Research ArticleClinical Studies

Tissue Expression and Prognostic Role of CXCL12 and CXCR4 in High-grade Serous Ovarian Carcinoma

HYUNJI LIM, SE IK KIM, EUN NA KIM, MARIA LEE, CHEOL LEE, JAE-WEON KIM and HYUN HOON CHUNG
Anticancer Research July 2023, 43 (7) 3331-3340; DOI: https://doi.org/10.21873/anticanres.16509

Abstract

Background/Aim: The complex of C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), plays an essential role in cancer cell proliferation, invasion, and metastasis. These are emerging therapeutic targets, and recent studies have reported that inhibition of CXCL12-CXCR4 signaling pathway enhances the effects of immune checkpoint inhibitors. Thus, we aimed to investigate tissue expression of CXCL12 and CXCR4 in high-grade serous ovarian carcinoma (HGSOC) and to determine their potential as prognostic markers. Patients and Methods: We used chemotherapy-naïve, formalin-fixed paraffin-embedded primary ovarian cancer tissues obtained from patients with advanced-stage HGSOC at the time of primary cytoreductive surgery. After histological reassessment, we constructed a tissue microarray and performed immunohistochemical staining for CXCL12 and CXCR4. Thereafter, clinicopathological characteristics and survival outcomes were compared between the high- and low-expression groups. Results: A total of 97 patients with FIGO stage IIIC-IV HGSOC were included: 15 (15.5%), 66 (68.0%), and 13 (13.4%) patients showed high expression of CXCL12, CXCR4, and both, respectively. The expression level of each protein was not associated with germline BRCA1/2 mutational status, FIGO stage, or residual tumor after primary cytoreductive surgery. In multivariate analysis adjusted for confounders, high CXCL12 expression was identified as an independent poor prognostic biomarker for progression-free survival (adjusted hazards ratio, 1.990; 95% confidence interval=1.090-3.633; p=0.025). However, CXCR4 expression was not associated with patient survival outcomes. Conclusion: The CXCL12 expression level may represent a prognostic biomarker for HGSOC. Proteins related to the CXCL12/CXCR4 complex may serve as therapeutic targets in HGSOC treatment.

Key Words:

Epithelial ovarian cancer (EOC) is one of the deadliest gynecologic malignancies, with a poor 5-year survival rate of less than 30% in the advanced stages (1). Owing to the lack of effective screening tools and early symptoms, more than 80% of EOC cases are diagnosed at an advanced stage, with high recurrence and mortality rates (2). Among the various histological subtypes of EOC, high-grade serous ovarian carcinoma (HGSOC) represents the most common subtype, accounting for 65% of EOC cases (3). Extensive cytoreductive surgery, followed by platinum- and taxane-based combination chemotherapy, remains the standard treatment for HGSOC. Despite primary treatment, most cases of HGSOC eventually relapse. Therefore, precise prediction of individual prognosis is important and represents the key to implementation of precision cancer medicine in HGSOC.

The tumor microenvironment can affect the entire process from cancer development to metastasis (4). C-X-C motif chemokine ligand 12 (CXCL12), also known as stromal cell-derived factor 1α, and G-protein-coupled C-X-C motif chemokine receptor 4 (CXCR4) represent two key factors in the tumor microenvironment. The CXCL12/CXCR4 complex plays an essential role in cancer cell proliferation, invasion, metastasis, and resistance to treatment. The complex promotes cancer cell proliferation and migration; however, it inhibits tumor apoptosis by activating nuclear factor kappa B through phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. It also interacts with vascular endothelial growth factor (VEGF) to induce tumor angiogenesis and peritoneal metastasis (5, 6). The level of the CXCL12/CXCR4 complex is increased in many types of cancer, including ovarian carcinoma (7-9). In previous studies, high expression of CXCL12 and CXCR4 has been found to be significantly related to metastasis and poor survival in various cancers, such as breast, gastric, pancreatic, colorectal, and ovarian cancers (5, 9-15).

