Prostate cancer (PCa), the second most prevalent malignancy in men worldwide, caused ~34,500 deaths in the United States in 2022 (1), and research has indicated that an estimated 15% of men receive a diagnosis of PCa during their lifetime (2). Obesity influences the pathogenesis of prostate disease, including benign prostate hyperplasia (BPH) and PCa (3–5). Notably, obesity can lead to alterations in endocrine status, including increased levels of estradiol due to the expression of the enzyme P450 aromatase in adipose tissue, which converts androgens to estrogen; this results in gonadotropin suppression and favors the development of BPH (6). Obesity also enhances sympathetic nervous activity, which impacts the severity of urinary voiding dysfunction, contributing to BPH (7,8). Additionally, obesity induces inflammatory processes, promoting microvascular disease and leading to tissue ischemia and oxidative stress, creating a favorable intraprostatic environment for hyperplastic growth and potential precancerous transformation (9).

Low serum testosterone levels are associated with aggressive PCa, since testosterone has a regulatory role in maintaining normal prostate cell growth (10), and men with low testosterone levels often exhibit a more aggressive PCa phenotype (11). Trials of 5α-reductase inhibitors, which inhibit the conversion of testosterone into dihydrotestosterone (a hormone that plays a crucial role in prostate growth), have shown a decreased overall risk of PCa but a higher Gleason score, reflecting the association between low serum testosterone and aggressive PCa (12). Insulin resistance, which is commonly associated with obesity, has been shown to promote PCa by increasing circulating levels of bioactive IGF-1, a growth factor implicated in numerous types of cancer (13). Among adipokines, leptin, which is elevated in central obesity, promotes angiogenesis in human PCa cell lines, thereby supporting cancer growth (14). Conversely, adiponectin, which has antitumor effects by inhibiting cancer cell proliferation and metastasis, has been detected at reduced levels in central obesity (15). Notably, multiple studies have reported an association between PCa and obesity (16,17), and three meta-analyses have reported a positive correlation between the incidence of PCa and obesity (18–20). It has also been indicated that obesity can affect the outcomes of PCa. A systematic review and meta-analysis identified that for every 5-kg/m² increase in the body mass index (BMI) of patients undergoing radical prostatectomy, the risk of biochemical recurrence of PCa increased by 20% and the risk of PCa-specific mortality increased by 15% (21).

Most studies on obesity define the condition and measure its degree using BMI (17–20); however, BMI is an inaccurate measure because it fails to directly account for the amount of adipose tissue in the body. Thus, researchers are increasingly considering the role of body composition, including the distribution of fat and lean tissue, in PCa. Several small-scale studies have implicated visceral and subcutaneous fat in the initiation and progression of PCa. Duong et al (22) demonstrated that adipocytes, the main cellular component of adipose tissue, were involved in solid tumor progression. Adipose tissue is considered to be more metabolically active than other tissues and to serve a prominent role in prostate tumorigenesis. Visceral fat cells produce multiple hormones and cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin and adiponectin (2,23). von Hafe et al (24) used computed tomography (CT) to determine that visceral obesity may be a risk factor for PCa, which could be explained by the activities of adipokines secreted by visceral fat cells, as well as the elevated levels of insulin and disturbances in steroid hormone homeostasis associated with visceral obesity. Furthermore, Zimmermann et al (25) demonstrated that patients with higher visceral fat volumes and densities exhibited more favorable biochemical outcomes after radical prostatectomy and postoperative radiotherapy.

Periprostatic adipose tissue (PPAT), a type of visceral adipose tissue, serves a key role in PCa; the extracapsular extension of cancer cells into PPAT has been reported to be associated with poor prognosis (26). PPAT is anatomically defined as the local adipose tissue that surrounds the prostate gland in the pelvic cavity. Spatial imaging, such as CT or magnetic resonance imaging (MRI), enables the measurement of distinct areas of adipose tissue (27). In addition to secreting multiple hormones and other protein factors, including adiponectin, leptin and IL-6, similar to general visceral adipose tissue, PPAT has been found to be correlated with PCa aggressiveness (28). van Roermund et al (28) demonstrated that fat-related parameters of PPAT, including area and density, were directly correlated with the aggressiveness of PCa and may serve as better markers of obesity than BMI. Multiple studies have also reported that PCa cells may alter adipocyte biology around the prostate gland, while in vivo studies have demonstrated the crosstalk between tumors and adipocytes (29–34).

