Tumor Cell-educated Periprostatic Adipose Tissue Acquires an Aggressive Cancer-promoting Secretory Profile

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 In a parallel study, we examined the PPA tissue from obese (ob/ob) mice which develop prostate hyperplasia (unpublished results).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.

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.

Periprostatic adipose tissue (PPAT) contributes to the pathogenesis of prostate cancer. The purpose of this study was to review and summarize the literature on the role of PPAT in prostate cancer pathogenesis. Moreover, we evaluated the clinical implication of PPAT in patients with prostate cancer. We performed a scoping literature review of PubMed from January 2002 to November 2024. Search terms included "periprostatic adipose tissue", "adipokines", and "prostate cancer". Secondary search involved reference lists of eligible articles. The key criterion was to identify studies that included PPAT, adipokines, and their role in prostate cancer biology and clinical features. In total 225 publications were selected for inclusion in this review. The studies contained in publications allowed us to summarize the data on the pathogenesis of PPAT as a contributor to prostate cancer biology and its aggressiveness. The review also presents new research directions for PPAT as a new target for the treatment of prostate cancer. Based on the current review, it can be stated that PPAT plays an important role in prostate cancer pathogenesis. Moreover, PPAT seems to be a promising target point when it comes to finding new therapies in patients with more aggressive and/or advanced stages of prostate cancer.

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.

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.

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.

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.

Background: Bone metastasis is one of the major clinical concerns that causes skeletal-related malignancies and increased mortality. Bone is one of the preferred sites for metastatic prostate cancer. The metastatic prostate cancer cells interact with bone cells (osteoblasts and osteoclasts), resulting in an imbalance in the bone homeostasis leading to increased activation of osteoblasts over osteoclasts. Our preliminary data indicated a non-tyrosine kinase receptor Neuropilin 2 (NRP2) is expressed in osteoclasts (OC) induced by PCa cells and acts as a negative regulator of osteoclasts' function. We hypothesize that PCa-induced NRP2 expression in OC is necessary for low osteolytic activity and thus favors an osteoblastic lesion in PCa bone metastasis. Methods: Mouse OC precursors were isolated from bone marrow of C57BL/6 mice as well as transgenic CSF1R-cre; NRP2 Flox/Flox inducible mice where addition of 4-hydroxytamoxifen depletes NRP2 specifically from the myeloid cells. Differentiation of OCs was conducted under the conditions of RANKL and M-CSF and in conditioned medium (CM) collected from PCa cell line LNCaP C4-2B (promotes high osteoblastic and low osteoclastic activity) and PC3 (predominantly osteoclastic activity) to mimic the conditions in normal bone and PCa bone metastasis. NRP2 expression at protein and mRNA was evaluated. TRAP staining and pit formation were conducted to confirm the differentiation and function of OCs. Results and Discussion: We observed an increase in NRP2 expression in OCs induced by RANKL and M-CSF and in PC3 and LNCaP C4-2B CM simultaneously. TRAP staining and activity confirmed the differentiation of OCs under these conditions. Interestingly, depletion of NRP2 and treatment either in RANKL and M-CSF or LNCaP C4-2B CM exhibited a drastic increase in osteoclast differentiation and function. mRNA analysis revealed an increase in expression of osteoclastic genes following NRP2 depletion in RANKL and M-CSF and LNCaP C4-2B CM. However, NRP2-depleted OC precursors when treated with PC3 CM showed no change in osteoclastogenesis. These findings advocate a role of NRP2 in inhibiting osteoclastic activity in PCa bone metastasis and that osteolytic PCa evades NRP2 inhibition. Using in vitro and transgenic mice, we will elucidate the molecular mechanisms through which NRP2 regulates osteoclast differentiation and function in normal bone and in LNCaP C4-2B CM. We will also address how PC3 CM-induced OCs escapes the inhibition of NRP2. Together, this approach will elucidate the role of NRP2 axis on OCs in promoting PCa-induced bone metastasis and will aid in determining whether NRP2 axis can be a therapeutic target. Citation Format: Navatha Shree Polavaram, Arup Bag, Samikshan Dutta, Kaustubh Datta. Role of Neuropilin 2 in orchestrating the functions of osteoclasts in promoting prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2117.