Popple et al. reported that high tissue expression of CXCL12 in EOC is associated with poor disease-specific survival (12). However, the histologic subtypes and stages of EOCs were not considered in this study. In addition, only eight patients received postoperative adjuvant platinum- and taxane-based combination chemotherapy, which is the current standard of care. Thus, in the present study, we aimed to investigate the tissue expression of CXCL12 and CXCR4 in advanced-stage HGSOC and to determine their potential as prognostic markers.

Patients and Methods

Study design. This retrospective cohort study was approved by the institutional review board of Seoul National University Hospital (SNUH; No. H-2101-054-1187). We included patients who met the following criteria: 1) diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III-IV HGSOC, 2) underwent primary cytoreductive surgery between June 2012 and December 2018, 3) received postoperative taxane- and platinum-based adjuvant chemotherapy, and 4) agreed to donate their pathologic specimens for research purposes and provided written informed consent. Exclusion criteria included: patients whose archival tissues could not be retrieved, patients who did not provide written consent before the surgery, diagnosed with malignancies other than HGSOC, lost to follow-up, or had insufficient clinicopathological data.

Immunohistochemistry for CXCL12 and CXCR4. We retrieved archival chemotherapy-naïve, formalin-fixed paraffin-embedded (FFPE) ovarian tissues that were obtained at the time of initial cytoreductive surgery of primary (non-metastatic) ovarian cancer. After histological reassessment using hematoxylin and eosin (H&E) staining, a tissue microarray (TMA) was generated by embedding three cores (2 mm in diameter) per patient in new recipient FFPE blocks. Subsequently, TMA blocks were cut into 4 μm thick sections and subjected to immunohistochemical (IHC) staining for CXCL12 and CXCR4 using a benchmark autostainer (Ventana, Tucson, AZ, USA) according to the manufacturer’s instructions. The following two monoclonal antibodies were used: 1:100 diluted MAB350 (R&D Systems, Inc., Minneapolis, MN, USA) for CXCL12 and 1:2,000 diluted ab124824 (Abcam, Cambridge, UK) for CXCR4. We included positive control tonsil tissue samples for CXCL12 and CXCR4. Antibodies were omitted for negative controls. CXCR4 and CXCL12 expression was evaluated in tumor cells. Two pathologists (C.L. and E.N.K.) independently evaluated the proportion of stained cells (Pi) and staining intensity (i) to calculate the histochemical score (H-score). The i values are indicated as 0 (no evidence of staining), 1 (weak staining), 2 (moderate staining), and 3 (strong staining). The Pi values vary from 0% to 100%. The final H-score is derived from the sum of i multiplied by Pi as the equation below (16).

Embedded Image

The average of the H-score values was regarded as patient specific. As there are no well-established cut-off values, we determined the optimal cut-off values for each IHC staining based on the sample distribution. Finally, the patients were stratified into high- and low-expression groups.

Data collection. We reviewed the patient medical records and collected their baseline data, such as age, initial serum cancer antigen (CA)-125 levels, FIGO stage, presence of residual tumor after cytoreductive surgery, adjuvant chemotherapy regimen, and the status of BRCA1/2 gene mutation. After completion of the primary treatment, all patients underwent surveillance involving computed tomography scans every three months for the first two years, every 4-6 months for the next two years, and thereafter every year. Disease progression was determined according to the Response Evaluation Criteria in Solid Tumors version 1.1 (17). In terms of survival data, progression-free survival (PFS) and overall survival (OS) were defined as time intervals from the date of primary cytoreductive surgery to the date of disease progression and to the date of cancer-related death or last visit to follow-up, respectively.

