
Neuropilin‑1 expression in primary and metastatic prostate cancer: Expression patterns and clinicopathological correlations
- Authors:
- Published online on: August 8, 2025 https://doi.org/10.3892/mco.2025.2887
- Article Number: 92
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Copyright: © Kowalczyk et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Prostate cancer (PCa) is the second most common malignant tumor in men worldwide, with 1,466,680 new cases diagnosed in 2022, accounting for ~397,000 fatalities (1). Although its mortality rate is comparatively low, it continues to be the primary cause of cancer-related death in numerous nations across the Caribbean, sub-Saharan Africa, Central and South America, as well as Sweden in Europe. Increasing incidence of PCa was noted in China, Baltic countries and Eastern Europe, which might be a result of widely adopted prostate-specific antigen (PSA) testing and more frequent transurethral resections (2-4).
Given the global trend of increasing life expectancy and the established correlation between PCa incidence and age, the number of men newly diagnosed with this type of cancer will likely rise in the foreseeable future (5). Prediction of patient prognosis following prostatectomy is currently based on classic clinicopathological parameters, however incorporating data related to specific tissue biomarkers might be a valuable addition in this context, especially for patients with aggressive disease prone to early recurrence.
Neuropilin-1 (NRP-1), a member of neuropilin family of receptor proteins, was initially identified as modulator of nervous system development, functioning as semaphorin coreceptor alongside plexin. Later, it was found to be receptor of vascular endothelial growth factor (VEGF) family (6). NRP-1, together with NRP-2, transfers signals for angiogenesis, cellular communication and migration (7). NRP-1has emerged as a focal point in tumor biology research due to its participation in vascular and lymphatic development, as well as its role in tumor cells (6,8,9).
Elevated expression of NRP-1 was demonstrated not only in PCa, but also in breast, colon, lung and bladder cancers as well as in neuroblastoma (10-14). NRP-1 is involved in tumor cell proliferation, migration, survival and therapy resistance (6,14,15).
As a transmembrane co-receptor NRP-1, alongside with VEGFR2 (VEGF tyrosine kinase receptor), activates VEGF-A-mediated vascular development (16,17). Targeted disruption of a single allele of VEGF gene in murine models is sufficient to induce vascular abnormalities and results in embryonic lethality, highlighting that the in vivo level of VEGF is crucial for proper vascular development (18,19). Furthermore, by interacting with VEGF165 NRP-1 activates c-MET receptor tyrosine kinase pathway, which leads to the subsequent activation of downstream effectors such as Src kinase and signal transducer and activator of transcription 3 (STAT3), culminating in the upregulation of anti-apoptotic proteins like myeloid cell leukemia-1 (Mcl-1). Mcl-1 is an established survival factor in PCa cells, which is upregulated in patients with PCa with bone metastasis (20). b1/b2 binding site of NRP-1 also interacts with extracellular domain of epidermal growth factor receptor (EGFR) leading to its phosphorylation and subsequent activation of the downstream PI3K/AKT/mTOR signaling pathway. This activation promotes proliferation and migration of PCa cells. Additionally, hypoxic conditions within the tumor microenvironment (TME) induce the accumulation of hypoxia-inducible factor 1-alpha (HIF1-α), which transcriptionally upregulates NRP-1 expression, further amplifying these oncogenic signaling cascades (21,22).
Proangiogenic function of NRP-1 is dependent on its b1/b2 binding site, whereas a1/a2 binding sites respond for semaphorin3A (SEMA3A) recognition (23). In addition to binding VEGF, NRP-1 is a co-receptor for SEMA3A, a protein involved in the regulation of sympathetic ganglion development and axon pathfinding (24). SEMA3A also acts as a tumor suppressor by promoting apoptosis, suppressing cell migration and angiogenesis, at least partly in NRP-1-dependent manner. Binding to NRP-1 initiates signaling cascades that inhibit endothelial cell lamellipodia formation, adhesion, migration and survival, thereby effectively suppressing angiogenesis. VEGF165 competes with SEMA3A for NRP-1 binding on endothelial cells and promotes the internalization of cell-surface NRP-1. Interestingly, SEMA3A requires a lower concentration to achieve similar effects, suggesting a higher affinity for NRP-1 (25,26). Notably, both VEGF165 and SEMA3A induce vascular permeability through interaction with their shared receptor (27). Hence, different NRP-1 functions in PCa may result from different downstream pathways activated by individual ligands (24,28-32).