The current medical treatments for PCa primarily target the hormonal pathway, with the immune checkpoint and homologous recombination pathways serving as secondary targets. Although current medical treatments have demonstrated promising efficacy, they face some limitations (35,36). Notably, current treatments for localized PCa, such as radical prostatectomy or radiation therapy, can achieve a high cure rate and low PCa-related mortality rate; however, there has been limited advancement in curing advanced PCa. Targeted therapies, such as androgen receptor (AR)-signaling inhibitors (ARSIs), poly (ADP-ribose) polymerase (PARP) inhibitors and radiopharmaceuticals [prostate-specific membrane antigen (PSMA) Lu-177 or radium-223], are novel treatments for advanced metastatic PCa aimed at disease control rather than cure (37,38). Notably, the treatment efficacy of these novel agents for advanced or metastatic PCa is limited by their targeting mechanisms. PARP inhibitors are effective in PCa with germline or somatic homologous recombination repair deficiencies; however, these mutations, including BRCA2, ATM, CDK12 and CHEK2, only account for one in four patients (39). ARSIs can achieve better chemical castration levels than conventional androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonist or antagonist, but patients may eventually progress to castration refractory PCa (CRPC), mainly due to AR mutation, splice variant formation, amplification, or progression to neuroendocrine PCa (40). Regarding radiopharmaceuticals, the effectiveness of PSMA-based treatments depends on PSMA expression in the tumor; however, the innate heterogeneity of PSMA expression is a notable limitation. Furthermore, downregulation of PSMA expression is widespread in patients with advanced metastatic CRPC, primarily due to lineage plasticity (41,42). The treatment efficacy of radium-223 is limited to metastatic bone lesions only, due to its bone-seeking calcium mimetic nature (43). Therefore, novel treatment strategies are warranted. Elucidating the interactions between PPAT and PCa may enable the design of novel anticancer strategies targeting different pathways.

The present study investigated the association between pelvic adipose tissue (PAT) distribution and PCa aggressiveness, as well as the underlying mechanisms. MRI was used to evaluate clinical morphological characteristics. In addition, PPAT collected during robot-assisted radical prostatectomy (RaRP) was used to prepare conditioned medium (CM), the effects of which were investigated on two PCa cell lines and one prostate epithelial cell line.

According to the literature, PPAT can markedly influence the progression of PCa. Woo et al (49) studied 190 patients with PCa who underwent MRI before radical prostatectomy and demonstrated that PPAT thickness, as determined through MRI, was significantly correlated with Gleason score and was an independent predictor of high-grade PCa. In addition, Zhang et al (50) discovered that periprostatic adiposity was significantly associated with Gleason scores and clinical stage after evaluating the MRI scans of 184 patients with PCa who underwent radical prostatectomy. Bhindi et al (51) demonstrated that PPAT volume, as estimated through transrectal ultrasound, can predict the presence and the grade of PCa. PPAT area and density have also been reported to be more strongly correlated with PCa aggressiveness than other obesity-related parameters, including waist circumference and BMI (28,49,50). In addition, the correlations of PPAT thickness with BMI and weight have been shown to be nonsignificant or weak (49–54). Therefore, measurements of PPAT may serve as independent predictors of PCa aggressiveness. In the current study, the volumes of PAT, PRAT and PPAT were measured using MRI to identify associations between PAT distribution and PCa aggressiveness. The present study revealed that serum iPSA levels were significantly associated with higher PAT and PPAT volumes. Furthermore, a higher PPAT volume was correlated with extracapsular extension, which is consistent with the findings of a study investigating the association between PPAT volume and tumor aggressiveness (55).

Although clinical findings have indicated an association between PPAT and PCa, the mechanisms underlying this association remain unclear. PPAT may provide a favorable microenvironment for aggressive PCa or may passively accumulate fat content in response to local PCa progression. Furthermore, PPAT may affect PCa progression and pathogenesis by providing cancer cells with fatty acids and other mitogens. A previous study identified factors secreted by both PPAT and PCa cells potentially capable of mediating bidirectional communication between them (56). Ribeiro et al (31) reported that PPAT-CM stimulated PC3 and LNCaP cell migration but inhibited LNCaP proliferation. Conversely, another study reported that PPAT-CM did not significantly affect the proliferation and motility of LNCaP or PC3 cells (57). In addition, a previous study indicated that the proliferation of PC3 cells was increased when cocultured with rat epididymal adipocytes (58), but these findings were not observed in a later study (33). These conflicting results are likely due to differences in the characteristics of the experimental methodologies and cell lines that were used.