201 Background: Monocyte chemoattractant protein 1 (CCL2 or MCP-1), a chemokine secreted by monocytic cells, is critical in recruiting Treg and MDSCs into the tumor microenvironment and in regulating prostate cancer (PCa) migration and proliferation. In this study, we examined circulating CCL2 levels in healthy vs PCa patients and used an in vitro coculture model to identify the source of the elevated CCL2. Methods: Serum CCL2 concentrations were evaluated via ELISA in 59 patients (19 health controls, 20 “treatment naïve” PCa, 20 mCRPC). Monocytic leukemia cells (U937) were either directly cocultured with PC3 PCa cell line or cultured in the PC3 conditioned medium (CM). The induction of CCL2 mRNA in the cultures was examined by qPCR. The secretion of CCL2 into cell culture supernatants was evaluated via human cytokine array. Neutralizing antibodies to several overexpressed inflammatory cytokines in PC3 cells were added into the PC3 CM to evaluate the contribution of these inflammatory cytokines to CCL2 induction. Results: Circulating CCL2 concentrations were significantly higher in prostate cancer patient serum compared to control patient serum (p=4.4e-6) (Table). To understand the potential source of elevated CCL2, we grew U937 and PC3 in coculture and evaluated with qPCR, revealing that while CCL2 was not expressed in PC3 cells, it was expressed at very low levels in U937 cells. Interestingly, coculture of PC3 with U937 increased CCL2 mRNA expression by over 10-fold, and the result was confirmed at protein levels by human cytokine array. Our results also indicated that IL-6 and GM-SCF were the two major cytokines released by PCa cells to induce CCL2 mRNA in U937 cells and MEK and JAK-STAT signaling were crucial for CCL2 induction. Conclusions: Prostate cancer cells induce CCL2 secretion from monocytes in an IL-6 and GM-CSF dependent manner. Given the critical role of CCL2 in mediating immunosuppressive tumor microenvironments, our study highlighted the CCL2 Concentrations in PCa vs Healthy Serum.[Table: see text]

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.

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.

Obesity is a prognostic risk factor in the progression of prostate cancer; however, the molecular mechanisms involved are unclear. In this study, we provide preclinical proof of concept for the role of a proinflammatory CXCL12-CXCR4/CXCR7 signaling axis in an obesity-driven mouse model of myc-induced prostate cancer. Analysis of the stromal vascular fraction from periprostatic white adipose tissue from obese HiMyc mice at 6 months of age revealed a dramatic increase in mRNAs encoding various chemokines, cytokines, growth factors, and angiogenesis mediators, with CXCL12 among the most significantly upregulated genes. Immunofluorescence staining of ventral prostate tissue from obese HiMyc mice revealed high levels of CXCL12 in the stromal compartment as well as high staining for CXCR4 and CXCR7 in the epithelial compartment of tumors. Prostate cancer cell lines derived from HiMyc tumors (HMVP2 and derivative cell lines) displayed increased protein expression of both CXCR4 and CXCR7 compared with protein lysates from a nontumorigenic prostate epithelial cell line (NMVP cells). CXCL12 treatment stimulated migration and invasion of HMVP2 cells but not NMVP cells. These effects of CXCL12 on HMVP2 cells were inhibited by the CXCR4 antagonist AMD3100 as well as knockdown of either CXCR4 or CXCR7. CXCL12 treatment also produced rapid activation of STAT3, NFκB, and MAPK signaling in HMVP2 cells, which was again attenuated by either AMD3100 or knockdown of CXCR4 or CXCR7. Collectively, these data suggest that CXCL12 secreted by stromal cells activates invasiveness of prostate cancer cells and may play a role in driving tumor progression in obesity. Targeting the CXCL12-CXCR4/CXCR7 axis could lead to novel approaches for offsetting the effects of obesity on prostate cancer progression. Cancer Res; 77(18); 5158-68. ©2017 AACR.