Additionally, recent research indicates that NRP-1 expression is dynamically regulated during the development of castration-resistant PCa (CRPC), particularly in response to androgen-targeted therapies (ATTs) and suggests its upregulation in metastatic compared with localized PCa. PCa cells with NRP-1 knockdown exhibited a less invasive morphology, characterized by reduced vimentin and enhanced E-cadherin expression, which was associated with decreased metastatic dissemination in a zebrafish xenograft model. Yet, the exact signaling mechanism between the androgen receptor (AR) and NRP-1 remains unclear (33).
Previous studies on potential prognostic and predictive utility of NRP-1 in PCa are encouraging, however, immunohistochemistry (IHC)-based data are limited and inconclusive (20,21,32-34). Moreover, the significance of NRP-1 levels in lymph node metastases of PCa has not been investigated. The present study systematically analyzed clinicopathological correlations of NRP-1 immunoreactivity in primary PCa and matched lymph node metastases.
Materials and methods
Patients and clinicopathological data
Patients included in the present study were those with histologically confirmed prostate adenocarcinoma (PRAD) who underwent radical prostatectomy with extended pelvic lymph node dissection between 2012 and 2018 at the University Urology Centre in Wrocław, Poland. Additional inclusion criteria were the availability of adequate formalin-fixed, paraffin-embedded (FFPE) tissue samples from both primary tumors and metastatic lymph nodes, as well as complete clinical documentation. Patients who had received any form of antitumor therapy prior to surgery, including androgen deprivation therapy, chemotherapy, or radiotherapy, were excluded from the analysis. Further exclusion criteria included incomplete clinical data, insufficient quality or quantity of tissue material for immunohistochemical evaluation, or a history of another malignancy. Out of an initial group of 95 patients, 73 men aged 42 to 79 years with PCa and lymph node metastases were included in the final analysis. A total of 22 patients were excluded due to incomplete clinical data and/or technical issues encountered during the construction and IHC staining of tissue microarrays (TMAs).
The tissue samples used in the present study were obtained from the archives of the Department of Clinical and Experimental Pathology (Wroclaw Medical University). For the purposes of the present study, archived FFPE tissue blocks were retrieved and accessed between January 2022 and March 2023, during the process of constructing the TMAs and performing immunohistochemical analyses.
Tumor stage and grade were compliant with the 8th edition of American Joint Committee on Cancer staging and 2019 International Society of Urological Pathology prostatic carcinoma grading consensus, respectively (35,36). The study protocol was approved (approval no. KB-545/2020) by the Ethics Committee of Wrocław Medical University (Wrocław, Poland). All procedures were conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from each recruited patient prior to sample collection.
Histopathological assessment was independently conducted by two experienced uropathologists. In cases of discrepancy, the final diagnosis was established by consensus during a joint review. Risk groups for biochemical recurrence of localized and locally advanced PCa were stratified according to European Association of Urology (EAU) (37). The radicality of prostatectomy was assessed by histopathological evaluation of surgical margins and by clinical measurements of PSA levels, with a threshold of <0.2 ng/ml at the first post-surgical measurement, typically done 6 weeks after the procedure.
Under hematoxylin and eosin (H&E) staining, normal prostate tissue is composed of well-formed glandular units lined by a dual layer: a basal cell layer and an inner luminal epithelial layer. The glands are typically round to oval, well-spaced, and separated by fibromuscular stroma. By contrast, PRAD, particularly acinar adenocarcinoma (the most common type), is characterized by infiltrative, irregularly shaped small glands that lack basal cells. These glands are often crowded, angulated, and may display cribriform, fused, or solid growth patterns in higher Gleason grades. Nuclei are typically enlarged with prominent nucleoli. These features are especially evident at the tumor invasive front, which defines the boundary between neoplastic and benign tissue. Surgical margin status was determined during standard histopathological evaluation of radical prostatectomy specimens. Margins were considered positive if cancer cells were present at the inked resection surfaces (capsular, apical, or bladder neck), and negative if no tumor cells were observed at these margins. The appearance of tumor glands at the margin is histologically similar to the rest of the carcinoma, but their location at or near the inked edge determines their clinical significance. Importantly, no unique architectural or cytological feature distinguishes tumor cells at the margin from those elsewhere in the tumor; the defining factor is their proximity to the resection surface. Overall survival (OS) was assessed from the date of radical prostatectomy, irrespective of the cause of death. The follow-up period ranged from 0 to 96 months. Background clinical and histopathological data were retrieved from archival hospital records.