Statistical analysis. The optimal cut-off values for CXCL12 and CXCR4 were determined by maximally selected log-rank statistics (maxstat) using R statistical software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria). Then, we compared baseline characteristics between the high- and low-expression groups using the Student’s t-test or Mann–Whitney U-test for continuous variables and the Pearson chi-square or Fisher exact test for categorical variables. Survival outcomes were compared between the two groups using the Kaplan–Meier method with the log-rank test. In the multivariate analyses, Cox proportional hazards regression analyses were conducted to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was set at p<0.05 based on a two-sided hypothesis. All statistical analyses were performed using the SPSS statistical software (version 27.0; IBM Corp., Armonk, NY, USA) and GraphPad Prism 5 software (GraphPad Inc., La Jolla, CA, USA).

Results

Patient characteristics. A total of 97 patients with FIGO stage III-IV HGSOC were included in this analysis. Expression levels (or scores) of CXCL12 and CXCR4 did not correlate with initial serum CA-125 levels (p=0.425 and p=0.712, respectively) (Figure 1). A significantly lower CXCL12 score was observed in patients with stage IIIA/B disease than in those with stage IIIC disease (median, 3.3 vs. 11.7; p=0.014) or those with stage IV disease (median, 3.3 vs. 13.3; p=0.003; Figure 2). However, no difference was observed in the CXCL12 score between patients with stage IIIC and stage IV disease (median, 11.7 vs. 13.3; p=0.243). CXCR4 scores were similar across the FIGO stages (p=0.988). Residual tumors after surgery were not associated with the CXCL12 (p=0.991) or CXCR4 score (p=0.853).

Figure 1.
Figure 1.

Correlation between serum cancer antigen-125 (CA-125) levels and (A) CXCL12 and (B) CXCR4 scores.

Figure 2.
Figure 2.

Relationship between the CXCL12 and CXCR4 scores and other characteristics. (A, C) International Federation of Gynecology and Obstetrics (FIGO) stage. (B, D) Residual tumor after surgery.

The cut-off values for CXCL12 and CXCR4 were 40 and 20, respectively (Figure 3). Of the patients, 66 (68.0%) and 15 (15.5%) patients showed high CXCR4 and CXCL12 expression levels, respectively. Furthermore, 13 of 15 patients (86.7%) in the high-CXCL12-expression group had high expression levels of CXCR4 (Figure 4).

Figure 3.
Figure 3.

Results of immunohistochemistry staining for CXCL12 and CXCR4: (A) High- and (B) Low-expression of CXCL12; (C) High- and (D) Low-expression of CXCR4. ×200.

Figure 4.
Figure 4.

Distribution of patients according to the expression levels of CXCL12 and CXCR4.

Table I shows the comparisons of patient clinicopathologic characteristics according to the expression level of CXCL12. No differences in patient age, serum CA-125 levels, FIGO stage, residual tumor after primary cytoreductive surgery, chemotherapy regimen, and germline BRCA1/2 mutational status were observed between the high- and low-expression groups. In relation to CXCR4, the high- and low-expression groups showed similar age, serum CA-125 levels, FIGO stage, residual tumor after surgery, chemotherapy regimen, and germline BRCA1/2 mutational status (Table II).

View this table:
Table I.

Clinicopathologic characteristics of the patients based on CXCL12 expression.

View this table:
Table II.

Clinicopathologic characteristics of the patients based on CXCR4 expression.

Survival outcomes. During 42.6 months of a median observation period, 65 patients (67.0%) experienced disease recurrence, and 17 patients (17.5%) died of the disease. Patients with high CXCL12 expression showed a significantly worse PFS than patients with low CXCL12 expression (median, 16.8 vs. 27.6 months; p=0.015); however, they showed a similar OS (3-year OS rate, 93.3% vs. 92.8%; p=0.145) (Figure 5A and B). Between the high- and low-CXCR4-expression groups, no differences in PFS (median, 26.0 vs. 27.7 months; p=0.515) and OS (3-year OS rate, 94.6% vs. 89.2%; p=0.860) were observed (Figure 5C and D).

