Obesity and metabolic dysfunction severely influence prostate cell function: role of insulin and IGF1

Obesity is a major health problem that courses with severe comorbidities and a drastic impairment of homeostasis and function of several organs, including the prostate gland (PG). The endocrine–metabolic regulatory axis comprising growth hormone (GH), insulin and IGF1, which is drastically altered under extreme metabolic conditions such as obesity, also plays relevant roles in the development, modulation and homeostasis of the PG. However, its implication in the pathophysiological interplay between obesity and prostate function is still to be elucidated. To explore this association, we used a high fat–diet obese mouse model, as well as in vitro primary cultures of normal‐mouse PG cells and human prostate cancer cell lines. This approach revealed that most of the components of the GH/insulin/IGF1 regulatory axis are present in PGs, where their expression pattern is altered under obesity conditions and after an acute insulin treatment (e.g. Igfbp3), which might have some pathophysiological implications. Moreover, our results demonstrate, for the first time, that the PG becomes severely insulin resistant under diet‐induced obesity in mice. Finally, use of in vitro approaches served to confirm and expand the conception that insulin and IGF1 play a direct, relevant role in the control of normal and pathological PG cell function. Altogether, these results uncover a fine, germane crosstalk between the endocrine–metabolic status and the development and homeostasis of the PG, wherein key components of the GH, insulin and IGF1 axes could play a relevant pathophysiological role.     

The Notch pathway in prostate development and cancer

Abstract The Notch family of transmembrane receptors are important mediators of cell fate determination. Accordingly, Notch signaling is intimately involved in the development of numerous tissues. Recent findings have highlighted a critical role for Notch signaling in normal prostate development. Notch signaling is required for embryonic and postnatal prostatic growth and development, for proper cell lineage specification within the prostate, as well as for adult prostate maintenance and regeneration following castration and hormone replacement. Evidence for Notch as a regulator of prostate cancer development, progression, and metastasis has also emerged. This review summarizes our current understanding of the role of Notch pathway elements, including members of the Jagged, Delta-like, hairy/enhancer-of-split, and hairy/enhancer-of-split related with YRPW motif families, in prostate development and tumorigenesis. Data supporting Notch pathway elements as oncogenes and tumor suppressors in prostate tumors, as well as data implicating Notch receptors and ligands as potential markers of normal prostate stem/progenitor cells and prostate cancer stem/initiating cells, are also presented.     

以前列腺干细胞抗原为靶点的前列腺癌免疫治疗研究进展

前列腺干细胞抗原(PSCA)为细胞膜表面抗原,在正常前列腺组织中低表达,在雄激素依赖性和非依赖性前列腺癌组织中高表达,有较高的组织特异性,是前列腺癌治疗的理想靶标,近年来以PSCA为靶点的前列腺癌治疗性疫苗的研究已成为热点。我们简要综述以PSCA为靶点治疗前列腺癌的研究进展。     

Tissue proteomics studies in the investigation of prostate cancer

Introduction: Prostate cancer (PCa) is one of the leading causes of death in the male population worldwide. Various clinical samples such as urine, blood serum, and prostatic fluid have been commonly used for the identification of PCa-associated molecular changes. Tissue, the site of oncogenesis, is increasingly gaining more attention as a study material for studies aimed at the discovery of biomarkers for predicting the disease outcome and therapeutic targets.

Areas covered: This review is the output of a systematic literature search on PubMed to retrieve articles relevant to the proteomic analysis of tissues for the study of PCa. Studies performed during the last 10 years using human tissues are summarized.

Expert commentary: Multiple proteomics studies were performed in the past 10 years focusing on PCa initial diagnosis and staging. Even though some reproducible findings have been reported, many studies lacked adequate validation of findings and relied on relatively lower-resolution proteomics techniques compared to the current state of the art. Incorporation of high-resolution proteomics techniques, including investigations of protein post-translational modifications (PTMs), is expected in the near future to complement other -omics and enhance current efforts toward the molecular subtyping of PCa for patient stratification.     