IHC
Archival FFPE tissue samples were used for NRP-1 IHC. Matched samples from the primary tumor and lymph node metastasis were analyzed for each patient using bright-field light microscope. TMAs with the tumor tissues were assembled as previously described (38). IHC reactions were performed on 4-µm TMA paraffin sections using Autostainer Link48 (Agilent Technologies, Inc.). Slides were deparaffined and epitope retrieval was carried out by treating the slides with EnVision FLEX Target Retrieval Solution (Agilent Technologies, Inc.) (97˚C, 20 min; pH 9) using PTLink (Agilent Technologies, Inc.). In order to block endogenous peroxidase activity slides were incubated for 5 min at room temperature with EnVision FLEX Peroxidase-Blocking Reagent (Agilent Technologies, Inc.). Afterwards, rabbit monoclonal primary antibody against NRP-1 (1:300; cat. no. ab81321; Abcam) was applied for 20 min at room temperature. Then slides were incubated with secondary antibodies conjugated with horseradish peroxidase-EnVision FLEX/HRP (20 min at room temperature). The reactions were visualized using substrate for horseradish peroxidase (3,3'-diaminobenzidine) with incubation for 10 min. Additionally, all sections were counterstained 5 min with EnVision FLEX Hematoxylin (Agilent Technologies, Inc.). Finally, slides were dehydrated in ethanol (70, 96%, absolute) and xylene. All slides were closed with coverslips in Dako Mounting Medium (Agilent Technologies, Inc.). The primary antibody was diluted in EnVision FLEX Antibody Diluent (Agilent Technologies, Inc.).
For IHC scoring, all slides were digitized using Pannoramic MIDI scanner (3DHISTECH, Ltd.). To assess NRP-1 expression, six TMA cores were evaluated for each patient (three from the primary prostate tumor and three from the metastatic lymph node). H-score was used for semi-quantitative analysis of IHC reactions. In brief, points for staining intensity (0: negative, 1: weak, 2: moderate, 3: strong) were multiplied by the percentage of positive cancer cells. Sum of products for each intensity gave the final H-score ranging from 0 to 300. Tumors were categorized into low (H-score ≤100), moderate (H-score 101-200) and high (H-score >200) expression groups.
The immunohistochemical evaluation of NRP-1 expression was performed independently by two experienced genitourinary pathologists. In cases of scoring discrepancies, the final H-score was determined by consensus.
Statistical analysis
The mean, standard deviation, minimum, maximum, median (Me), lower quartile (Q1), and upper quartile (Q3) for quantitative variables were calculated. The empirical distribution of quantitative variables was examined to fit a normal distribution using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Spearman's rank correlation coefficient was calculated to assess the association between monotonic relationships between variables. Differences in NRP-1 expression levels between sample types were assessed using Student's t-test (for normally distributed data) or the Mann-Whitney U test (for non-normally distributed data). For subgroup comparisons, expression levels were categorized as low or moderate (≤200), or high (>200) based on predefined H-score thresholds. The Mann-Whitney U test was used to assess differences in quantitative parameters between two independent groups with varying NRP-1 marker expression levels. For qualitative factors, Pearson's Chi-square test or Fisher's exact test was employed to evaluate independence. Kaplan-Meier survival analysis was performed to assess the impact of NRP-1 expression on 5-year OS, with comparisons between groups conducted using the log-rank test. A significance level of P<0.05 was applied for all statistical tests. All statistical analyses were performed using Statistica v.13.3 (TIBCO Software Inc.).
Results
Positive NRP-1 staining was detected in all specimens-primary and metastatic tumors. NRP-1 expression was significantly higher in lymph node metastases (NRP1-N) compared with primary prostate tumors (NRP1-P), with Me H-scores of 215 vs. 170, respectively (P<0.001). High NRP-1 expression (>200 H-score) was more frequent in lymph node metastases than in primary prostate tumors (57.5% vs. 27.4%; P<0.001), whereas moderate expression was predominant in primary tumors (65.8%). The proportion of low expression was small in both groups as seen in Table I. The general characteristics of the patients are presented in Table II.
![]() | Table INRP1 expression in primary prostate cancers and lymph node metastases from 73 patients after radical prostatectomy. |
The expression of NRP-1 in lymph node metastases was significantly higher than in primary tumors (median H-score: 215 vs. 170; P<0.001, Fig. 1). High expression (>200 H-score) was more frequently observed in metastatic than primary tumors (57.5% vs. 27.4%; P<0.001). A total of 14 patients (19.2%) had high NRP-1 expression both primary and metastatic tumors.
