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182
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December 2010 - present
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- Professor
Description
- The Biology of the Prostate in Health and Disease: Present Emphasis is on the Role of Hypoxia in the Progression of Hormone Refractive Metastatic Prostate Cancer and the Development of New Drugs to Restore Normoxia and Reverse the Cancer.
January 2007 - December 2015
Publications
Publications (182)
Prostate cancer accounts for around 15% of male deaths in Western Europe and is the second cause of cancer death in men after lung cancer. Mounting evidence suggests that prostate cancer deposits exist within a hypoxic environment and this contributes to radio-resistance thus hampering one of the major therapies for this cancer. Recent reports have...
The objective is to establish the feasibility of using dynamic instrumented palpation, a novel technique of low-frequency mechanical testing, applied here to diagnose soft tissue condition. The technique is applied, in vitro, to samples of excised prostate gland affected by benign prostate hyperplasia and/or prostate cancer. Particular attention is...
This paper presents a novel way of assessing the quality of biological tissue for diagnostic purposes, dynamic instrumented palpation. The method involves applying a controlled modulated strain or displacement to the tissue and measuring the resulting force as a function of time. The method is distinct from dynamic elastography in that the force an...
A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate...
Background:
Both genetics and the environment are implicated as risk factors for prostate cancer (PCa). This population-based case-control study evaluated four single-nucleotide polymorphisms (SNPs) previously identified by genome-wide association studies to be associated with increased PCa susceptibility. Potential relationships between serum con...
The potential application of multiplexed quantum dot labeling (MQDL) for cancer detection and prognosis and monitoring therapeutic responses has attracted the interests of bioengineers, pathologists and cancer biologists. Many published studies claim that MQDL is effective for cancer biomarker detection and useful in cancer diagnosis and prognosis,...
Estrogens and androgens have both been implicated as causes of benign prostatic hyperplasia (BPH). Although epidemiological data on an association between serum androgen concentrations and BPH are inconsistent, it is generally accepted that androgens play a permissive role in BPH pathogenesis. In clinical practice, inhibitors of 5α-reductase (which...
Prostate cancer cells can exist in a hypoxic microenvironment, causing radioresistance. Nitric oxide (NO) is a radiosensitiser of mammalian cells. NO-NSAIDs are a potential means of delivering NO to prostate cancer cells. This study aimed to determine the effect and mechanism of action of NO-sulindac and radiation, on prostate cancer cells and stro...
ContextMedical therapies derived from natural sources have been used for centuries. Many are as effective as synthetic medications. The use of plant-derived medications for benign prostatic hyperplasia (BPH) is no exception. In particular, extracts of Serenoa repens (SrE), the fruit of the American dwarf palm, are widely available, and their use is...
Research into the hypoxic tumour microenvironment is accelerating and the reversal of hypoxia is increasingly being suggested as a mechanism for improving cancer treatment. Recent studies have suggested that hypoxia is also a feature in prostate cancer and is associated with a poor prognosis. Hypoxia has been shown to cause radio-resistance and hen...
Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher f...
Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism o...
Prostate cancer cells exist under hypoxic conditions. Hypoxia has a detrimental effect on the efficacy of treatment and final outcome in patients with prostate cancer. There have been a large number of endogenous markers of hypoxia described previously across a range of cancer types, both in vitro and in vivo. The aim of this study was to evaluate...
Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), g...
Oestrogens have been implicated as a cause of benign prostatic hyperplasia (BPH). Previous animal studies led to the hypothesis that oestrogens can stimulate prostate growth, resulting in hyperplasia of the gland. In humans, the precise role of oestrogens in BPH pathogenesis is currently unclear. We investigated the direct effects of oestradiol on...
This paper concerns the operation of the actuator for a prototype micro-engineered mechanical palpation device for deployment via a cystoscope to measure the dynamic mechanical properties of the prostate gland in vivo. The subassembly consists of a 400x200 microm silicon (Si) piston manufactured using deep reactive ion etching (DRIE) housed within...