Changing perspectives on the origin of eukaryotes

From the initial application of molecular techniques to the study of microbial organisms, three domains of life emerged, with eukaryotes and archaea as sister taxa. However, recent analyses of an expanding molecular data set reveal that the eukaryotic genome is chimeric with respect to archaea and bacteria. Moreover, there is now evidence that the primitive eukaryotic group ‘Archezoa' once harbored mitochondia. These discoveries have challenged the traditional stepwise model of the evolution of eukaryotes, in which the nucleus and microtubules evolve before the acquisition of mitochondria, and consequently compel a revision of existing models of the origin of eukaryotic cells.     

Acid phosphatase activity in gerbil prostate: comparative study in male and female during postnatal development

The prostate is present in both male and female mammals. It is composed of secretory epithelium, connective stroma, smooth muscle and neuroendocrine cells, which are under hormonal regulation. Acid phosphatases catalyze the hydrolysis of orthophosphate monoesters. We have compared the expression of acid phosphatases in gerbil (Meriones unguiculatus) prostate glands in both sexes using young, adult and old animals. Eighteen prostates were isolated, frozen, sectioned, fixed, incubated with sodium beta-glycerophosphate sodium, washed with acetate buffer solution, treated with ammonium sulfide and counterstained with Methyl-Green aqueous solution. Ultracytochemical analyses were also conducted. This substrate revealed total acid phosphatase activity. The expression of the enzyme was heterogeneous, occurring in all ages during postnatal development. The data revealed that the female prostate matured before the male prostate. In addition, acid phosphatase activity in both sexes was regulated by androgen variation concomitant with development.     

多拷贝异种化前列腺干细胞抗原融合基因片段的构建及真核表达

目的：构建一系列含有人前列腺干细胞抗原（PSCA）主要T细胞表位的多拷贝异种化融合基因片段,并分别在人胚肾293T细胞中表达。方法：通过重叠延伸PCR法合成单拷贝异种化PSCA基因片段PSCA1,随即应用同尾酶法将该片段串联形成2、3、4拷贝异种化PSCA基因片段PSCA2、PSCA3和PSCA4,并将上述4种基因片段分别插入真核表达载体pCI-Fc-GPI中,构建最终目的片段1～4拷贝异种化PSCA-Fc-GPI（即PSCA1-Fc-GPI～PSCA4-Fc-GPI）,随即分别将重组质粒pCI-PSCA1-Fc-GPI～PSCA4-Fc-GPI体外转染293T细胞,利用间接免疫荧光和流式细胞仪检测其表达情况。结果：测序证实PSCA1片段与设计一致,酶切鉴定证明目的基因片段PSCA1-Fc-GPI～PSCA4-Fc-GPI构建成功;间接免疫荧光和流式细胞仪的检测结果显示,在293T细胞中1～4拷贝异种化PSCA融合基因片段均获得较好表达。结论：构建了目的基因片段PSCA1-Fc-GPI～PSCA4-Fc-GPI,为以PSCA为靶抗原的抗前列腺癌DNA疫苗的构建及功能研究奠定了重要基础。     

Targeted treatment of prostate cancer

Over a half century ago, Charles Huggins demonstrated the response of prostate cancer to androgen deprivation therapy. Subsequently, many discoveries and evolving findings continued to support a research rationale focused on the androgen receptor (AR) as a key target for prostate cancer. More recently, preliminary trials have suggested that other targets could also be useful in the treatment of prostate cancer, and the proposed strategies for treatment have ranged from targeted toxins to immunotherapeutic agents. We provide an overview of some of these approaches, with an emphasis on those that employ prostate specific membrane antigen (PSMA) as a target.     

Establishment of a three-dimensional human prostate organoid coculture under microgravity-simulated conditions: Evaluation of androgen-induced growth and psa expression