Patients with high NRP-1 expression in primary tumors presented significantly lower percentage of affected lymph nodes (9.5% vs. 15.0%, P=0.027, Fig. 2) and significantly lower postoperative PSA level (0.02 vs. 0.21 ng/ml, P=0.039, Fig. 3). A comparison of NRP-1 expression levels in the PCa and metastatic lymph nodes is demonstrated in Fig. 4. However, no association was observed between NRP-1 expression and any of the analyzed parameters-postoperative International Society of Urological Pathology Gleason Grade Group (ISUP GGG), pT stage, extranodal extension, surgical margin, neurovascular invasion, lymph-vascular invasion, EAU risk group, Body mass intex, patient's age. Also, 5-year survival was not related to NRP-1 expression (Fig. 5).
Discussion
Despite significant advancements in PCa diagnostics in recent years, it continues to pose a considerable challenge for urologists and uropathologists with regard to accurate diagnosis and effective treatment strategies. Considering the global increase in life expectancy and the well-documented link between PCa incidence and aging, it is projected that the incidence of PCa will increase in the near future (5). The current reliance on traditional clinicopathological parameters, such as PSA levels, GGG, and pT stage, underscores the need to identify novel, specific biomarkers that could improve the accuracy of survival prognosis and the assessment of cancer dissemination risk in patients following prostatectomy and to incorporate them into current urological guidelines for PCa management.
The present study provided new insights into the role of NRP-1in PCa progression, particularly in the context of lymph node metastases. None of previous studies on NRP-1 in PCa investigated its expression in lymph node metastases, highlighting the novelty of the present study (20,21,33,39-42).
Although the literature on the clinical implications of NRP-1 expression in PCa is limited, several studies reported a positive association between NRP-1 levels in PCa tissue and poor prognosis. In a study by Hu et al (42) NRP-1 expression correlated with OS; however, only in Caucasian-American patients and not in Chinese and African American men. In another study, IHC analysis of TMAs demonstrated a positive correlation between elevated NRP-1 expression and higher Gleason grade, pathological T stage, lymph node involvement and primary treatment failure. Moreover, multivariate analyses identified NRP-1 expression at the time of radical prostatectomy as an independent prognostic factor for biochemical recurrence following radiotherapy, as well as for metastatic progression and cancer-specific mortality. Interestingly, NRP-1 was identified as a gene repressed by androgen signaling, with its expression upregulated during the adaptive response to ATTs, ultimately contributing to the progression toward metastatic CRPC (33).
Notably, roles of NRP-1 observed in animal and in vitro models of PCa, may not reflect clinical conditions (20,21,32,34). Moreover, other studies reporting high biomarker expression in PCa also identified certain methodological inconsistencies related to selection bias and result assessment methods (20,21).
In one study, NRP-1 overexpression was positively associated with PCa progression and bone metastasis. However, a bias in patient selection was noted, as only two patients with a Gleason score of 6 were included in the analysis, compared with 43 cases with Gleason scores of 8-10(20).
Another study reported significantly higher NRP-1 levels in PCa specimens from patients with poor prognosis (higher Gleason score, high PSA, advanced T stage lymph node metastasis). Further, NRP-1 expression was associated with worse disease-free survival, shorter OS and cancer-specific survival (21). Nonetheless, IHC staining in that study was evaluated using the immunoreactivity score, which has certain limitations and lacks the broader a dynamic range provided by the H-score used in the analysis of the present study. Although the H-score is more time-consuming and requires a higher level of expertise from the pathologist, it offers a more detailed assessment of the material, accounting for intra-tumoral heterogeneity in antigen expression and potentially improving accuracy (43,44).
In addition, some studies failed to corroborate earlier findings or yielded unclear results (39-41). Talagas et al (39) did not find any association between NRP-1 and unfavorable clinicopathological parameters in patients with clinically localized PCa after radical prostatectomy. In turn, elevated endothelial expression of NRP-1 was an independent predictor for the absence of distant relapse in PCa.
Another study reported a 10-fold increase in NRP-1 mRNA levels in tumor specimens compared with benign tissue samples. Interestingly, a comparison between benign prostate hyperplasia (BPH) and malignant tissues revealed that NRP-1 IHC staining was elevated in PCa specimens; however, it was confined to the stroma and absent in malignant epithelial cells, which contradicts previous studies. In addition, the stroma exhibited positive staining in all samples, with no significant variation in intensity across different tumor specimens. Consequently, staining intensity could not be associated with Gleason score or recurrence risk (40).
Finally, Yacoub et al (41) hypothesized in their study, that the function of NRP-1 in PCa varies depending on the specific ligand to which it is attached (SEMA3A/VEGF). In contrast to VEGF, SEMA3A presented lower protein expression in hormone-refractory PCa (HRPC) compared with localized cancer. In localized cancer, SEMA3A was linked to lower pT stage and showed a close correlation with NRP-1 expression.
