Research ArticleExperimental Studies

Relationship Between Stage-specific Embryonic Antigen-4 and Anti-cancer Effects of Neoadjuvant Hormonal Therapy in Prostate Cancer

TSUTOMU YUNO, YASUYOSHI MIYATA, TOMOHIRO MATSUO, YUTA MUKAE, ASATO OTSUBO, KENSUKE MITSUNARI, KOJIRO OHBA, TETSUJI SUDA, SEIICHI SAITO and HIDEKI SAKAI
Anticancer Research October 2020, 40 (10) 5567-5575; DOI: https://doi.org/10.21873/anticanres.14569

Abstract

Background/Aim: Stage-specific embryonic antigen-4 (SSEA-4) expression is associated with malignant aggressiveness and is useful as a marker for identifying cancer stem cells. Our aim was to assess the relationship between hormonal therapy and SSEA-4 expression in prostate cancer (PC). Materials and Methods: SSEA-4 expression in paired specimens from PC patients who underwent neoadjuvant hormonal therapy (NHT) and radical prostatectomy (60 pre-NHT specimens and 60 post-NHT specimens) was evaluated using immunohistochemistry. Proliferation index (PI) and apoptotic index (AI) were also evaluated. Results: Post-NHT tissues had significantly elevated SSEA-4 expression whereas anti-tumor effects of NHT were inversely correlated with SSEA-4 expression level. SSEA-4 expression in post-NHT tissues was significantly associated with biochemical recurrence-free survival. SSEA-4 expression in the post-NHT tissues was positively associated with PI and negatively done with AI. Conclusion: SSEA-4 is a potential therapeutic target for limiting the malignant potential in hormone-naïve PC when considering the use of NHT.

Prostate cancer (PC) is the most commonly diagnosed cancer among men and the second leading cause of cancer-related deaths among men in the United States (1). Although many patients with early PC have elevated serum concentrations of prostate-specific antigen (PSA), approximately one-third of patients already have metastasis at the time of diagnosis (2). In general, hormonal therapy involves androgen-deprivation therapy (ADT), which is a standard and effective treatment for patients with metastatic PC. Unfortunately, the majority of androgen-dependent PC cells gradually become androgen-independent cells during ADT, which leads to metastatic PC becoming resistant to hormonal therapy and progressing to castration-resistant prostate cancer (CRPC) (3). There are various treatments for CRPC, which involve chemotherapeutic agents, androgen receptor-axis-targeted agents, and immunotherapeutic agents (4-6). While these treatments can improve survival outcomes in CRPC cases, the increase in progression-free survival (PFS) and overall survival (OS) remains suboptimal.

The suboptimal outcomes in CRPC cases are partly related to our poor understanding of the molecular mechanisms that lead to hormonal therapy resistance. In this context, it is important to understand that cancer stem cells (CSCs) play important roles in PC tumor growth and treatment resistance, as their pluripotency and self-renewal capability allow these cells to differentiate into diverse new cancer cells (7). Sex determining region Y-box-2 (Sox-2) is a major CSC marker, and its expression in PC cells is increased after androgen deprivation. The latter has been positively associated with cell growth and resistance to anti-androgen agents in both androgen-dependent and androgen-independent PC cells (8). Therefore, it is important to understand the interactions between hormonal therapy and CSCs, which may provide insight regarding PC tumor development and resistance to hormonal therapy.

Changes in carbohydrate chains are associated with malignant phenotypes in various cancers (9, 10). Gangliosides are sialic acid-containing glycosphingolipids involved in cell adhesion, motility, and invasion (10). Our group and other researchers have demonstrated that positive immunostaining for monosialosyl globopentaosylceramide (MSGb5, originally known as stage-specific embryonic antigen-4 or SSEA-4) was observed in most renal cell carcinoma and testicular tumors (11-15). We have also recently found that SSEA-4 expression plays crucial roles in malignant aggressiveness and outcomes among patients with hormone-naïve PC (16). Furthermore, SSEA-4 is a well-known specific marker for pluripotent stem cells and a useful marker for identifying CSCs (17). Moreover, SSEA-4 expression is associated with remodeling and renewal in a variety of malignant cells (18-20) and is reportedly correlated with regenerative potential and loss of the epithelial phenotype in PC cells (21, 22). Therefore, we hypothesized that SSEA-4 may be a CSC marker in PC, and that its expression might be associated with hormonal therapy resistance in these patients.

