Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment.

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood.

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment.

In prostate cancer, cancer-associated fibroblasts (CAF) exhibit contrasting biological properties to non-malignant prostate fibroblasts (NPF) and promote tumorigenesis. Resolving intercellular signaling pathways between CAF and prostate tumor epithelium may offer novel opportunities for research translation. To this end, the proteome and phosphoproteome of four pairs of patient-matched CAF and NPF were characterized to identify discriminating proteomic signatures.

Elevated seminal plasma estradiol and epigenetic inactivation of and is associated with CP/CPPS.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III ( 50; median age 39.

Novel imaging of the prostate reveals spontaneous gland contraction and excretory duct quiescence together with different drug effects.

Prostate carcinoma and benign prostate hyperplasia (BPH) with associated lower urinary tract symptoms (LUTS) are among the most prevalent and clinically relevant diseases in men. BPH is characterized by an enlargement of prostate tissue associated with increased tone of smooth muscle cells (SMCs) which surround the single glands composing the prostate. Secretions of the glands leave the prostate through local excretory ducts during the emission phase of ejaculation.

Convergence of regenerative medicine and synthetic biology to develop standardized and validated models of human diseases with clinical relevance.

In order to progress beyond currently available medical devices and implants, the concept of tissue engineering has moved into the centre of biomedical research worldwide. The aim of this approach is not to replace damaged tissue with an implant or device but rather to prompt the patient's own tissue to enact a regenerative response by using a tissue-engineered construct to assemble new functional and healthy tissue. More recently, it has been suggested that the combination of Synthetic Biology and translational tissue-engineering techniques could enhance the field of personalized medicine, not only from a regenerative medicine perspective, but also to provide frontier technologies for building and transforming the research landscape in the field of in vitro and in vivo disease models.

A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment.

Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs).

In vitro modeling of the prostate cancer microenvironment.

Prostate cancer is the most commonly diagnosed malignancy in men and advanced disease is incurable. Model systems are a fundamental tool for research and many in vitro models of prostate cancer use cancer cell lines in monoculture. Although these have yielded significant insight they are inherently limited by virtue of their two-dimensional (2D) growth and inability to include the influence of tumour microenvironment.

Aromatase transgenic upregulation modulates basal cardiac performance and the response to ischemic stress in male mice.

Estrogen in females is conventionally considered a cardioprotective influence, but a role for estrogen in male cardioprotection has yet to be defined. Estrogen biosynthesis from testosterone is regulated by aromatase. Aromatase has recently been shown to be expressed in the adult heart, although little is known about its involvement in the regulation of myocardial function and stress responses.

A bioengineered microenvironment to quantitatively measure the tumorigenic properties of cancer-associated fibroblasts in human prostate cancer.

Stromal-epithelial cell interactions play an important role in cancer and the tumor stroma is regarded as a therapeutic target. In vivo xenografting is commonly used to study cellular interactions not mimicked or quantified in conventional 2D culture systems. To interrogate the effects of tumor stroma (cancer-associated fibroblasts or CAFs) on epithelia, we created a bioengineered microenvironment using human prostatic tissues.

Estrogen receptor β activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations.

Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells.

Brief report: a bioassay to identify primary human prostate cancer repopulating cells.

Cancer cells are heterogeneous in both their phenotypes and ability to promote tumor growth and spread. Xenografting is used to identify the most highly capable cells of regenerating tumors, referred to as cancer repopulating cells. Because prostate cancers (PCa's) rarely grow as xenografts, indentifying PCa repopulating cells has not been possible.

Aromatase and regulating the estrogen:androgen ratio in the prostate gland.

Although androgens and estrogens both play significant roles in the prostate, it is their combined action--and specifically their balance--that is critically important in maintaining prostate health and tissue homeostasis in adulthood. In men, serum testosterone levels drop by about 35% between the ages of 21 and 85 while estradiol levels remain constant or increase. This changing androgen:estrogen (T:E) ratio has been implicated in the development of benign and malignant prostate disease.

Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy.

Prostatitis causes substantial morbidity to men, through associated urinary symptoms, sexual dysfunction, and pelvic pain; however, 90% to 95% of cases have an unknown etiology. Inflammation is associated with the development of carcinoma, and, therefore, it is imperative to identify and study the causes of prostatitis to improve our understanding of this disease and its role in prostate cancer. As estrogens cause prostatic inflammation, here we characterize the murine prostatic phenotype induced by elevated endogenous estrogens due to aromatase overexpression (AROM+).

The dual, opposing roles of estrogen in the prostate.

Both androgens and estrogens play a significant role in the prostate and are critical for normal prostate growth and development. The role of androgens in the prostate and in prostate disease is well known, however, the role for estrogens in the prostate and in prostate disease is complex and is still only just beginning to be appreciated. Our understanding of the role and action of estrogens in the prostate has advanced significantly recently due to important discoveries, including the discovery of a second estrogen receptor subtype (ER-beta), the detection of aromatase in the prostate, and the identification of rapid nongenomic estrogen signaling.

Estrogen-regulated development and differentiation of the prostate.

Both androgens and estrogens play a significant role in the prostate and are critical for normal prostate growth and development, as well as the maintenance of adult prostatic homeostasis throughout life. It is the balance of these two hormones, rather than each individually, that is important for prostatic development and differentiation. Estrogen action is mediated by the estrogen receptors, ERalpha and ERbeta.

Estrogen action on the prostate gland: a critical mix of endocrine and paracrine signaling.

Although modern biotechnology has provided us with a greater understanding of the molecular events in endocrine-related diseases, such as benign prostatic hyperplasia and prostate cancer, these conditions continue to be a significant healthcare problem world-wide. As the number of men afflicted by these diseases will only continue to grow with the aging population, finding new strategies and new therapeutic options for the treatment of both of these diseases is crucial. A better knowledge of the mechanisms of hormone action is pivotal to making progress in the development of new hormone-based therapies.

Treating prostate cancer: a rationale for targeting local oestrogens.

Prostate cancer is the most commonly diagnosed cancer and the second most common cause of cancer-related death in men, and benign prostatic hyperplasia is the most common benign condition known to occur in ageing men. Oestrogen has been implicated in the development of prostate cancer, and offers a promising new avenue for treatment. Despite this, the role of oestrogens in the prostate is complex.

Essential role for estrogen receptor beta in stromal-epithelial regulation of prostatic hyperplasia.

Estrogens, acting via estrogen receptors (ER) alpha and beta, exert direct and indirect actions on prostate growth and differentiation. Previous studies using animal models to determine the role of ERbeta in the prostate have been problematic because the centrally mediated response to estrogen results in reduced androgen levels and prostatic epithelial regression, potentially masking any direct effects via ERbeta. This study overcomes this problem by using the estrogen-deficient aromatase knockout mouse and tissue recombination to provide new insight into estrogen action on prostate growth and pathology.

Local aromatase expression in human prostate is altered in malignancy.

Tissue-specific aromatase production is significant in breast cancer and osteoporosis. Prostatic aromatase expression has been equivocal, and any local actions of estrogens are considered secondary to centrally mediated androgen suppression. We examine local aromatase expression and estrogen biosynthesis in the human prostate.