No significant relationship was observed between NRP-1 and VEGF in localized disease, and no significant correlation was found between NRP-1 and SEMA3A in HRPC. The expression of both SEMA3A and NRP-1 was linked to predictors of favorable prognosis, such as lower preoperative PSA levels, a low Gleason score for NRP-1, and a lower pT stage for SEMA3A, while VEGF expression correlated with elevated PSA levels.
Consequently, the function of NRP-1 in PCa may vary depending on VEGF/SEMA3A ratio. When SEMA3A is the primary ligand, as observed in clinically localized PCa, NRP-1 expression could be indicative of a favorable prognosis due to its anti-tumoral effects. Conversely, in cases of metastatic HRPC where VEGF is the predominant ligand, NRP-1 expression might be associated with a more aggressive disease profile due to its pro-tumoral nature (16,17).
The analysis of the present study revealed that patients with high NRP-1 expression in PCa samples exhibited a significantly lower percentage of affected lymph nodes compared with those with lower expression (9.5% vs. 15.0%, P=0.027). The percentage of metastatic lymph nodes, commonly referred to as lymph node density, is widely recognized as a reliable predictor of clinical recurrence. Its prognostic value has been demonstrated in multiple studies, emphasizing its importance in guiding postoperative management and risk stratification in patients with PCa (45,46).
Additionally, the group with higher NRP-1 staining exhibited a significantly lower postoperative PSA level (0.02 vs. 0.21 ng/ml, P=0.039), which is also considered a positive prognostic factor. Postoperative PSA levels are strongly correlated with an increased risk of biochemical recurrence and overall mortality in patients following prostatectomy (47-50). These observations could be explained by the hypothesis proposed by Yacoub et al (41), suggesting that the function of NRP-1may depend on the ligand to which it is bound (SEMA3A or VEGF). SEMA3A may mediate anti-angiogenic and pro-apoptotic effects through NRP-1, potentially counteracting the pro-tumoral influence of VEGF, as documented in several studies (26,30,31).
Notably, all patients in the present cohort study had lymph node involvement; however, their disease was clinically localized and had been treated with curative intent. Consequently, these cases represent hormone-sensitive PCa. These findings highlight the importance of further exploring NRP-1expression as a prognostic biomarker in this specific patient subgroup.
Despite a thorough outcome analysis, no statistically significant associations were identified between high NRP-1 expression and key clinicopathological parameters, including pT stage, Gleason score, surgical margin status, or extracapsular extension. Moreover, NRP-1 expression was not found to influence 5-year survival rates, a result consistent with earlier studies (39,41). These findings suggest that, while NRP-1 may play a role in specific TME interactions, its utility as a standalone prognostic marker for long-term outcomes in PCa remains limited.
While the present study highlighted the potential of NRP-1 as a biomarker, several important limitations must be acknowledged. Most notably, the retrospective design and single-center setting represent significant constraints that may limit the generalizability and external validity of the present study's findings. Although these factors are common in exploratory studies, the results should be interpreted with caution and the findings underscore the need for prospective validation, preferably focusing on hormone-sensitive patients with PCa and lymph node involvement. Secondly, the lack of data on specific VEGF/SEMA3A ratios in patient samples is another limitation-studies incorporating quantitative analysis of VEGF and SEMA3A expression will help clarify the ligand-dependent role of NRP-1 in tumor biology. The patient groups in the present study were relatively small-future research should focus on validating these findings in larger, multicenter cohorts and exploring the molecular mechanisms underlying NRP-1's role in PCa. Additionally, investigating its interaction with other pathways critical to PCa progression, such as AR signaling, could also yield valuable information. TMAs were selected for the present study to enable efficient, standardized immunohistochemical analysis across a large number of patient samples. TMAs allow simultaneous staining and evaluation of multiple cases under uniform conditions, minimizing inter-assay variability and conserving valuable tissue. This approach is particularly advantageous when assessing biomarker expression semi-quantitatively across matched tumor regions. However, it is important to note that TMAs represent only selected areas of the tumor and do not include its full architecture, such as surgical margins, which limits their use for margin assessment. Finally, a comparative analysis of NRP-1 staining between cancerous and non-cancerous tissues (such as BPH tissue) could further enhance the study's robustness. In conclusion the present study evaluated the role of NRP-1in PCa, particularly in lymph node metastases-a novel area of focus. Positive NRP-1 immunohistochemical staining was detected in both PCa and metastatic lymph nodes. Patients with high NRP-1 expression demonstrated significantly lower percentage of affected lymph nodes and lower postoperative PSA level. NRP-1 expression was not associated with other clinicopathological parameters or survival rates. These findings highlight a complex ligand-dependent role of NRP-1, where SEMA3A may mediate anti-tumoral effects in clinically localized PCa, counteracting VEGF's pro-tumoral influence in more advanced cancers. While the results of the present study suggested that NRP-1 holds promise as a prognostic biomarker in clinically localized, hormone-sensitive PCa, its clinical utility remains to be established. Additional studies are necessary to validate these observations in larger patient cohorts and to explore the molecular mechanisms that regulate NRP-1 function in PCa. In particular, assessing NRP-1 expression in the context of VEGF/SEMA3A balance and AR signaling pathways may provide critical insights for its future use in establishing prognosis and therapy.