The present study aimed to delineate the relationship between hormonal therapy and SSEA-4 expression in PC tissues, in order to better understand its pathological and prognostic significance. However, from a practical and ethical perspective, it would be difficult to compare SSEA-4 expression and its pathological significance before and after hormonal therapy for patients with advanced PC. Therefore, we investigated three topics: i) changes in SSEA-4 expression among patients who underwent neoadjuvant hormonal therapy (NHT) and radical prostatectomy (RP), ii) the prognostic significance of SSEA-4 expression based on histological findings and biochemical recurrence (BCR) following NHT, and iii) the pathological significance of SSEA-4 expression based on cancer cell proliferation and apoptosis indexes.

Materials and Methods

Patients. We investigated SSEA-4 expression in 60 patients with PC that underwent diagnostic biopsy, NHT, and RP at the Nagasaki University Hospital. In short, a total 120 specimens composed of pre-NHT and post-NHT specimens were analyzed. In this study, all patients underwent magnetic resonance imaging (MRI) of the prostate, computed tomography (CT) of the abdomen and pelvis, bone scanning, and lung x-ray photography. Subjects were excluded if they had: i) a short duration of NHT (<3 months), ii) T4 disease, iii) presence of metastasis, or iv) non-adenocarcinoma histological types. In addition, we also excluded the patients judged as low-risk cancer (T1-T2a, Gleason score/ grade group 6, and PSA <10 ng/ml). The patients' clinicopathological features are shown in Table I. The median duration of NHT was 7 months [interquartile range (IQR)=4-10 months], and the treatments consisted of anti-androgen agents alone (n=1, 1.7%), luteinizing hormone-releasing hormone agonists alone (n=28, 46.7%), or maximum androgen blockade (n=31, 51.7%). All tumors were judged to be adenocarcinomas.

Immunohistochemistry. We have previously reported our detailed immunohistochemical staining methods for SSEA-4 in PC tissues (16). In addition, cancer cell proliferation (proliferation index; PI) and cancer cell apoptosis (apoptotic index; AI) in PC tissues were evaluated using methods from previous reports (23-25). A monoclonal mouse IgM antibody (clone RM1) that targets MSGb5 (SSEA-4) was used as the primary antibody (12). This antibody was a gift from the department of the urology, University of the Ryukyus (Okinawa, Japan). Previous reports have indicated that this antibody is useful for immunohistochemistry and has detected SSEA-4 expression in several malignancies (15, 16, 26). For the present study, the tissue sections were also incubated with peroxidase using the CSA II kit (Dako Corp., Carpinteria, CA, USA). The PI was evaluated using an antibody that targets Ki-67 (Dako Corp.) and the Dako EnVision+™ Peroxidase kit (Dako Corp.). The peroxidase reaction for the SSEA-4 and Ki-67 assays was visualized using liquid 3,3’-diaminobenzidine tetrahydrochloride substrate (Thermo Fisher Scientific, Rockford, IL, USA), and the sections were counterstained using hematoxylin. The AI was evaluated using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the ApopTag In Situ Apoptosis Detection Kit (Intergen Company, Purchase, NY, USA).

View this table:
Table I.

Clinicopathological features.

