Periprostatic Adipose Tissue as a Contributor to Prostate Cancer Pathogenesis: A Narrative Review.

Obesity is associated with more aggressive prostate cancer (PCa), with visceral obesity conferring an even higher risk than generalized obesity. However, the mechanism by which obesity fuels PCa progression remains unclear. As an active endocrine organ, adipose tissue contributes to metabolic regulation, and current data suggest that the periprostatic adipose (PPA) tissue from obese PCa patients promotes a tumor permissive microenvironment. We hypothesized that altered lipid metabolism in the PPA tissue may be one mechanism for this activity. In this pilot study, we used MR spectroscopy, a technique which could be readily utilized in vivo to obtain the FA signature of tissues non-invasively, to compare the fatty acid (FA) profiles of PPA tissue and subcutaneous adipose (SQA) tissue taken from PCa patients (n=12). The FA profiles of fat biopsies were obtained from proton MR spectra as follows: PRESS localized spectra were acquired from 8μL voxels in fresh tissue on a 600MHz Bruker Avance spectrometer using recycle time TR 4000ms, echo delay time TE 7.5ms, spectral width 8000Hz, number of complex points 16k, and 256 averages. The various functional groups in FA were identified by peaks appearing at characteristic frequencies (chemical shifts) in the proton spectrum. Peak integrals of FA functional groups were measured from which the fractions of saturated (fS), mono-unsaturated (fM), and poly-unsaturated fatty acids (fP), as well as the fractions of 16C FA (f16C) and 18C FA (f18C) were calculated using published methods (Ren, et al. J. Lipid Res. 49: 2055, 2008). We found that mono-unsaturated FA fraction (fM ∼0.40) was higher than saturated or poly-unsaturated FA fraction in both PPA and SQA tissues from PCa patients. However, in the PPA, fM > fS > fP, whereas in the SQA tissue, fM > fP ∼ fS. In a parallel study, we examined the PPA tissue from obese (ob/ob) mice which develop prostate hyperplasia (unpublished results). In these samples, the mono-unsaturated fatty acids were the predominant FA (fM 0.44) while in wildtype control mice polyunsaturated fatty acids (fP 0.47) were the major FA in the PPA tissue. In the human tissues, while f18C > f16C in both adipose depots, the ratio (f16C/ f18C) was significantly higher in PPA (0.59) than in SQA (0.14). This increased abundance of shorter chain length FA (f16C) suggests that PPA may be metabolically more active than SQA in PCa patients, as shorter chain length FA are mobilized at a higher rate. These data support the potential utility of MR spectroscopy to establish FA profiles of PPA tissue, and in ongoing studies we will test tissues from obese PCa patients and normal controls to determine if differences can be exploited to provide additional diagnostic or prognostic information using this noninvasive technique. (Supported by an award from the Prostate Cancer Foundation, a pilot grant award from NorthShore University HealthSystem, and NIH S10 RR13880) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-321. doi:10.1158/1538-7445.AM2011-LB-321

The aim of this study was to determine fatty acid composition in periprostatic adipose tissue (PPAT) of patients undergoing surgery for either prostatic cancer or benign prostatic hyperplasia (BPH). PPAT were obtained from 12 patients undergoing radical prostatectomy for clinically localized prostate tumors (TPPAT, age range 55-70 years) and 11 patients undergoing adenomectomy for BPH (BPPAT, age range 57-79 years). Fatty acid methyl esters of total lipids of PPAT were processed and then analyzed by gas chromatography-mass spectrometry. Quantitation was performed by comparing the percentage area of each FAME peak on the chromatogram with that of the internal standard of known weight, and expressed as percentage of total fatty acids. There were differences in fatty acid content of PPAT, with higher levels of palmitic acid (16:0; P = 0.036) and dihomo-gammalinolenic acid (20:3 n-6; P = 0.020) and lower levels of arachidonic acid (20:4 n-6; P = 0.030) in prostate cancer PPAT, along with a higher 20:4/20:3 (P = 0.001) and lower 20:3/18:2 (P = 0.027) fatty acid ratio in benign prostate hyperplasia PPAT. To the best of our knowledge, this study represents the first attempt at comparing periprostatic fat pad lipid composition in different prostate pathologies. Fatty acid analysis and lipidomics may be important tools to further understand events that occur in tumor microenvironment during prostate cancer disease.

