The hematopoietic stem cell (HSC) niche in the bone marrow has been studied extensively over the past few decades, yet the bone marrow microenvironment that supports the growth of metastatic prostate cancer (PCa) has only been recently considered to be a specialized “niche” as well. New evidence supports the fact that disseminated tumor cells (DTCs) of PCa actually target the HSC niche, displace the occupant HSCs, and take up residence in the pre-existing niche space. This review describes some of the evidence and mechanisms by which DTCs act as molecular parasites of the HSC niche. Furthermore, the interactions between DTCs, HSCs, and the niche may provide new targets for niche-directed therapy, as well as insight into the perplexing clinical manifestations of metastatic PCa disease.
Dormancy; Hematopoietic Stem Cell; Osteoblasts; Prostate Cancer; Metastasis; Niche
aggressiveness; germline; Genome Wide Association Studies; GWAS; inherited; linkage; mutation; single nucleotide polymorphisms; SNPs; susceptibility
This retrospective cohort study from a single clinical practice enrolled patients with evidence of calcified Peyronie’s disease (PD) plaques detected on penile ultrasound at the time of initial presentation. The primary objective was to describe the effect of pentoxifylline (PTX) treatment on subtunical calcifications in men with PD. A PD-specific questionnaire was administered and sonographic evaluations were performed at baseline and follow-up visits. Descriptive statistics and χ2 analysis were used to characterize the effect of PTX on calcified tunical plaques. In all, 71 men (mean age: 51.9 years) with PD and sonographic evidence of calcification were identified. Of them, 62 of these men were treated with PTX for a mean duration of 1 year, and nine with vitamin E or no treatment. Improvement or stabilization in calcium burden at follow-up was noted in 57 (91.9%) of men treated with PTX versus four (44.4%) of those not treated with PTX (P< 0.001). PTX users were much less likely to have a subjective worsening of their clinical condition (25.0% versus 78.3%, P=0.002). Treatment with PTX appeared to stabilize or reduce calcium content in PD plaques. A randomized controlled trial is warranted to further explore this effect.
penile calcifications; pentoxifylline; Peyronie’s disease; treatment
Hypoxia and transforming growth factor-β1 (TGF-β1) increase vascular endothelial growth factor A (VEGFA) expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines (HPV7 and RWPE1) and prostate cancer cell lines (DU145 and PC3). Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β type I receptor (ALK5) kinase inhibitor partially blocked hypoxia-mediated VEGFA165 secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor (VEGFR) 1 (Flt-1) and 2 (Flk-1/KDR). Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.
cell migration; hypoxia; prostate cancer; transforming growth factor-β1 (TGF-β1); vascular endothelial growth factor A (VEGFA)
Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling that is frequently altered in expression in several types of cancers. In prostate cancer (PCa), Cyr61 is highly expressed in organ-confined disease. Further, Cyr61 expression levels are associated with a lower risk of disease recurrence, and can be quantitatively measured in the serum. Considered together, these results indicate that Cyr61 is a potential and clinically useful tissue, as well as serum-based biomarker for differentiating lethal and non-lethal PCa.
Cyr61; lethal prostate cancer; non-lethal prostate cancer; overdiagnosis; overtreatment; prostate cancer
Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents with wholly distinct mechanisms of action (sipuleucel-T, cabazitaxel and abiraterone). Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this space. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that newer trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this disease state.
The contemporary problem of prostate cancer overtreatment can be partially attributed to the diagnosis of potentially indolent prostate cancers that pose low risk to aged men, and lack of sufficiently accurate risk stratification methods to reliably seek out men with indolent diseases. Since progressive acquisition and accumulation of genomic alterations, both genetic and epigenetic, is a defining feature of all human cancers at different stages of disease progression, it is hypothesized that RNA and DNA alterations characteristic of indolent prostate tumors may be different from those previously characterized in the setting of clinically significant prostate cancer. Approaches capable of detecting such alterations on a genome-wide level are the most promising. Such analysis may uncover molecular events defining early initiating stages along the natural history of prostate cancer progression, and ultimately lead to rational development of risk stratification methods for identification of men who can safely forego treatment. However, defining and characterizing indolent prostate cancer in a clinically relevant context remains a challenge, particularly when genome-wide approaches are employed to profile formalin-fixed paraffin-embedded (FFPE) tissue specimens. Here, we provide the conceptual basis underlying the importance of understanding indolent prostate cancer from molecular profiling studies, identify the key hurdles in sample acquisition and variables that affect molecular data derived from FFPE tissues, and highlight recent progresses in efforts to address these technical challenges.
active surveillance; formalin-fixed paraffin-embedded; indolent prostate cancer; microarray; molecular profiling; prostate cancer; prostate cancer progression; risk stratification
Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B12 (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case–control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P = 0.01 and P = 0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l−1; P = 0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.
folate; idiopathic male infertility; semen quality; vitamin B12
Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer. While efficacious, ADT is associated with multiple side effects, including decreased libido, erectile dysfunction, diabetes, loss of muscle tone and altered body composition, osteoporosis, lipid changes, memory loss, gynecomastia and hot flashes. The breadth of literature for the treatment of hot flashes is much smaller in men than that in women. While hormonal therapy of hot flashes has been shown to be effective, multiple non-hormonal medications and treatment methods have also been developed. This article reviews current options for the treatment of hot flashes in patients taking ADT.