Evaluation of SSEA-4 expression, cancer cell proliferation, and apoptosis. Cancer cells' expression of SSEA-4 was semi-quantitatively evaluated based on the staining intensity and proportion, as previously reported (2, 27, 29). The proportion of staining was graded as i) no staining (−; score 0), ii) weak and/or focal staining (<10 % of cells; score 1+), iii) intermediate staining (10-50 % of cells; score 2+), and iv) moderate or strong staining (>50 % of cells, score 3+). For the present study, low SSEA-4 expression was defined as expression scores of 0-1+ and high SSEA-4 expression was defined as expression scores of 2-3+. The PI was evaluated based on the proportion of Ki-67-positive to negative cells and the AI was evaluated based on the proportion of TUNEL-positive to negative cells, with a minimum evaluation of >300 cancer cells.

These semi-quantitative analyses were independently performed by three investigators (TY, TM, and YM), who were blinded to the patients' clinicopathological features and hormonal therapy. The SSEA-4 expression statuses were judged based on the majority opinions without any major disagreements. All slides were examined using a Nikon E-400 microscope and digital images were captured (Nikon DU100, Japan). The various scores were assigned using a computer-aided image analysis system (Win ROOF, version 5.0; MITANI Corp., Japan).

Figure 1.
Figure 1.

Representative expression of SSEA-4. (A) pre-NHT biopsy specimens (magnification ×200) and (B) post-NHT radical prostatectomy specimens (magnification ×200). NHT: Neoadjuvant hormonal therapy.

Evaluation of anti-cancer effects. Patients were considered to have developed BCR if their serum concentrations of PSA were >0.2 ng/ml. The histopathological effects of NHT were evaluated according to the Japanese Urological Association guidelines in the “General Rule for Clinical and Pathological Study on Prostate Cancer”. This system classifies the histological response to NHT as non-effective (almost all cancer cells were viable or <50% of cancer cells were nonviable) and effective (>50% of cancer cells were nonviable) (23).

Ethics. This retrospective study complied with the principles of the Declaration of Helsinki and its revisions. The study protocol was approved by the institutional review board of Nagasaki University Hospital (16K15690), and a written informed consent was obtained from all patients.

Statistical analyses. Data were expressed as median, IQR. The Mann-Whitney U-test was used to compare continuous variables. Changes in SSEA-4 expression following NHT were evaluated using the Wilcoxon signed rank test. Categorical variables were compared using the chi-squared test and the Fisher's exact test, as appropriate. Survival analyses were performed using Kaplan-Meier curves and the log-rank test, as well as Cox proportional hazards models, with the results reported as hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). The results of the logistic regression analyses were reported as odds ratios (ORs) and 95%CIs. Pearson's correlation coefficient was used to evaluate the relationship between continuous variables, and Spearman's rank correlation coefficient was used to confirm these findings. To evaluate the correlations according to SSEA-4 expression, the expression scores were converted to: i) no expression to 1, ii) 1+ expression to 2, iii) 2+ expression to 3, and iv) 3+ expression to 4. All statistical analyses were two-sided, and significance was defined as p-values of <0.05. All analyses were performed using the StatView for Windows package (version 5.0; Abacus Concept Inc., Berkeley, CA, USA).

Results

Changes of SSEA-4 expression after NHT. Representative figures of SSEA-4 expression in pre-NHT biopsy specimens and post-NHT RP specimens are shown in Figures 1A and B. We have previously reported that SSEA-4 is mainly expressed in the cytoplasm of hormone-naïve PC cells (16). The present study revealed similar findings in post-NHT PC tissues. As shown in Figure 2, SSEA-4 expression was significantly higher in the post-NHT specimens compared to the pre-NHT specimens (p=0.003). Moreover, cases with no SSEA-4 expression were substantially less common in the post-NHT group compared to the pre-NHT group (13.3% vs. 44.3%).