This study examines the expression of the insulin-like growth factor type 1 receptor (IGF-1R) in colorectal neoplasia. Previous studies have shown that the IGF-1R is expressed at high levels in normal embryonic stem cells and in many cancer phenotypes. However, lower IGF-1R levels are expressed in some advanced cancer phenotypes. The timing of and...
Dermcidin (DCD) is a candidate survival gene in breast cancer. DCD gene expression has been identified in prostate cancer cell lines and primary prostate cancer tissue. The DCD protein is composed of proteolysis-inducing factor-core peptide (PIF-CP) and the skin antimicrobial DCD-1. The aim of this work was to: (i) establish if the DCD gene confers...
Aberrant expression of vascular endothelial growth factor (VEGF) is associated with human prostate cancer (PCa) metastasis and poor clinical outcome. We found that both phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and VEGF levels were significantly elevated in patient bone metastatic PCa specimens. A PCa ARCaP progression...
Anti-epidermal growth factor receptor strategies are now established in cancer treatment We have recently described the presence of EGFRvIII (a variant EGFR) in prostatic tumours from UK white men and this is now a target for anti-prostate cancer treatments. However, there has been no report on the expression of this abnormal protein in black men....
In vitro macro- and micro-indentation test systems have been designed to measure the dynamic micro-mechanical properties of human prostate tissues at actuation frequencies between 5 Hz and 30 Hz, and 0.5 Hz and 20 Hz, respectively. The development of in vitro test systems was aimed at assessing the capacity of such an in vivo medical probe to provi...
To investigate the relationship between the morphology and mechanical properties of benign and malignant prostatic tissues measured in vitro.
Fresh tissue specimens were collected from patients undergoing transurethral resection of the prostate (TURP) for benign or malignant prostatic enlargement. Individual TURP chippings underwent immediate mecha...
To investigate the relationship between the morphology and the mechanical properties of benign prostatic tissues measured in vitro.
Fresh tissue specimens were collected from 17 patients undergoing transurethral resection of the prostate for benign prostatic obstruction. Individual tissue specimens underwent immediate mechanical testing, by applyin...
Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed...
The phytotherapeutic agent Serenoa repens is an effective dual inhibitor of 5alpha-reductase isoenzyme activity in the prostate. Unlike other 5alpha-reductase inhibitors, Serenoa repens induces its effects without interfering with the cellular capacity to secrete PSA. Here, we focussed on the possible pathways that might differentiate the action of...
To develop a method for obtaining morphometric measurements representative of individual chips from transurethral resection of the prostate (TURP).
In all, 232 sections were cut in pairs from 25 TURP chips, collected from four patients undergoing TURP for benign prostatic hyperplasia. Individual tissue chips were processed, embedded in paraffin wax...
Prostatic carcinogenesis has been associated with alterations in the expression of the androgen receptor (AR) and the epidermal growth factor receptor (WT-EGFR), and over-expression of the constitutively active variant epidermal growth factor receptor (EGFRvIII). Changes in the expression of AR, WT-EGFR and EGFRvIII were evaluated in serial section...
New nitric oxide (NO) donating nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized to counteract the side effects of conventional NSAIDs. Mounting evidence suggests that NSAIDs may have a possible chemopreventative/therapeutic role in prostate cancer. NO is a powerful biological messenger with multiple cellular effects. We establish...
Purpose: New nitric oxide (NO) donating nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized to counteract the side effects of conventional NSAIDs. Mounting evidence suggests that NSAIDs may have a possible chemopreventative/therapeutic role in prostate cancer. NO is a powerful biological messenger with multiple cellular effects. We...
