Research Evidence on High-Fat Diet-Induced Prostate Cancer Development and Progression

Although recent evidence has suggested that a high-fat diet (HFD) plays an important role in prostate carcinogenesis, the underlying mechanisms have largely remained unknown. This review thus summarizes previous preclinical studies that have used prostate cancer cells and animal models to assess the impact of dietary fat on prostate cancer development and progression. Large variations in the previous studies were found during the selection of preclinical models and types of dietary intervention. Subcutaneous human prostate cancer cell xenografts, such as LNCaP, LAPC-4, and PC-3 and genetic engineered mouse models, such as TRAMP and Pten knockout, were frequently used. The dietary interventions had not been standardized, and distinct variations in the phenotype were observed in different studies using distinct HFD components. The use of different dietary components in the research models is reported to influence the effect of diet-induced metabolic disorders. The proposed underlying mechanisms for HFD-induced prostate cancer were divided into (1) growth factor signaling, (2) lipid metabolism, (3) inflammation, (4) hormonal modulation, and others. A number of preclinical studies proposed that dietary fat and/or obesity enhanced prostate cancer development and progression. However, the relationship still remains controversial, and care should be taken when interpreting the results in a human context. Future studies using more sophisticated preclinical models are imperative in order to explore deeper understanding regarding the impact of dietary fat on the development and progression of prostate cancer

Macrophage inhibitory cytokine-1 induced by a high-fat diet promotes prostate cancer progression by stimulating tumor-promoting cytokine production from tumor stromal cells

Background Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation. Methods We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated. Results HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor alpha-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy. Conclusion HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression

Specific Gut Microbial Environment in Lard Diet-Induced Prostate Cancer Development and Progression

Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with a fish oil diet (FOD). High gut microbial divergency resulted from difference in diets, and the abundance of several bacterial species, such as in the orders Clostridiales and Lactobacillales, was markedly altered in the feces of LD- or FOD-fed mice. The proportion of the order Lactobacillales in the gut was negatively involved in SMFA-induced body weight gain and PCa progression. We found the modulation of lipid metabolism and cholesterol biosynthesis pathways with three and seven commonly up- and downregulated genes in PCa tissues, and some of them correlated with the abundance of the order Lactobacillales in mouse gut. The expression of sphingosine 1-phosphate receptor 2, which is associated with the order Lactobacillales and cancer progression in mouse models, was inversely associated with aggressive phenotype and weight gain in patients with PCa using the NCBI Gene Expression Omnibus database. Therefore, SMFA may promote PCa progression with the abundance of specific gut microbial species and overexpression of lipogenic genes in PCa. Therapeutics with alteration of gut microbiota and candidate genes involved in diet-induced PCa progression may be attractive in PCa

First-line axitinib therapy is less effective in metastatic renal cell carcinoma with spindle histology

Axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, will be used in combination first-line therapies against metastatic renal cell carcinoma (mRCC), but its effects as a first-line monotherapy are unclear. Thus, we aimed to elucidate pretreatment clinical factors that predict the prognosis of patients with mRCC receiving first-line axitinib therapy. We enrolled 63 patients with mRCC treated with axitinib as first-line therapy between Nov. 2003 and Jul. 2018. Progression-free survival (PFS) and overall survival (OS) were assessed using the Wald chi (2) statistic in Cox proportional hazards regression. Median patient age was 67 (range: 25-85) years. Seven (11.1%) patients were classified as being at favorable risk, 33 (52.4%) at intermediate risk, and 23 (36.5%) at poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification system. Median follow-up duration after axitinib initiation was 14 (range: 1-72) months. Median PFS and OS were 18 months and 65 months, respectively. Cox regression analyses of clinical predictors revealed that high C-reactive protein (CRP) levels were significantly correlated with shorter PFS [hazard ratio (HR), 1.63; 95% confidence interval (CI) 1.7-4.0)], whereas spindle cells and poor IMDC risk scores were related to worse OS (HR, 2.87 and 2.88, respectively; 95% CI 1.4-11.0 and 1.1-8.5, respectively). Thus, patients with mRCC and spindle histology or poor IMDC risk scores had worse OS, and those with high CRP levels had shorter PFS in first-line axitinib treatment. Other therapies might be more suitable for initial management of such patients

The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the obesity paradox

Although obesity increases the risk of renal cell carcinoma (RCC), obese patients with RCC experience longer survival than non-obese patients. However, the mechanism of this obesity paradox is unknown. We examined the impact of preoperative BMI, serum total adiponectin (sAd) level, total adiponectin secretion from perinephric adipose tissue, and intratumoral expression of adiponectin receptors on RCC aggressiveness and survival. We also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells stimulated with exogenous adiponectin. Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003 and p = 0.027, respectively). Cancer-specific survival was significantly longer in overweight and obese patients than in normal patients in all patients (p = 0.035). There was a weak inverse correlation between sAd level and BMI in RCC patients (r = -0.344, p = 0.002). Tumor size was slightly correlated with sAd level, and high sAd was significantly associated with poor overall survival rates in patients with non-metastatic RCC (p = 0.035). Adiponectin levels in perinephric adipose tissue and intratumoral AdipoRl/R2 expression were not correlated with RCC aggressiveness or survival. Proliferation significantly increased in 786-0 and Caki-2 cells exposed to exogenous adiponectin, whereas cell invasion and migration were unaffected. In addition, exogenous adiponectin significantly inhibited starvation-and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL levels. In summary, low BMI and high adiponectin levels are associated with aggressive cell behaviors and poor survival in surgically-treated RCC patients. The effects of adiponectin on proliferation and apoptosis might underlie the obesity paradox of RCC