Biological significance of SSEA-4 expression. Figure 3 shows the relationship between SSEA-4 expression and PI or AI. Expression of SSEA-4 was not associated with PI in the pre-NHT group (p=0.639). However, in the post-NHT group, the median PI in SSEA-4-positive tissues was significantly higher compared to SSEA-4-negative tissues [6.6 (IQR=4.5-9.3) vs. 2.5 (IQR=1.7-4.0), p<0.001] (Figure 3A). Thus, it appeared that SSEA-4 expression was associated with increased proliferation in post-NHT tissues. In fact, expression of SSEA-4 appeared significantly associated with AI in both pre-NHT and post-NHT groups (Figure 3B), which suggests that SSEA-4 expression is associated with decreased apoptosis, regardless of the NHT status.

We also evaluated the relative changes in SSEA-4 expression following NHT, based on the post/pre ratios for PI and AI. The post-NHT/pre-NHT ratio of SSEA-4 expression was positively correlated with the post-NHT/pre-NHT ratio of PI (r=0.42, p<0.001) (Figure 4A). In contrast, the post-NHT/pre-NHT ratio of SSEA-4 expression was inversely correlated with the post-NHT/pre-NHT ratio of AI (r=0.377, p=0.003) (Figure 4B).

Figure 2.
Figure 2.

Quantification of SSEA-4 expression. in post-NHT tissues. SSEA-4 expression was significantly higher compared to pre-NHT tissues. The frequency of no SSEA-4 expression in post-NHT tissues was remarkably lower compared to that of pre-NHT tissues (13.3% vs. 43.3%). NHT: Neoadjuvant hormonal therapy. The portion of stained tissue was shown as mean±SD.

Impact of SSEA-4 expression on treatment response and prognosis. Twenty-four specimens (53.5%) out of the 45 pre-NHT specimens with a low level of SSEA-4 expression were judged to have a positive histological response to NHT (Table II), while only 2 specimens (13.3%) out of the 15 specimens with a high level of SSEA-4 expression had a positive histological response to NHT. Thus, the SSEA-4 expression level in pre-NHT tissues was inversely associated with a histological response to NHT (p=0.001). Similarly, the inverse correlation was also observed when we considered the post-NHT specimens (Table II). The Kaplan-Meier survival curves revealed that the high level of SSEA-4 expression in post-NHT tissues obtained by radical prostatectomy was associated with a significantly shorter BCR-free survival period, relative to cases with low level of SSEA-4 expression (log-rank p=0.020) (Figure 5). The prognostic value of SSEA-4 expression was evaluated using a multivariate model with adjustment for clinicopathological features. After adjusting for clinical T status, grade group, and duration of NHT, high expression of SSEA-4 in biopsy specimens was a strong negative predictor of histological response (OR=0.06, 95%CI=0.10-0.41, p=0.004). Similarly, high expression of SSEA-4 expression in RP specimens was associated with an elevated risk of BCR (HR=2.35, 95%CI=1.04-5.32, p=0.040) in a multi-variate analysis model including pathological T status and duration of NHT.

Discussion

In the present study we evaluated the relationship between SSEA-4 expression and hormonal therapy in PC tissues. We showed that NHT increased SSEA-4 expression in PC cells, suggesting that SSEA-4-positive cells were resistant to hormonal therapy, and therefore survived and proliferated, whereas SSEA-4-negative cells were vulnerable to hormonal therapy. In addition, the SSEA-4 expression level in pre-NHT tissues was inversely associated with the histological response to NHT, and its expression in post-NHT tissues was a significant predictor of BCR after RP. In this context, SSEA-4 expression could be involved in drug resistance as increased expression of SSEA-4 has been observed in renal cell carcinoma and breast cancer in relation to chemotherapy resistance (11, 13, 15, 29). Furthermore, SSEA-4 expression is reportedly increased during carcinogenesis, and has been observed as such in various tumors in association with the malignant potential (16, 26, 27, 29, 30). Our findings here support these relationships.

In addition to its pathological significance, SSEA-4 expression is a marker for CSCs and is associated with a loss of the epithelial phenotype in a variety of cancers (20, 30, 31). Moreover, CSCs are typically resistant to conventional therapies and exhibit a dynamic self-renewal potential (21), thus, it is unlikely that ADT will have a substantial effect on prostate CSCs (7, 32). These findings support our conclusion that SSEA-4 expression may be a useful marker for predicting anti-cancer effects among patients with PC who undergo NHT and RP, including the histological response and BCR-free survival.