In human prostate, dehydroepiandrosterone (DHEA) is a substrate for two major metabolic pathways that produce functionally opposing sex steroids. In one pathway, DHEA is converted into potent androgens such as testosterone and 5alpha-dihydrotestosterone. In the other, DHEA is metabolized to 7alpha-hydroxy-DHEA (7HD). Recently, CYP7B, a novel P450 e...
CaP has a higher incidence and mortality in Black men. We hypothesized that subpopulation differences in AR expression may contribute to this phenomenon.
AR immunostaining was compared in epithelium and PES of normal, BPH, and CaP tissues from Black African men and UK Caucasian men.
AR expression was similar in normal prostatic epithelium of both g...
Recommendations regarding the use of plant-derived medications for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) state that every brand should be fully evaluated and considered separately. Disparity between a number of brands in terms of their stated and actual doses has been recently highli...
The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, unscheduled breakthrough bleeding (BTB), leads to discontinuation in a proportion of users. The LNG-IUS down-regulates endometrial progesterone and estrogen receptors and this may play a role in the mechanism responsible for BTB. LNG is an andro...
Considerable evidence has accumulated demonstrating that the 5alpha-reduction of testosterone to dihydrotestosterone occurs more efficiently in the normal and benign hyperplastic prostate than in prostate cancer tissues. Efforts have also been channeled into investigating the distribution of 5alpha-reductase isoenzymes in primary prostate tissues a...
To detect the expression and transcription pattern of MUC1 in benign and malignant disease, and in two widely studied cell lines, and to investigate the glycosylation of MUC-1 in bone metastasis of prostate cancer, as mucins have been implicated in the progression and behaviour of several cancers.
RNA extracted from cell lines (DU145 and PC3), five...
Although there is considerable data concerning the metabolism of androgens and to a lesser extent oestrogens, in benign and malignant disease in the prostate, surprisingly little data has been presented on the potential interaction between biosynthetic pathways of these active steroid hormones. The presence of oestrogen biosynthesis in benign prost...
A major impediment to our understanding of the biology of stem cells is the inability to distinguish them from their differentiating progeny. We made use of the known association of stem cells with basement membranes to isolate prostate epithelial stem cells. We show that, in vivo, putative stem cells express higher levels of the alpha(2)-integrin...
Storage of unstained paraffin slides may lead to the deterioration of specimens and failure to detect cellular proteins immunohistochemically. Although the implication of age-induced alterations on multicenter immunohistochemical studies would be considerable, they have not been investigated previously. The current study was undertaken to examine t...
Storage of unstained paraffin slides may lead to the deterioration of specimens and failure to detect cellular proteins immunohistochemically. Although the implication of age-induced alterations on multicenter immunohistochemical studies would be considerable, they have not been investigated previously. The current study was undertaken to examine t...
Dehydroepiandrosterone (DHEA) is the most prominent circulating steroid in humans, and it is a precursor for sex-steroid synthesis in peripheral tissues, including the prostate. Recently, enzyme-mediated pre-receptor metabolism has been recognized as a key step in determining steroid action in vivo. Hydroxylation of 3beta-steroids at the 7alpha-pos...
Dehydroepiandrosterone (DHEA) is the most prominent circulating steroid in humans, and it is a precursor for sex-steroid synthesis in peripheral tissues, including the prostate. Recently, enzyme-mediated pre-receptor metabolism has been recognized as a key step in determining steroid action in vivo. Hydroxylation of 3β-steroids at the 7α-position h...
To investigate the effects of the phytotherapeutic agent, Permixon(R), on primary cultures of fibroblast and epithelial cells from the prostate, epididymis, testes, kidney, skin and breast and to determine the selectivity and specificity of the action of the drug.
All primary cultures were examined by electron microscopy before and following treatm...
The search for novel agents for the treatment of the lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is dependent on an increased understanding of the pathophysiology of the disease. Unfortunately, in vitro and animal models have been of limited value.
This article describes a novel model system in which the i...