Figure 5.
Figure 5.

Comparisons of survival outcomes between high- and low-expression groups of CXCL12 (upper) and CXCR4 (lower). (A, C) Progression-free survival. (B, D) Overall survival.

In multivariate analysis adjusted for confounders, residual tumor after surgery (adjusted HR=1.729; 95%CI=1.036-2.886; p=0.036) and high CXCL12 expression (adjusted HR=1.997; 95%CI=1.039-3.840; p=0.038) were identified as independent poor prognostic factors for PFS. However, CXCR4 expression was not associated with patient survival (Table III). Next, we investigated the co-expression of CXCL12 and CXCR4. In total, 13 patients who had high expression of both CXCL12 and CXCR4 showed significantly worse PFS (median PFS, 16.3 vs. 27.6 months; p=0.004) and OS (3-year OS rate, 92.3% vs. 93.0%; p=0.035) (Figure 6). When multivariate analysis was conducted with CXCL12/CXCR4 co-expression, co-overexpression of the two biomarkers was also an independent predictable biomarker (adjusted HR=2.413; 95%CI=1.179-4.940; p=0.016; Table III).

Figure 6.
Figure 6.

Comparison of survival outcomes between high expression of both CXCL12 and CXCR4 and others. (A) Progression-free survival. (B) Overall survival.

View this table:
Table III.

Univariate and multivariate analyses of progression-free survival in all study population.

Discussion

Among patients with advanced-stage HGSOC, 68.0% showed high CXCR4 expression, while 15.5% showed high CXCL12 expression. Based on our study results, high CXCL12 expression may represent a poor prognostic biomarker in advanced-stage HGSOC, as CXCL12 expression was associated with significantly worse PFS. Furthermore, worse PFS and OS were observed in patients with high expression of both CXCL12 and CXCR4. However, this should be interpreted carefully because the number of deaths was rather small. Considering the relatively worse PFS in the high-CXCL12-expression group, CXCL12 might induce chemoresistance in ovarian cancer. Previously, Zhang et al. reported that CXCL12 expression increases cancer-associated fibroblasts and that CXCL12 can activate the Wnt/β-catenin pathway in EOC via the CXCL12/CXCR4 axis to induce epithelial–mesenchymal transition and platinum treatment resistance (18). Therefore, for patients whose surgically resected tissues have high CXCL12 expression such that a high recurrence rate is predicted, an intensive surveillance schedule may be offered after completion of the primary treatment.

Notably, the CXCR4 expression level alone was not associated with survival outcomes in our study. This is unexpected because previous studies have reported an association between CXCR4 and cancer metastasis (11, 19, 20). Jiang et al. reported that CXCR4 expression is higher in patients with refractory/recurrent ovarian cancer than in those without recurrence. The high-CXCR4-expression group (n=26) showed significantly worse PFS (median, 15 months vs. not reached, p=0.0004) and OS (median, 27 months vs. not reached, p=0.017) than those of the low-CXCR4-expression group (n=18) (11). Furthermore, in colorectal cancer, CXCR4 expression is significantly higher in patients with liver metastasis and is associated with recurrence and death (19). Ottaiano et al. reported that the over-expression of both CXCR4 and VEGF is related to the metastasis of colorectal cancer and suggested that CXCR4 can stimulate clonogenic growth, induce VEGF release, and up-regulate intercellular adhesion molecule-1 (20). These results support the possibility of proteins related to CXCL12/CXCR4 complex might be prognostic biomarkers of HGSOC. Possible explanations for the inconsistency between the results of this study and previous ones in literature may be attributed to differences in study populations and designs between studies. Also, antibodies used for IHC and IHC condition in this study may be different from those of previous research. In addition, different cut-off values were used in the determination of high CXCR4 expression. Based on the different cut-off values, the proportion of patients with tumors with high CXCR4 expression also differed among the studies. While 68.0% of patients had high CXCR4 expression in the present study, this proportion ranged from 59-80% in previous studies (5, 11). Hence, a consensus on cut-off values for CXCR4 and CXCL12 expression is required.