Prognostic value of plasminogen activator inhibitor-1 in biomarker exploration using multiplex immunoassay in patients with metastatic renal cell carcinoma treated with axitinib

Background and AimsVascular endothelial growth factor-directed therapies play a significant role in patients with metastatic renal cell carcinoma (mRCC). Biomarkers for predicting treatment efficacy and resistance are required to develop personalized medicine. We evaluated multiple serum cytokine levels in patients with mRCC treated with axitinib to explore predictive biomarkers. MethodsFrom September 2012 to October 2015, serum samples were collected from 44 patients with mRCC before treatment and 4weeks after axitinib initiation. Bio-Plex Pro Human Cancer Biomarker Panels 1 and 2 were used to measure levels of 34 serum biomarkers related to angiogenesis and cell proliferation. ResultsPatients with partial response or stable disease had significantly decreased serum plasminogen activator inhibitor-1 (PAI-1) level from pre-treatment to 4weeks after axitinib initiation compared with those with progressive disease (P = .022). The median progression-free survival (PFS) and median overall survival (OS) in patients with increased serum PAI-1 level from pre-treatment to 4weeks after axitinib initiation were significantly shorter than those with decreased serum PAI-1 level (P = .027 and P = .026, respectively). Increased serum PAI-1 level from pre-treatment to 4weeks after axitinib initiation was an independent prognostic marker for shorter PFS and OS in multivariate analyses (P = .015 and P = .032, respectively). The immunohistochemical staining intensity of PAI-1 in tumor specimens was significantly associated with Fuhrman grade and presence of distant metastasis (P = .026 and P = .010, respectively). ConclusionsThe initial change in serum PAI-1 level in the early stage of axitinib treatment could be a useful prognostic biomarker in patients with mRCC

Severe Immune-Related Adverse Events in Patients Treated with Nivolumab for Metastatic Renal Cell Carcinoma Are Associated with PDCD1 Polymorphism

Single nucleotide polymorphisms (SNPs) reportedly influence the effect of nivolumab in metastatic renal cell carcinoma (mRCC). This study aimed to evaluate the relationship between the clinical outcomes of patients with mRCC and SNPs in programmed cell death protein 1 (PD-1) protein-coding gene (PDCD1) and explore any potential correlation with patient prognosis and incidence of immune-related adverse events (irAEs). In total, 106 patients with mRCC, who were treated with nivolumab alone (n = 59) or nivolumab and ipilimumab (n = 47), were enrolled in the study. Three SNPs in the PDCD1 gene, namely PD-1.3, PD-1.5, and PD-1.6, were assessed. Patients harboring the PD-1.6 G allele experienced more severe (odds ratio, 3.390; 95% confidence interval 1.517-7.756; p = 0.003) and multiple (OR, 2.778; 95% CI, 1.020-6.993 p = 0.031) irAEs than those harboring the AA genotype. Thus, the existence of the PDCD1 PD-1.6 polymorphism (G allele) was associated with the occurrence of severe and multiple irAEs in patients with mRCC. Further evaluation of PDCD1 polymorphisms might help identify patients experiencing irAE by nivolumab treatment

BRCA2 Frameshift Mutation in de novo Small-Cell Neuroendocrine Carcinoma of the Prostate: A Case Report

A 66-year-old male was diagnosed with cT4N0M1b small-cell neuroendocrine carcinoma of the prostate. Four months after the administration of combined androgen blockade, multiple novel metastatic regions in the lung and liver and progression of bone metastasis were observed. The patient was referred to our hospital because of biochemical and radiographic progression after four cycles of docetaxel as a first-line therapy for castration-resistant prostate cancer. Transurethral resection of the prostate and hepatic biopsy revealed small-cell carcinoma with positive expression of neuroendocrine markers. The FoundationOne CDx next-generation sequencing test revealed several pathogenic variants, including BRCA2 (W1692fs*3), KEAP1 (R320W), and TP53 (C2385) mutation. After four cycles of chemotherapy with carboplatin plus etoposide (CE), the metastatic regions regressed markedly. The prostate-specific antigen (PSA) and neuron-specific enolase (NSE) level decreased by 96.9% and 91.6%, respectively. However, 2 months after the completion of four cycles of CE, elevation of tumor marker levels, and re-growth of the metastatic regions were observed. Although olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), achieved a 45.2% decrease in NSE, the patient rejected to continue therapy because of G2 adverse events. After receiving an additional two cycles of CE and one cycle of cabazitaxel, the patient died because of cancer progression 24 months after the initial treatment for prostate cancer. Here, we present a case of BRCA2-altered small-cell neuroendocrine prostate cancer treated with both platinum-containing chemotherapy and PARPi. Both therapies achieved an initial response; however, durable responses were not obtained. Additional discussion regarding the optimal treatment strategy for BRCA-altered small-cell/neuroendocrine prostate cancer is required