The present study used the LNCaP and C4-2 cell lines as the experimental models because the present clinical analysis focused on patients with T2 stage PCa, ensuring that the adipose tissue was free from potential contamination by PCa cells. LNCaP cells, known for their well-established use in PCa research, have lower malignancy and AR positivity, representing earlier-stage PCa, compared to other commonly used PCa cell lines, such as PC-3, DU145 and CWR22R-v1 (59). By contrast, C4-2 cells, derived from LNCaP cells, exhibit higher invasiveness and metastatic potential, representing a more advanced stage of PCa (60,61). While C4-2 cells indeed exhibit higher invasiveness and metastatic potential compared with LNCaP cells, they still inherently express AR, representing relatively early stages of PCa. Conversely, other commonly used PCa cell lines, such as PC-3, DU145 and CWR22R-v1, demonstrate higher malignancy, representing advanced stages of PCa. In addition, PC-3 and DU145 cells lack AR expression, with DU145 further classified as a CRPC cell line (62–64). Similarly, although CWR22R-v1 is AR-positive, it is also classified as a CRPC cell line (65). Therefore, to mimic the T2 tumor stage of the clinical specimens, C4-2 cells were chosen as another PCa cell line for investigation. This selection allows for the study of differential responses between less and more aggressive PCa cells, and may improve understanding of the impact of the adipose tissue secretome on tumors at different stages of malignancy. Additionally, the present study incorporated experiments using the prostate normal epithelial cell line PZ-HPV-7 to provide a comprehensive comparison and to observe the effects on normal prostate cells. The proliferation rate of prostate cells was significantly lower in the PPAT-CM group compared with that in the control- and PVAT-CM groups. However, when comparing the cell proliferation rates between the PVAT- and PPAT-CM groups, the cells in the PPAT-CM group showed a trend of slower growth, but the difference was not statistically significant, possibly due to the insufficient number of groups used in the experiment. The un-paired Student's t-test did not show statistical significance, likely due to individual variations among the samples. Collecting more cases could reduce these individual differences and achieve statistical significance. Furthermore, the cells cultured in PPAT-CM exhibited more pronounced apoptosis than those cultured in control- and PVAT-CM did. Compared with the PCa cell lines, although the CM had a slight effect on the prostate normal epithelial cell line, the impact on PCa cells appeared to be more pronounced. RNA-seq and analysis revealed that immune responses, and the cell death and apoptosis pathways were more activated in PPAT-CM-cultured cells than in PVAT-CM-cultured cells. These findings indicated that the cytokines and other factors secreted from PPAT-CM may have induced PCa cell apoptosis.

Evidence has indicated that adipose tissue can act as an energy reservoir, and it is a metabolically active organ (66) that produces growth factors, hormones and adipokines (67). The secretions of adipose tissue affect both physiological cellular responses, and the paracrine and autocrine signaling networks, especially in tumor microenvironments, where hormonal dependence mediates cancer progression (32,57,68–71). Several cytokines and adipokines, such as IL-6, leptin and vascular endothelial growth factor, have been associated with tumor progression (72,73); however, several others, including adiponectin (74), suppress tumor growth, whereas the effects of factors such as TNF-α remain unclear (75).

The secretome of adipose tissue may vary across different stages of PCa. Sacca et al (76) analyzed PPAT-CM from patients either with PCa (including stage T2 and T3 tumors) or from those with benign diseases using liquid chromatography-mass spectrometry-based proteomics. The results observed that the PPAT from patients with cancer exhibited stronger immune responses. Moreover, the PPAT from patients with stage T3 PCa was rich in catalytic proteins, whereas that from patients with stage T2 PCa was rich in defense and immune response proteins. These findings indicated that, in the early stages of localized PCa, the secretome of PPAT, including cytokines, may activate immune defense responses and induce cell apoptosis. This mechanism potentially acts as a first line of defense in the early stages of PCa. However, when the disease progresses and cancer cells extend to adipose tissue, their crosstalk with the tissue may induce catalytic activity and alter the tumor microenvironment, triggering progression or invasion.

The present study explored the role of PPAT in the early stages of PCa and revealed that the secretome of PPAT could inhibit cell proliferation by inducing apoptosis. However, this study has several limitations. First, PPAT was obtained only from patients harboring early-stage tumors (T2); samples from patients with more advanced PCa are required to further validate that PPAT inhibits cell proliferation. Second, different PCa cell lines cultured with PPAT should be used to thoroughly understand the influence of adipose tissue on cancer cells. Finally, the mechanism underlying the changes in the secretome of PPAT with the progression of PCa and its related signaling pathways remain to be elucidated.

In conclusion, the present study revealed that PPAT was significantly associated with extracapsular PCa extension. Furthermore, in vitro experiments revealed that PPAT could inhibit PCa cell proliferation by secreting factors that activated immune responses and could thereby promote cancer cell apoptosis. This mechanism may act as a first line of defense in the early stages of PCa. The mechanisms underlying further crosstalk between PPAT and PCa cells remain to be elucidated.