Earlier studies have demonstrated an unexplained depletion of the epidermal growth factor receptor (EGFR) protein expression in prostatic cancer. We now attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is highly expressed in malignant prostatic neoplasms. In a retrospective study, normal, benign hyperplastic and malignant...
The aim of this study was to determine the effect of the phytotherapeutic agent, Permixon, on a novel coculture model of benign prostatic hyperplasia (BPH) in an effort to better understand the mode of action of the drug in vivo.
The effect of Permixon, at the calculated therapeutic concentration, on the activity of 5alpha-reductase isoenzymes was...
The functional activity of the 5α-reductase isoenzyme in the human prostate is gradually depleted as the gland undergoes transformation from the normal to the metastatic state. There are two isoforms of this enzyme expressed in the prostate and recent studies have demonstrated that the type II isoenzyme is the one most affected by the onset of neop...
The cellular pathways involved in the pathogenesis of hormone resistance remain unclear. Studies evaluating the role of changes in human androgen receptor (hAR) expression in the progression of prostatic tumors have been inconclusive. Androgenic influence over prostatic growth is mediated via the regulation of interactions between stromal and epith...
AIMS: To investigate the effects of slide storage on immunohistochemical staining, since recent reports have indicated that storage of unstained paraffin slides for up to 12 weeks may lead to false negative immunostaining of tumour markers. METHODS: 11 antibodies (anti-cytokeratin, epithelial membrane antigen (EMA), vimentin, smooth muscle actin, P...
To compare the efficacy of two tests, prostate-specific antigen (PSA) and skeletal alkaline phosphatase (SAP) as staging markers to discriminate patients with cancer of the prostate (CaP) with bony metastases (M1) from those without bony metastases (Mo).
Forty-seven untreated patients with Mo (n = 26) and M1 (n = 21) CaP were entered in this study....
Paracrine interactions between primary cultured prostate epithelial cells and stromal fibroblasts were investigated in relation to morphology, growth, androgen sensitivity and secretory activities using co-cultures in which the two populations were separated by a microporous membrane. In this new model system, both cell types maintained several asp...
Stromal cells derived from benign prostatic hyperplasia synthesize and secrete measurable levels of insulin-like growth factor (IGF). Seventy-two-hour conditioned medium obtained from these cells contains IGF-II at levels ranging from 125-177 ng/mL.10(6) cells. IGF-I is almost undetectable. RT-PCR analysis has demonstrated that the genes for both t...
The expression and localisation of mRNAs for 5 alpha reductase Type I (5 alpha R-I) and Type II (5 alpha R-II) isoenzymes in human benign prostatic hyperplasia (BPH) were investigated by RT-PCR and by in mini hybridisation (ISH) using digoxigenin labelled riboprobes. In addition, we also examined the isoenzymes mRNA expression in primary BPH cultur...
Beta-nerve growth factor (beta-NGF) acts on high- and low-affinity receptors to effect sympathetic innervation. It is produced in the human prostate. This study aimed to demonstrate the presence of beta-NGF receptors and the distribution of p75LNGFR receptor protein in the human prostate. Radioligand binding assays were performed using microsomal p...
We have developed a coculture system for primary fibroblast and epithelial cells derived from benign prostatic hyperplasia (BPH) that retained many of the characteristics of the intact human prostate. In contrast to separately cultured prostate fibroblast and epithelial cells, cocultures of fibroblasts and epithelial cells maintained messenger ribo...
Introduction: Prostatic epithelial cells in culture require the epidermal growth factor (EGF) for proliferation. Androgens have been shown to stimulate the proliferation of these cells in vitro by increasing the number and the binding capacity of epidermal growth factor receptors (WT-EGFRs). However, in vivo all prostate cancers (CaPs) eventually b...
Introduction: Prostate cancer (CaP) is more common and more aggressive in black men and racial differences in the expression of molecular factors of the disease have been suggested as a possible explanation for this observation. We have recently described the presence of possible mechanisms for hormone resistance in CaP specimens from (UK) white me...