We believe that our findings highlight important information regarding the pathobiological significance of SSEA-4-positive PC cells. For example, even though the NHT duration was relatively short, SSEA-4 expression in post-NHT tissues was significantly higher compared to pre-NHT tissues. Previous reports have indicated that hormonal therapy, including anti-androgen, ADT, and castration, may trigger of the development and expansion of prostate CSCs based on both in vivo and in vitro experiments (3, 33, 34). It is unclear whether these changes occur in early-stage PC tissues, although it has been thought to commonly occur in advanced PC and CRPC (35). In this sense, for the first time we showed that the increased SSEA-4 expression following NHT was observed in organ-confined disease without metastasis, indicating CSC as designated by SSEA-4 expression will expand even in early PC. Thus, we speculate that SSEA-4 expression may help identify the acquisition of stem cell-like characteristics in PC cells, even in hormone-naïve PC. A previous report has also indicated that ADT leads to the expansion of prostate CSCs (36), and ADT-treated PC cells often develop very aggressive phenotypes, such as neuroendocrine or squamous differentiation and sarcomatous changes (37, 38). Similarly, increased SSEA-4 expression has been associated with loss of the epithelial phenotype in solid tumor cells (21), which supports our theory that SSEA-4 expression can predict anti-cancer effects and outcomes among patients who are receiving NHT for PC.

Figure 3.
Figure 3.

Cancer cell proliferation. In prostate cancer tissues with high SSEA-4 expression proliferation was significantly higher (p<0.001) compared to negative expression post-NHT tissues. Such a significant relationship was not detected in pre-NHT tissues, while an inverse correlation was found between SSEA-4 expression and cancer cell apoptosis for both of pre- and post-NHT tissues. NHT: Neoadjuvant hormonal therapy.

Another important result from this study is that SSEA-4 expression was associated with cancer cell proliferation and apoptosis in PC tissues. Previous reports have also indicated that SSEA-4 expression is significantly associated with cancer cell apoptosis in several cancers, including PC (6, 16, 37). It is of note that significant anti-apoptotic functions remained in SSEA-4-positive PC cells following NHT. Moreover, we observed a significant relationship between SSEA-4 expression and PI in post-NHT tissues, which was not observed in pre-NHT tissues. Regarding the relationship between SSEA-4 expression and cancer cell proliferation, we have previously reported that SSEA-4 expression was not associated with PI in cancer cells from 117 RP specimens that had not been exposed to NHT (16). Although PI was measured using needle biopsy specimens in that study, both of these findings suggest that SSEA-4 expression is not significantly related to cancer cell proliferation before hormonal therapy exposure, which would imply that SSEA-4 plays little or no role in the proliferation of hormone-naïve PC cells. However, it is reasonable that SSEA-4-positive cells potentially have a high proliferative capacity because these cells took on mesenchymal characteristics (21). The other molecular changes induced by NHT, which are related to proliferative activity, may be linked to the increase in SSEA-4 expression. Although it was assumed that the stimulating function of SSEA-4 on proliferation may be influenced by hormonal therapy in PC, we cannot definitively comment on the potential underlying mechanisms, based on the study design.

Figure 4.
Figure 4.

Change of cancer cell proliferation by neo-adjuvant hormonal therapy. (post/pre ratio of proliferation index) was positively correlated to change of SSEA-4 expression by the therapy (A). In contrast, post/pre ratio of apoptotic index was negatively correlated to post/pre ratio of SSEA-4 expression (B). NHT: Neoadjuvant hormonal therapy.

Figure 5.
Figure 5.

Kaplan-Meier survival curves. SSEA-4 expression in post-NHT tissues obtained through radical operation was identified as a useful predictor for biochemical recurrence-free survival rate. NHT: Neoadjuvant hormonal therapy.