Background: Periprostatic adipose tissue (PPAT) fibrosis is a histological feature potentially linked to prostate cancer (PCa) aggressiveness, though its role is not fully understood. This study investigates the correlation between PPAT fibrosis and PCa aggressiveness and develops a radiomics model based on PPAT MRI features for non-invasive prediction. Methods: This retrospective study included 51 patients who underwent radical prostatectomy. PPAT samples were collected, stained with Sirius Red and quantitatively evaluated for fibrosis using 12 indices via 3D reconstruction with Imaris software. Patients were stratified by cancer aggressiveness based on Grade Groups. Radiomic features were extracted from T1-weighted MRIs of the PPAT. An XGBoost model was developed to predict aggressiveness using these features. Results: Significant correlations were found between multiple PPAT fibrosis indices and PCa aggressiveness (p < 0.05), with more aggressive tumors showing increased fiber complexity. PPAT fibrosis was also significantly associated with primary tumor location in the peripheral zone (p < 0.05). Conversely, PPAT volume showed no significant correlation with aggressiveness (p = 0.616). The radiomics model based on PPAT features achieved an AUC of 0.86 in predicting cancer aggressiveness. Conclusions: PPAT fibrosis is a promising marker of PCa aggressiveness, superior to PPAT volume. The significant link with tumor location provides new insights into the tumor microenvironment (TME). MRI-based radiomics of PPAT offers a potential non-invasive method for assessing fibrosis and aggressiveness, aiding in early diagnosis and personalized treatment.

Background/Aims: The microenvironment produces important factors that are crucial to prostate cancer (PCa) progression. However, the extent to which the cancer cells stimulate periprostatic adipose tissue (PPAT) to produce these proteins is largely unknown. Our purpose was to determine whether PCa cell-derived factors influence PPAT metabolic activity. Methods: Primary cultures of human PPAT samples from PCa patients (adipose tissue organotypic explants and primary stromal vascular fraction, SVF) were stimulated with conditioned medium (CM) collected from prostate carcinoma (PC3) cells. Cultures without CM were used as control. We used multiplex analysis and ELISA for protein quantification, qPCR to determine mitochondrial DNA (mtDNA) copy number and zymography for matrix metalloproteinase activity, in order to evaluate the response of adipose tissue explants and SVFs to PC3 CM. Results: Stimulation of PPAT explants with PCa PC3 CM induced adipokines associated with cancer progression (osteopontin, tumoral necrosis factor alpha and interleukin-6) and reduced the expression of the protective adipokine adiponectin. Notably, osteopontin protein expression was 13-fold upregulated. Matrix metalloproteinase 9 activity and mitochondrial DNA copy number were higher after stimulation with cancer CM. Stromovascular cells from PPAT in culture were not influenced by tumor-derived factors. Conclusion: The modulation of adipokine expression by tumor CM indicates the pervasive extent to which tumor cells command PPAT to produce factors favorable to their aggressiveness.

To investigate the role of MRI measurements of peri-prostatic adipose tissue (PPAT) in predicting bone metastasis (BM) in patients with newly diagnosed prostate cancer (PCa). We performed a retrospective study on 156 patients newly diagnosed with PCa by prostate biopsy between October 2010 and November 2022. Clinicopathologic characteristics were collected. Measurements including PPAT volume and prostate volume were calculated by MRI, and the normalized PPAT (PPAT volume/prostate volume) was computed. Independent predictors of BM were determined by univariate and multivariate logistic regression analysis, and a new nomogram was developed based on the predictors. Receiver operating characteristic (ROC) curves were used to estimate predictive performance. PPAT and normalized PPAT were associated with BM (P<0.001). Normalized PPAT positively correlated with clinical T stage(cT), clinical N stage(cN), and Grading Groups(P<0.05). The results of ROC curves indicated that PPAT and normalized PPAT had promising predictive value for BM with the AUC of 0.684 and 0.775 respectively. Univariate and multivariate analysis revealed that high normalized PPAT, cN, and alkaline phosphatase(ALP) were independently predictors of BM. The nomogram was developed and the concordance index(C-index) was 0.856. Normalized PPAT is an independent predictor for BM among with cN, and ALP. Normalized PPAT may help predict BM in patients with newly diagnosed prostate cancer, thus providing adjunctive information for BM risk stratification and bone scan selection.