androgen deprivation therapy; hot flashes; vasomotor symptoms
Recent data from several laboratories have provided evidence that the newly fertilized oocyte inherits epigenetic signals from the sperm chromatin that are required for proper embryonic development. For the purposes of this review, the term epigenetic is used to describe all types of molecular information that are transmitted from the sperm cell to the embryo. There are at least six different forms of epigenetic information that have already been established as being required for proper embryogenesis in mammals or for which there is evidence that it may do so. These are (1) DNA methylation, (2) sperm specific histones, (3) other chromatin associated proteins, (4) the perinuclear theca proteins, (5) sperm born RNAs, and, the focus of this review, (6) the DNA loop Domain organization by the sperm nuclear matrix. These epigenetic signals should be considered when designing protocols for the manipulation and cryopreservation of spermatozoa for ART, as necessary components for effective fertilization and subsequent embryo development.
Sperm nuclear matrix; sperm DNA; embryogenesis
Curettage of the epithelium of the vas deferens might be a safe and effective method of male sterilization. We conducted a pilot study of vasectomy by epithelial curettage with a novel microcurette called the Vas-X in 12 normal men requesting elective sterilization. Seminal fluid analysis was obtained monthly after the procedure for 6 months. Pain was assessed by questionnaire. Three months after the procedure, all men attained sperm concentrations of less than 0.2 million sperm per mL, and seven were azoospermic. Post-procedural pain was minimal. Nine men ultimately achieved and maintained azoospermia; however, 4 to 6 months after the procedure, sperm concentrations increased in three of the 12 subjects, necessitating repeat vasectomy. Microscopic examination of the vas deferens from these failures revealed re-canalization. Vasectomy by epithelial curettage can result in effective sterilization; however, 1/4 of the subjects were not effectively sterilized by the procedure due to re-canalization of the vas deferens. Epithelial curettage will require further refinement to determine if it is a viable form of vasectomy.
male contraception; male sterilization; re-canalization; spermatogenesis; vas deferens; vasectomy failure
Race, family history and age are the unequivocally accepted risk factors for prostate cancer (PCa). Androgen receptor (AR)-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR (A1675T) (T559S) substitution mutation in the DNA-binding domain in three PCa-affected members of an African-American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR (T559S) mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR (A1675T) allele to early-onset and/or familial PCa in African Americans.
African Americans; androgen receptor; familial prostate cancer; germline mutation
Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.
androgen receptor; germline; mutation; prostate cancer; signaling; somatic
In regard to erectile function, Yin is flaccidity and Yang erection. In the past decade, research has mostly focused on the Yang aspect of erectile function. However, in recent years, the Yin side is attracting increasingly greater attention. This is due to the realization that penile flaccidity is no less important than penile erection and is actively maintained by mechanisms that play critical roles in certain types of erectile dysfunction (ED); for example, in diabetic patients. In addition, there is evidence that the Yin and Yang signaling pathways interact with each other during the transition from flaccidity to erection, and vice versa. As such, it is important that we view erectile function from not only the Yang but also the Yin side. The purpose of this article is to review recent advances in the understanding of the molecular mechanisms that regulate the Yin and Yang of the penis. Emphasis is given to the Rho kinase signaling pathway that regulates the Yin, and to the cyclic nucleotide signaling pathway that regulates the Yang. Discussion is organized in such a way so as to follow the signaling cascade, that is, beginning with the extracellular signaling molecules (e.g., norepinephrin and nitric oxide) and their receptors, converging onto the intracellular effectors (e.g., Rho kinase and protein kinase G), branching into secondary effectors, and finishing with contractile molecules and phosphodiesterases. Interactions between the Yin and Yang signaling pathways are discussed as well.
erectile function; erectile dysfunction; molecular mechanisms; Rho kinase signaling; cyclic nucleotide signaling; Yin–Yang
To study the relationship between circulating androgens (total testosterone [TT], free testosterone [fT] and dihydrotestosterone [DHT]) and HDL-C in men with and without CVD.
Cross-sectional analyses included 1 661 baseline samples from the Massachusetts Male Aging Study (MMAS), a population-based cohort of men ages 40–70 years. Serum hormones were measured by radioimmunoassay and HDL-C was determined following precipitation of the lower density lipoproteins. CVD was determined by self-report. Analyses were performed using multiple linear regression.
TT and HDL-C were positively correlated in the entire sample (r = 0.11, P = 0.0001). After adjusting for confounders, we found this relationship was mostly limited to the 209 men with CVD. Among men with CVD, TT (P = 0.0004), fT (P = 0.0172) and DHT (P = 0.0128) were all positively correlated with HDL-C, whereas in men without CVD only TT correlated with HDL-C (P = 0.0099).
Our results suggest that if androgens contribute to CVD in middle-aged men, the effect is not related to a suppressive effect of endogenous T on HDL-C.
testosterone; high-density lipoprotein cholesterol; androgens; epidemiology