Acknowledgements
Not applicable.
Funding
Funding: The present study was supported by (grant no. SUBZ.C090.23.080) the Wroclaw Medical University.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
KK, MK and BM confirm the authenticity of all the raw data. KK, MK, BM and PK conceived and designed the study. KK, AG, DK, MK, JK, TS, PD and AH acquired data (acquired and managed patients and provided facilities). AP, KD, MK, KK, WK and AH analyzed and interpreted the data (such as statistical, biostatistics and computational analyses). KK and MK wrote and/or revised the manuscript, and provided administrative, technical or material support (such as reporting or organizing data and constructing databases). BM, TS, AH, WK, PD and MK supervised the study. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
The study protocol was approved (approval no. KB-545/2020) by the Ethics Committee of Wrocław Medical University (Wrocław, Poland). All procedures were conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from each recruited patient prior to sample collection.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:229–263. 2024.PubMed/NCBI View Article : Google Scholar | |
Seraphin TP, Joko-Fru WY, Kamaté B, Chokunonga E, Wabinga H, Somdyala NIM, Manraj SS, Ogunbiyi OJ, Dzamalala CP, Finesse A, et al: Rising prostate cancer incidence in Sub-saharan africa: A trend analysis of data from the african cancer registry network. Cancer Epidemiol Biomarkers Prev. 30:158–165. 2021.PubMed/NCBI View Article : Google Scholar | |
Culp MB, Soerjomataram I, Efstathiou JA, Bray F and Jemal A: Recent global patterns in prostate cancer incidence and mortality rates. Eur Urol. 77:38–52. 2020.PubMed/NCBI View Article : Google Scholar | |
Schafer EJ, Jemal A, Wiese D, Sung H, Kratzer TB, Islami F, Dahut WL and Knudsen KE: Disparities and trends in genitourinary cancer incidence and mortality in the USA. Eur Urol. 84:117–126. 2023.PubMed/NCBI View Article : Google Scholar | |
Rawla P: Epidemiology of prostate cancer. World J Oncol. 10:63–89. 2019.PubMed/NCBI View Article : Google Scholar | |
Bagri A, Tessier-Lavigne M and Watts RJ: Neuropilins in tumor biology. Clin Cancer Res. 15:1860–1864. 2009.PubMed/NCBI View Article : Google Scholar | |
Chaudhary B, Khaled YS, Ammori BJ and Elkord E: Neuropilin 1: Function and therapeutic potential in cancer. Cancer Immunol Immunother. 63:81–99. 2014.PubMed/NCBI View Article : Google Scholar | |
Staton CA, Kumar I, Reed MWR and Brown NJ: Neuropilins in physiological and pathological angiogenesis. J Pathol. 212:237–248. 2007.PubMed/NCBI View Article : Google Scholar | |
Guttmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y and Neufeld G: The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett. 231:1–11. 2006.PubMed/NCBI View Article : Google Scholar | |
Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G and Mercurio AM: Vascular endothelial growth factor is an autocrine survival factor for Neuropilin-expressing breast carcinoma cells. Cancer Res. 61:5736–5740. 2001.PubMed/NCBI | |
Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M and Ellis LM: Neuropilin-1 in human colon cancer: Expression, regulation, and role in induction of angiogenesis. Am J Pathol. 164:2139–2151. 2004.PubMed/NCBI View Article : Google Scholar | |
Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY, et al: Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 13:4759–4768. 2007.PubMed/NCBI View Article : Google Scholar | |
Dong Y, Ma WM, Shi ZD, Zhang ZG, Zhou JH, Li Y, Zhang SQ, Pang K, Li BB, Zhang WD, et al: Role of NRP1 in bladder cancer pathogenesis and progression. Front Oncol. 11(685980)2021.PubMed/NCBI View Article : Google Scholar | |
Fakhari M, Pullirsch D, Abraham D, Paya K, Hofbauer R, Holzfeind P, Hofmann M and Aharinejad S: Selective upregulation of vascular endothelial growth factor receptors neuropilin-1 and -2 in human neuroblastoma. Cancer. 94:258–263. 2002.PubMed/NCBI View Article : Google Scholar | |