Periprostatic adipose tissue (PPAT) has emerged as a key player in the prostate cancer (PCa) microenvironment. In this study, we evaluated the ability of PPAT to promote PCa cell migration, as well as the molecular mechanisms involved. Methods: We collected conditioned mediums from in vitro differentiated adipocytes isolated from PPAT taken from PCa patients during radical prostatectomy. Migration was studied by scratch assay. Results: Culture with CM of human PPAT (AdipoCM) promotes migration in two different human androgen-independent (AI) PCa cell lines (DU145 and PC3) and upregulated the expression of CTGF. SB431542, a well-known TGFβ receptor inhibitor, counteracts the increased migration observed in presence of AdipoCM and decreased CTGF expression, suggesting that a paracrine secretion of TGFβ by PPAT affects motility of PCa cells. Conclusions: Collectively, our study showed that factors secreted by PPAT enhanced migration through CTGF upregulation in AI PCa cell lines. These findings reveal the potential of novel therapeutic strategies targeting adipocyte-released factors and TGFβ/CTGF axis to fight advanced PCa dissemination.

Emerging evidence links periprostatic adipose tissue (PPAT) inflammation, a consequence of metabolic impairment, and certain features of prostate cancer (PCa) aggressiveness. AT thromboinflammation, mediated by the proteolytic activation of protease‐activated receptors (PARs) particularly by thrombin and Factor Xa (FXa), drives AT dysfunction. Nevertheless, the contribution of PPAT thromboinflammation to early prostatic neoplastic alterations has not been investigated. Here, we utilized a non‐obese prediabetic rat model to assess prostatic neoplasia in association with PPAT thromboinflammation. Mild hypercaloric diet (MHC)‐fed rats exhibited hyperinsulinemia, hypertriglyceridemia, a lower metabolic efficiency, and a higher fat/lean ratio in comparison to regular chow‐fed rats. When compared to regular chow‐fed rats, MHC‐fed rats exhibited PPAT with larger adipocytes, enhanced oxidative stress and increased immune cell influx. Concurrently, prostates from MHC‐fed rats displayed higher number of prostatic intraepithelial neoplasia (PIN), enhanced expression of the proliferation markers Ki67 and PCNA, enhanced expression of cytokeratin 8 (CK8), pronounced fibrosis and increased immune cell influx. Further profiling of macrophage polarization in PPAT and the prostate is underway. Importantly, these prostatic and adipocytic manifestations were attenuated in MHC‐fed rats treated with non‐hemorrhagic doses of rivaroxaban, a direct FXa inhibitor. Ongoing in vitro investigation demonstrates that rivaroxaban reduces the migratory potential of murine prostate cancer cells (Plum‐AD); and the effect of rivaroxaban on the colony forming and sphere forming capacities of Plum‐AD cells are being studied. Further investigation is ongoing to delineate the molecular underpinnings of rivaroxaban‐associated amelioration of PPAT inflammation and the associated prostatic neoplastic alterations.

&lt;div&gt;Abstract&lt;p&gt;Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an &lt;i&gt;in vitro&lt;/i&gt; model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results.&lt;/p&gt;Implications:&lt;p&gt;Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.&lt;/p&gt;&lt;/div&gt;

The periprostatic adipose tissue (PPAT) is a site of invasion of prostate cancer (PCa) and is part of the microenvironment. It was shown that PPAT secretes factors and fatty acids (FAs) that alter the microenvironment of the PCa. The PPAT secretome of patients with PCa-T3 stage (PPAT-T3) has a metabolic profile enriched in several pathways related to energy production, indicating a greater energy requirement by the tumor, when compared to that of patients in the PCa-T2 stage (PPAT-T2). PPAT-T3 also shows enrichment in pathways related to hormone response, polyamine synthesis, and control of protein synthesis, through amino acid, RNA, and nucleotide metabolism. PPAT-T2 and PPAT-BPH secretomes have less complex metabolic profile, both related with energy balance, while PPAT-BPH has hormone response through insulin pathway. Undoubtedly, a deeper characterization of the human PPAT will lead to a better understanding of the disease and possibly allow new stratification factors and the design of a specific therapy that targets crucial components of the tumor microenvironment as another way to treat or control the disease.