The retinoblastoma (RB) gene has been reported to be deleted in a number of human cancers including urologic tumors. In the present study, we used polymerase chain reaction (PCR) employing total RNA extracted from snap-frozen tumor specimens of ten benign prostatic hyperplasia and nine cancer specimens to test for the presence of a short sized mRNA...
The value of Prostate-Specific Antigen (PSA) for the early detection of Prostate Cancer (CaP) is controversial due to an appreciable false positive rate causing unnecessary biopsies. As PSA exits in both free and bound forms the percentage of free PSA was found to be lower in CaP than in Benign Prostatic Hyperplasia (BPH). We investigated whether t...
Over many years, a great deal of attention has focused on the growth regulatory effects of androgens in prostate cells. This, has also prompted widespread interest in the role of these steroid hormones in prostate cancer pathogenesis. Even so, no-one has so far been able to identify the exact relationship between androgenic hormone levels and the r...
We investigated whether the free-to-total prostate-specific antigen (PSA) ration (f-PSA/t-PSA ratio; i.e. percentage of free PSA) represents a better discriminator for the detection of cancer of the prostate (CaP). In a retrospective analysis, the percentage of free PSA was determined in the sera of 35 patients with histologically proven benign pro...
The 5 alpha-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5 alpha-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concent...
RT-PCR analysis of total RNA prepared from the prostate cancer cell lines DU145 and PC3 and from primary epithelial cells indicated the presence of endothelin-1 (ET-1) messenger RNA (mRNA). Neither the LNCaP cell line nor primary prostatic stromal cells possess ET-1 mRNA transcripts. Seventy-two-hour-conditioned media derived from DU145, PC3, and p...
We investigated whether the free-to-total prostate-specific antigen (PSA) ratio (f-PSA/t-PSA ratio; i. e. percentage of free PSA) represents a better discriminator for the detection of cancer of the prostate (CaP). In a retrospective analysis, the persentage of free PSA was determined in the sera of 35 patients with histologically proven benign pro...
beta-NGF is a determinant of sympathetic innervation and a neural differentiation factor. In the present study, we have examined 15 benign prostatic hyperplastic and 15 prostate cancer patients for the expression and localisation of beta-NGF by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, immunohistochemistry and ELIS...
Epithelial cells cultured from prostatic acini do not demonstrate significant (P > 0.05) growth response to the testosterone metabolite dihydrotestosterone (DHT) at concentrations of 0.001-10.0 nM. In addition, the nonsteroidal antiandrogen hydroxyflutamide (HO-F) does not influence primary epithelial cell proliferation in this concentration range....
Objective To determine whether the proportion of total serum prostate-specific antigen (tPSA) which is unbound or free (free PSA) offers a better discriminant for the detection of patients with prostate cancer (CaP) and those with benign prostatic hyperplasia (BPH) than does serum tPSA alone.
Patients and methods In a retrospective analysis, the pr...
We studied the metabolism of testosterone in primary cultures of prostate epithelial cells and fibroblasts obtained from patients with benign prostatic hyperplasia (BPH). The conversion of 3H-testosterone in both cell cultures was predominantly to the oxidative pathway, with the formation of 3H-androstenedione increasing with cell number and time o...
To compare the efficacy of two tests, prostate-specific antigen (PSA) and skeletal alkaline phosphatase (SAP) as staging markers to discriminate patients with cancer of the prostate (CaP) with bone metastases (M+) from those without bone metastases (M0).
Thirty-nine untreated patients with CaP M0 (n = 22) and CaP M+ (n = 17) along with 10 patients...
Secondary deposits of prostate tumours are frequently found in the skeleton where they produce osteoblastic lesions. In this study both osteoblast-like cells and bone marrow from the proximal femur have been cultured to determine whether or not they can release factors which could support the growth of secondary prostate tumours. Media conditioned...