Kiełb P, Kowalczyk K, Gurwin A, Nowak Ł, Krajewski W, Sosnowski R, Szydełko T and Małkiewicz B: Novel histopathological biomarkers in prostate cancer: Implications and perspectives. Biomedicines. 11(1552)2023.PubMed/NCBI View Article : Google Scholar | |
Fuh G, Garcia KC and de Vos AM: The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. J Biol Chem. 275:26690–26695. 2000.PubMed/NCBI View Article : Google Scholar | |
Sharma S, Ehrlich M, Zhang M, Blobe GC and Henis YI: NRP1 interacts with endoglin and VEGFR2 to modulate VEGF signaling and endothelial cell sprouting. Commun Biol. 7(112)2024.PubMed/NCBI View Article : Google Scholar | |
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, et al: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 380:435–439. 1996.PubMed/NCBI View Article : Google Scholar | |
Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ and Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 380:439–442. 1996.PubMed/NCBI View Article : Google Scholar | |
Zhang S, Zhau HE, Osunkoya AO, Iqbal S, Yang X, Fan S, Chen Z, Wang R, Marshall FF, Chung LW and Wu D: Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells. Mol Cancer. 9(9)2010.PubMed/NCBI View Article : Google Scholar | |
Zhang P, Chen L, Zhou F, He Z, Wang G and Luo Y: NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation. Cell Death Dis. 14(159)2023.PubMed/NCBI View Article : Google Scholar | |
Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J, Neufeld G and Tamagnone L: Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res. 72:5801–5811. 2012.PubMed/NCBI View Article : Google Scholar | |
Gu C, Limberg BJ, Whitaker GB, Perman B, Leahy DJ, Rosenbaum JS, Ginty DD and Kolodkin AL: Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. J Biol Chem. 277:18069–18076. 2002.PubMed/NCBI View Article : Google Scholar | |
Maden CH, Gomes J, Schwarz Q, Davidson K, Tinker A and Ruhrberg C: NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system. Dev Biol. 369:277–285. 2012.PubMed/NCBI View Article : Google Scholar | |
Narazaki M and Tosato G: Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A. Blood. 107:3892–3901. 2006.PubMed/NCBI View Article : Google Scholar | |
Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA and Klagsbrun M: Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: Functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol. 146:233–242. 1999.PubMed/NCBI View Article : Google Scholar | |
Acevedo LM, Barillas S, Weis SM, Göthert JR and Cheresh DA: Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood. 111:2674–2680. 2008.PubMed/NCBI View Article : Google Scholar | |
Goshima Y, Ito T, Sasaki Y and Nakamura F: Semaphorins as signals for cell repulsion and invasion. J Clin Invest. 109:993–998. 2002.PubMed/NCBI View Article : Google Scholar | |
Chédotal A, Kerjan G and Moreau-Fauvarque C: The brain within the tumor: New roles for axon guidance molecules in cancers. Cell Death Differ. 12:1044–1056. 2005.PubMed/NCBI View Article : Google Scholar | |
Bagnard D, Sainturet N, Meyronet D, Perraut M, Miehe M, Roussel G, Aunis D, Belin MF and Thomasset N: Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells. Mol Cell Neurosci. 25:722–731. 2004.PubMed/NCBI View Article : Google Scholar | |
Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ and Mercurio AM: Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res. 63:5230–5233. 2003.PubMed/NCBI | |
Miao HQ, Lee P, Lin H, Soker S and Klagsbrun M: Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 14:2532–2539. 2000.PubMed/NCBI View Article : Google Scholar | |
Tse BWC, Volpert M, Ratther E, Stylianou N, Nouri M, McGowan K, Lehman ML, McPherson SJ, Roshan-Moniri M, Butler MS, et al: Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene. 36:3417–3427. 2017.PubMed/NCBI View Article : Google Scholar | |
Jia H, Cheng L, Tickner M, Bagherzadeh A, Selwood D and Zachary I: Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity. Br J Cancer. 102:541–552. 2010.PubMed/NCBI View Article : Google Scholar | |
Buyyounouski MK, Choyke PL, McKenney JK, Sartor O, Sandler HM, Amin MB, Kattan MW and Lin DW: Prostate cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 67:245–253. 2017.PubMed/NCBI View Article : Google Scholar | |