View this table:
Table II.

Correlation between SSEA-4 expression and histological effect.

The growth of androgen-sensitive PC cells was increased by hormonal therapy in one study, and MUC-1was a key regulator of this mechanism (39). In our current study, increased expression of SSEA-4 after NHT has helped enhance cancer cell proliferation in post-NHT tissues, reflected in the increased proportion of SSEA-4-positive prostate CSCs after NHT. Moreover, it is possible that other factors modulate the proliferative activity of SSEA-4 according to the status of hormonal therapy. For example, SSEA-4 activity in solid tumors is reportedly influenced by a variety of growth factors, genetic background, as well as the tissue microenvironment, including immune status, the epithelial to mesenchymal transition, and exosomes (40-42). Therefore, more detailed studies are needed to evaluate the effects of hormonal therapy on the proliferative function of SSEA-4 in order to clarify the pathological significance of SSEA-4 expression after NHT in PC.

The present study has several limitations. The first limitation is the relatively small sample size, although we believe this is the first study to evaluate the changes in SSEA-4 expression after NHT using paired clinical specimens. In contrast, in previous studies, which compared pre-NHT and post-NHT specimens from different individuals, it may be difficult to interpret the results precisely because the backgrounds of clinicopathological and genetic features were different. The second limitation is that there are still conflicting opinions regarding the identification of prostate CSCs and their contribution to malignant aggressiveness and tumor progression in PC. Our findings indicate that SSEA-4 expression can help identify prostate CSCs, which have an increased likelihood of malignant behavior and hormonal therapy resistance. Nevertheless, it remains unclear whether SSEA-4 expression is related to the expression of other known prostate CSCs markers, such as CD34, CD44, and CD133 (43-45). Therefore, detailed studies are needed to compare CSCs that are positive for SSEA-4 and other known CSC markers, which may help improve our understanding of prostate CSC identification and malignant potential. The final limitation here is that our study population has patients with grade group 6 and it is not a prospective study. In general, NHT is not recommended for low-risk PC (46). Therefore, we excluded these patients to avoid the bias for survival analyses.

In conclusion, SSEA-4 expression was increased in organ-confined PC tissues following NHT. In addition, SSEA-4 expression was an independent predictor for the histological response to NHT and BCR-free survival following NHT and RP. Furthermore, an inverse relationship between SSEA-4 expression and apoptosis was observed in both pe-NHT and post-NHT tissues, while a positive association between SSEA-4 expression and proliferation was shown only in post-NHT tissues. Therefore, SSEA-4 expression is speculated to be associated with resistant mechanisms against hormonal therapy.

Acknowledgements

This study was supported in part by funds provided by KAKENHI (Grant-in-Aid for Exploratory Research) to Yasuyoshi Miyata (16K15690).

Footnotes

  • Authors' Contributions

    Study concept: YMi and SS. Study design: YM. Clinical data collection: TY, YM, YMu, AO. Immunohistochemical analyses: TY, YMu, AO, KM, TM, OK and TS. Statistical analyses: YM. Manuscript preparation: TY and YMi. Manuscript editing: SS. Manuscript review: HS. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    None of the Authors have any conflicts of interest regarding this study.

  • Received July 6, 2020.
  • Revision received July 29, 2020.
  • Accepted August 3, 2020.

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Relationship Between Stage-specific Embryonic Antigen-4 and Anti-cancer Effects of Neoadjuvant Hormonal Therapy in Prostate Cancer
TSUTOMU YUNO, YASUYOSHI MIYATA, TOMOHIRO MATSUO, YUTA MUKAE, ASATO OTSUBO, KENSUKE MITSUNARI, KOJIRO OHBA, TETSUJI SUDA, SEIICHI SAITO, HIDEKI SAKAI
Anticancer Research Oct 2020, 40 (10) 5567-5575; DOI: 10.21873/anticanres.14569
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