Because the prostatic capsule is often indistinct, recognition of extraprostatic extension by carcinoma depends heavily on the identification of carcinoma cells in the periprostatic adipose tissue. However, the distribution of adipose tissue along the prostatic surfaces has not been studied extensively. The authors analyzed the periprostatic adipose tissue in specimens from 100 patients treated with radical retropubic prostatectomy and bilateral pelvic lymphadenectomy for prostatecarcinoma. Each specimen was totally embedded and examined by the whole mount method. The presence or absence of adipose tissue on the anterior, posterior, right, and left surfaces of the prostate was determined and analyzed. Periprostatic adipose tissue was present on 48% of all prostatic surfaces examined. The distribution of periprostatic adipose tissue varied among the different surfaces of the prostate, with the anterior, posterior, right, and left surfaces showing 44%, 36%, 59%, and 57% adipose tissue, respectively. The amount of periprostatic adipose tissue was similar among specimens from operations performed by different surgeons (P = 0.72). However, nerve-sparing procedures resulted in less adipose tissue (46%) than non-nerve-sparing procedures (54%) (P = 0.01). Less than half of the prostatic surfaces examined were covered by adipose tissue. The absence of adipose tissue over large areas of the prostatic surface, especially the posterior surface, makes the evaluation of extraprostatic extension difficult and unreliable. Further refinement of the prostate carcinoma staging system is needed.

Background: The aim of this study was to test the association between periprostatic adipose tissue (PPAT)—apparent diffusion coefficient (ADC) value recorded at multiparametric magnetic resonance imaging (mpMRI) and determinants of prostate cancer (PCa) aggressiveness in the preoperative setting. Methods: Data from 219 consecutive patients undergoing prostate biopsy (PBx) for suspicion of PCa, between January 2020 and June 2022, at our institution were retrospectively evaluated. Only patients who had mpMRI performed before PBx were included. The distribution of demographics and clinical features among PPAT-ADC values up to vs. above the median was studied using both parametric and non-parametric tests, according to variables. Linear and logistic regression models tested the association between PPAT-ADC values and determinants of PCa aggressiveness and the presence of intermediate-high risk PCa, respectively. Results: Of 132 included patients, 76 (58%) had PCa. Median PPAT-ADC was 876 (interquartile range: 654 − 1112) × 10−6 mm2/s. Patients with PPAT-ADC up to the median had a higher rate of PIRADS (Prostate Imaging—Reporting and Data System) 5 lesions (41% vs. 23%, p = 0.032), a higher percentage of PBx positive cores (25% vs. 6%, p = 0.049) and more frequently harbored ISUP (International Society of Urological Pathology) > 1 PCa (50% vs. 28%, p = 0.048). At univariable linear regression analyses, prostate-specific antigen (PSA), PSA density, PIRADS 5, and percentage of PBx positive cores were associated with lower PPAT-ADC values. PPAT-ADC up to the median was an independent predictor for intermediate-high risk PCa (odds ratio: 3.24, 95%CI: 1.17−9.46, p = 0.026) after adjustment for age and body mass index. Conclusions: Lower PPAT-ADC values may be associated with higher biopsy ISUP grade group PCa and a higher percentage of PBx-positive cores. Higher-level studies are needed to confirm these preliminary results.

Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo.

