RPE: Radical prostatectomy; TMPRSS2: Transmembrane proliferation . We found previously that features with protease, serine 2; ERG: ETS-related gene fusion; TMA: Tissue microarray a role in cell cycle control (p16 orAPE1 ) were significantly associated with a high Ki67 labeling index. Acknowledgements We thank Julia Schumann, Sünje Seekamp and Inge Brandt for excellent Molecular attributes linked to genomic instability (MSH6/ technical assistance. PMS2/MLH1 , ELAV1 , or HOOK3 ) were found to be associated with chromosomal deletion. The Availability of data and materials lack of clear-cut association with these features argues All data generated or analyzed during this study are included in this against a relevant impact of PSCA on cell proliferation published article [and its Additional file 1]. Heinrich et al. BMC Cancer (2018) 18:612 Page 8 of 9 Authors’ contributions 12. Ono H, Hiraoka N, Lee YS, Woo SM, Lee WJ, Choi IJ, Saito A, Yanagihara K, MCH, AH, RS, and GS designed the study, and drafted the manuscript. HH1, Kanai Y, Ohnami S, et al. Prostate stem cell antigen, a presumable organ- MG, CB and TS participated in study design. MCH, AH, CG, CS1, CS2 dependent tumor suppressor gene, is down-regulated in gallbladder performed IHC analysis and scoring. PL and EB participated in pathology carcinogenesis. Genes Chromosomes Cancer. 2012;51(1):30–41. data analysis. CH-M and RS performed statistical analysis. TS, CK, MK, MCH, 13. Saeki N, Ono H, Sakamoto H, Yoshida T. Down-regulation of immune- HH2 and AH participated in data interpretation, and helped to draft the related genes by PSCA in gallbladder Cancer cells implanted into mice. manuscript. All authors read and approved the final manuscript. Anticancer Res. 2015;35(5):2619–25. 14. Wang L, Sang Y, Tang J, Zhang RH, Luo D, Chen M, Deng WG, Kang T. Ethics approval and consent to participate Down-regulation of prostate stem cell antigen (PSCA) by slug promotes The ethics committee of the Ärztekammer Hamburg approved this study metastasis in nasopharyngeal carcinoma. J Pathol. 2015;237(4):411–22. (WF-049/09 and PV3652). According to local laws (HmbKHG, §12,1) informed 15. Zhigang Z, Wenlv S. Prostate stem cell antigen (PSCA) expression in human consent was not required for this study. prostate cancer tissues: implications for prostate carcinogenesis and progression of prostate cancer. Jpn J Clin Oncol. 2004;34(7):414–9. Competing interests 16. 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Published: May 31, 2018