With the rapid development of new drugs, targeted therapy using agents, such as bevacizumab (humanized anti-VEGF-A monoclonal antibody) and poly ADP-ribose polymerase (PARP) inhibitors is being widely used in addition to standard chemotherapy. In particular, the use of PARP inhibitors has become more popular as maintenance therapy because they show survival benefits in patients with HGSOC and homologous recombinant-related gene deficiency compared to patients without genetic alterations (21-25). In addition, pembrolizumab, an immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1), is effective in treating microsatellite instability-high, mismatch repair gene-deficient ovarian cancer and cancer with expression of programmed cell death ligand 1 (PD-L1) (26-28). Moreover, recent studies have reported that inhibition of CXCL12-CXCR4 signaling pathway enhances the response of tumor cells to anti-PD-1 drugs by modifying the tumor microenvironment in murine models, serving as evidence which supports the effect of CXCR4/PD-1-targeting combination therapy (29, 30). Since the CXCL12/CXCR4 complex interacts with VEGF for mediating tumor metastasis, anti-CXCL12/CXCR4 drug plus bevacizumab combination therapy may represent another treatment option (5, 6, 20). Thus, the presence of certain genetic alterations and protein expression becomes more important in predicting the prognosis of EOC by providing more opportunities for treatment. Hence, routine analysis of CXCL12 expression levels may facilitate individualized treatment and surveillance.

The strength of this study is the larger sample size relative to other CXCL12/CXCR4 complex-related research for HGSOC. In addition, we focused on chemotherapy-naïve tissue samples to avoid any misinterpretation of results confounded by treatment with platinum and taxane-based chemotherapeutics. However, our study had several limitations. First, owing to the retrospective study design, there may be inevitable issues, such as selection bias. Second, only 15 patients showed CXCL12 over-expression, thus a much larger sample size is needed. Third, the level of expression was subjective. Although two pathologists evaluated the IHC results and calculated the H-score for all specimens separately, there could be inter-observer variability. Therefore, we defined patient specific H-score as the average value of scores from two pathologists. Lastly, the underlying mechanisms between CXCL12 levels and poor survival outcomes were not elucidated in this study.

Conclusion

Tissue expression of CXCL12 may represent a prognostic biomarker for predicting HGSOC recurrence. Proteins related to the CXCL12/CXCR4 complex may serve as therapeutic targets for HGSOC treatment. Subsequent cell-line or animal studies are warranted.

Footnotes

  • Authors’ Contributions

    S.I.K. and H.H.C. contributed to the study conception and design. H.L., S.I.K., E.N.K., and C.L. collected and analyzed data. H.L., S.I.K., M.L., J.-W.K, and H.H.C. interpreted the results. H.L and S.I.K wrote the manuscript. All Authors have approved this manuscript.

  • Conflicts of Interest

    All Authors have no conflicts of interest to declare in relation to this study.

  • Funding

    This work was supported by the Korea Medical Device Development Fund grants funded by the Korea government: the Ministry of Trade, Industry and Energy (Project Number: 1711137954, RS-2020-KD000028) and the Ministry of Science and ICT (Project Number: 1711135020, RS-2020-KD000106).

  • Received May 7, 2023.
  • Revision received May 23, 2023.
  • Accepted May 24, 2023.

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Tissue Expression and Prognostic Role of CXCL12 and CXCR4 in High-grade Serous Ovarian Carcinoma
HYUNJI LIM, SE IK KIM, EUN NA KIM, MARIA LEE, CHEOL LEE, JAE-WEON KIM, HYUN HOON CHUNG
Anticancer Research Jul 2023, 43 (7) 3331-3340; DOI: 10.21873/anticanres.16509
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