Adenocarcinoma of the prostate is one of the most common cancers in men worldwide and is the second leading cause of cancer-specific death in the United States. Over the past 15 years, significant advances have been made in the treatment of prostate cancer, largely owing to earlier diagnosis and the evolution of surgical techniques and improvements in radiation therapy. Nevertheless, tremendous uncertainty and controversy exist regarding the appropriate clinical management of prostate cancer in many cases. Similarly, despite the magnitude of the problem, understanding of the pathogenesis, biology, and natural history of human prostate cancer remains incomplete and unclear. Progress has been made in the past decade in elucidating the molecular and genetic changes involved in prostate cancer development and progression. A better understanding of the underlying disease mechanisms will allow rational treatment strategies and improved outcomes. The classic model of tumor development describes a multistep process in which a series of genetic alterations leads to aberrant, uncontrolled cell growth. This is best characterized in the case of colon cancer, for which specific genetic changes have been correlated with clinical and pathologic disease progression. These genetic alterations can be both hereditary (germ-line mutation) and acquired (somatic mutation). The paradigm is less established in prostate cancer (Fig. 1). We discuss the current understanding of the molecular genetics and biology of prostate cancer development, including genetic predispositions, early changes associated with prostatic intraepithelial neoplasia (PIN), and the traditional classes of genes involved in promoting and repressing cancer development (protooncogenes/oncogenes and tumor suppressor genes, respectively). In addition, we describe recent studies on the role of genetic instability, telomerases, growth factors, cell-adhesion molecules, DNA ethylation, and the androgen receptor (AR) in prostate cancer. Figure 1. Schematic illustrating the potential factors in the development of prostatic intraepithelial neoplasia and prostate cancer and the subsequent progression of prostate cancer. AR = androgen receptor; FGF = fibroblast growth factor; TGF = transforming growth factor; RER = replication error. Keywords: Cancer; Prostrate; Genetics

Background/Objectives: This study aimed to describe the population pharmacokinetics of cefazolin (CFZ) using unbound serum and periprostatic adipose tissue concentrations and to optimize dosing regimens for patients undergoing robotic-assisted radical prostatectomy (RARP). Methods: We investigated the population pharmacokinetics of CFZ using 295 unbound serum and 67 periprostatic adipose tissue samples from 67 individuals. CFZ concentrations were determined in all samples. A nonlinear mixed-effects model was developed. The pharmacodynamic target was defined as maintaining unbound trough and periprostatic adipose tissue concentrations exceeding the minimum inhibitory concentration (MIC) against methicillin-susceptible Staphylococcus aureus (MSSA) for over 90% of the dosing interval (MIC90; 0.5 mg/L). Results: Systemic clearance of unbound CFZ was significantly associated with creatinine clearance (CLcr). In patients with normal renal function, simulations showed that a 1 g CFZ infusion over 15 min maintained unbound concentrations exceeding the MSSA MIC90 for >90% of the 3 h interval after the initial dose. Notably, in patients with mild renal impairment (CLcr ≤ 80 mL/min), a 5 h dosing interval also achieved a >90% probability of maintaining the target CFZ concentration. Conclusions: The simulations demonstrated that the probability of target attainment of >90% was maintained for up to 5 h in patients with mild renal impairment (CLcr ≤ 80 mL/min). These findings provide a pharmacokinetic rationale suggesting that the standard additional dose may not be necessary for this subgroup; however, future clinical studies are needed to validate safety and efficacy.

Recently, the interferon (IFN) antiviral pathways and prostate cancer genetics and have surprisingly converged on a single-strand specific, regulated endoribonuclease. Genetics studies from several laboratories in the U.S., Finland, and Israel, support the recent identification of the RNase L gene, RNASEL, as a strong candidate for the long sought after hereditary prostate cancer 1 (HPC1) allele. Results from these studies suggest that mutations in RNASEL predispose men to an increased incidence of prostate cancer, which in some cases reflect more aggressive disease and/or decreased age of onset compared with non-RNASEL linked cases. RNase L is a uniquely regulated endoribonuclease that requires 5'-triphosphorylated, 2',5'-linked oligoadenylates (2-5A) for its activity. The presence of both germline mutations in RNASEL segregating with disease within HPC-affected families and loss of heterozygosity (LOH) in tumor tissues suggest a novel role for the regulated endoribonuclease in the pathogenesis of prostate cancer. The association of mutations in RNASEL with prostate cancer cases further suggests a relationship between innate immunity and tumor suppression. It is proposed here that RNase L functions in counteracting prostate cancer by virtue of its ability to degrade RNA, thus initiating a cellular stress response that leads to apoptosis. This monograph reviews the biochemistry and genetics of RNase L as it relates to the pathobiology of prostate cancer and considers implications for future screening and therapy of this disease.