Summary A novel in vitro human prostate cancer model was established by using a coculture technique in which isolated human prostate fibroblasts were observed to grow as a mixed culture with isolated human prostate cancer cells (LNCaP) on microcarrier beads under microgravity-simulated conditions. This model appears to be promising and deserves further exploration because: (a) cocultured human prostate fibroblasts and cancer epithelial cells appear to undergo patterns of histogenesis similar to those observed in human prostate tumors and (b) unlike the conventional cell culture on plastic dishes, cocultured human prostate fibroblasts and LNCaP cells in microgravity-simulated conditions responded to the inductive signals of growth and differentiation from dihydrotestosterone in a manner similar to that observed in the in vivo condition. These results offer an opportunity to examine molecular mechanisms of cellular signaling in response to androgen stimulation during normal and aberrant human prostate development. The microgravity-simulated three-dimensional prostate epithelial cell culture with prostate fibroblasts can be further explored as an ideal in vitro model for the study of normal and neoplastic prostate development. This model could also be adopted as a drug screening program for the discovery of novel therapeutic agents in the treatment of human prostate cancer and benign hyperplastic growth.     

Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis

Abstract Several tissue-specific regulatory genes have been found to play essential roles in both organogenesis and carcinogenesis. In the prostate, the Nkx3.1 homeobox gene plays an important role in normal differentiation of the prostatic epithelium while its loss of function is an initiating event in prostate carcinogenesis in both mouse models and human patients. Thus, the Nkx3.1 homeobox gene provides a paradigm for understanding the relationship between normal differentiation and cancer, as well as studying the roles of homeobox genes in these processes. Here, we review recent findings concerning the roles of Nkx3.1 in development and discuss how its normal function is disrupted in processes of early prostate carcinogenesis.     

Angiogenesis and prostate cancer tumor growth

The initiation of new blood vessels through angiogenesis is critical to tumor growth. Tumor cells release soluble angiogenic factors that induce neovascularization, without which nutrients and oxygen would not be available to allow tumors to grow more than 2-3 mm in diameter. This "angiogenic switch" or angiogenic phenotype requires an imbalance between proangiogenic and antiangiogenic factors since the formation of new blood vessels is highly regulated. This review discusses angiogenesis mediators, and the potential for manipulation of angiogenic factors as a practical cancer therapy, particularly in prostate cancer.     

Prostate inflammation and its potential impact on prostate cancer: a current review

Recent studies have identified a role for inflammation in the development and progression of several cancers, such as liver, stomach and the large intestine. Data from several studies has shown correlations between soluble inflammatory mediators, such as cytokines, chemokines and growth factors. However, a direct relationship between inflammation and prostate cancer has yet to be identified. Two major hurdles currently exist which limit the study of this relationship are first that animal models available for studying prostate inflammation are limited, and secondly that relatively little is known about the inflammatory response in the prostate. Here we first review the data demonstrating a correlation between inflammation and prostate cancer as well as review what is currently known about the inflammatory response in the prostate and the impact this inflammation has on the prostate tissue.     

Citrate transport and metabolism in mammalian cells

Citrate, an organic trivalent anion, is a major substrate for generation of energy in most cells. It is produced in mitochondria and used either in the Krebs' cycle or released into cytoplasm through a specific mitochondrial carriers. Citrate can also be taken up from blood through different plasma membrane transporters. In the cytoplasm, citrate can be used ultimately for fatty acid synthesis, which is increased in cancer cells. Here, we review the ways in which citrate can be transported and discuss the changes in transport and metabolism that occur in cancer cells. The primary focus is on the prostate gland, which is known to produce and release large amounts of citrate during its normal secretory function. The significant changes that occur in citrate‐related metabolism and transport in prostate cancer are the second focus. This review strives to relate these mechanisms to molecular biology on the one hand and to clinical applications on the other.     

Circulating microRNAs as potential diagnostic biomarkers and therapeutic targets in prostate cancer: Current status and future perspectives

Prostate cancer (PCa) is one of the most common malignancies among men. Despite advancement in technology and medicine over past decades, late diagnosis remains a critical milestone in effective treatment. Therefore, it is necessary to identify novel and reliable biomarkers which are specifically sensitive and specific for prognosis and prediction of clinical outcomes. MicroRNAs (miRNAs) play important roles in posttranslational regulations of genes. Circulating and exosomal miRNAs can be applied as useful diagnostic markers for a different type of malignancies, including PCa. Herein, we summarized various roles of miRNAs (diagnostic, therapeutic, and prognostic) in PCa. Moreover, we highlighted exosomal miRNAs as a new candidate in diagnosis and monitoring response to therapy in patients with PCa.