van Leenders GJLH, van der Kwast TH, Grignon DJ, Evans AJ, Kristiansen G, Kweldam CF, Litjens G, McKenney JK, Melamed J, Mottet N, et al: The 2019 international society of urological pathology (ISUP) consensus conference on grading of prostatic carcinoma. Am J Surg Pathol. 44:e87–e99. 2020.PubMed/NCBI View Article : Google Scholar | |
Cornford P, van den Bergh RCN, Briers E, Van den Broeck T, Brunckhorst O, Darraugh J, Eberli D, De Meerleer G, De Santis M, Farolfi A, et al: EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate Cancer-2024 update. Part I: Screening, diagnosis, and local treatment with curative intent. Eur Urol. 86:148–163. 2024.PubMed/NCBI View Article : Google Scholar | |
Kiełb P, Kaczorowski M, Kowalczyk K, Piotrowska A, Nowak Ł, Krajewski W, Chorbińska J, Dudek K, Dzięgiel P, Hałoń A, et al: Role of IL-17A and IL-17RA in prostate cancer with lymph nodes metastasis: Expression patterns and clinical significance. Cancers (Basel). 15(4578)2023.PubMed/NCBI View Article : Google Scholar | |
Talagas M, Uguen A, Garlantezec R, Fournier G, Doucet L, Gobin E, Marcorelles P, Volant A and DE Braekeleer M: VEGFR1 and NRP1 endothelial expressions predict distant relapse after radical prostatectomy in clinically localized prostate cancer. Anticancer Res. 33:2065–2075. 2013.PubMed/NCBI | |
Vanveldhuizen PJ, Zulfiqar M, Banerjee S, Cherian R, Saxena NK, Rabe A, Thrasher JB and Banerjee SK: Differential expression of Neuropilin-1 in malignant and benign prostatic stromal tissue. Oncol Rep. 10:1067–1071. 2003.PubMed/NCBI | |
Yacoub M, Coulon A, Celhay O, Irani J, Cussenot O and Fromont G: Differential expression of the semaphorin 3A pathway in prostatic cancer. Histopathology. 55:392–398. 2009.PubMed/NCBI View Article : Google Scholar | |
Hu P, Chung LWK, Berel D, Frierson HF, Yang H, Liu C, Wang R, Li Q, Rogatko A and Zhau HE: Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: An interracial comparative study. PLoS One. 8(e73081)2013.PubMed/NCBI View Article : Google Scholar | |
Detre S, Saclani Jotti G and Dowsett M: A ‘quickscore’ method for immunohistochemical semiquantitation: Validation for oestrogen receptor in breast carcinomas. J Clin Pathol. 48:876–878. 1995.PubMed/NCBI View Article : Google Scholar | |
Fedchenko N and Reifenrath J: Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue-a review. Diagn Pathol. 9(221)2014.PubMed/NCBI View Article : Google Scholar | |
Daneshmand S, Quek ML, Stein JP, Lieskovsky G, Cai J, Pinski J, Skinner EC and Skinner DG: Prognosis of patients with lymph node positive prostate cancer following radical prostatectomy: Long-term results. J Urol. 172:2252–2255. 2004.PubMed/NCBI View Article : Google Scholar | |
Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A and Studer UE: Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. Eur Urol. 54:344–352. 2008.PubMed/NCBI View Article : Google Scholar | |
Moreira DM, Presti JC Jr, Aronson WJ, Terris MK, Kane CJ, Amling CL and Freedland SJ: Natural history of persistently elevated prostate specific antigen after radical prostatectomy: Results from the SEARCH database. J Urol. 182:2250–2255. 2009.PubMed/NCBI View Article : Google Scholar | |
Ploussard G, Fossati N, Wiegel T, D'Amico A, Hofman MS, Gillessen S, Mottet N, Joniau S and Spratt DE: Management of persistently elevated prostate-specific antigen after radical prostatectomy: A systematic review of the literature. Eur Urol Oncol. 4:150–169. 2021.PubMed/NCBI View Article : Google Scholar | |
Moreira DM, Presti JC Jr, Aronson WJ, Terris MK, Kane CJ, Amling CL and Freedland SJ: Definition and preoperative predictors of persistently elevated prostate-specific antigen after radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int. 105:1541–1547. 2010.PubMed/NCBI View Article : Google Scholar | |
Preisser F, Chun FKH, Pompe RS, Heinze A, Salomon G, Graefen M, Huland H and Tilki D: Persistent Prostate-specific antigen after radical prostatectomy and its impact on oncologic outcomes. Eur Urol. 76:106–114. 2019.PubMed/NCBI View Article : Google Scholar |