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Biomedical subjects

R Bicknell

Publications and source records attributed to R Bicknell.

At least 19 recordsLinked to original sources
PubMed2006

Adrenomedullin and tumour angiogenesis.

The angiogenic activity of peptide adrenomedullin (AM) was first shown in 1998 . Since then, a number of reports have confirmed the ability of AM to induce the growth and migration of isolated vascular endothelial and smooth muscle cells in vitro and to promote angiogenesis in xenografted tumours in vivo. In addition, knockout murine models point to an essential role for AM in embryonic vasculogenesis and ischaemic revascularisation. AM expression is upregulated by hypoxia (a typical feature of solid tumours) and a potential role as a regulator of carcinogenesis and tumour progression has been proposed based on studies in vitro and in animal models. Nevertheless, translational research on AM, and in particular, confirmation of its importance in the vascularisation of human tumours has lagged behind. In this commentary, we review current progress and potential directions for future research into the role of AM in tumour angiogenesis.

Adrenomedullin↗
PubMed2005

Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma.

Elevated thymidine phosphorylase has been shown to correlate with increased angiogenesis and poor prognosis in many cancers including transitional cell carcinoma of the bladder. In vitro studies have demonstrated that thymidine phosphorylase activity causes cellular oxidative stress and increases secretion of vascular endothelial growth factor. In this study, we show that thymidine phosphorylase activity also augments levels of the hypoxia-inducible factor-1alpha during in vitro hypoxia, and that thymidine phosphorylase activity and hypoxia act in concert to increase vascular endothelial growth factor (VEGF) secretion. We also demonstrate that thymidine phosphorylase overexpression confers tumorigenicity on an orthotopically implanted transitional cell carcinoma cell line. Administration of the antioxidant N-acetylcysteine together with a blocking anti-VEGF antibody abrogates the increase in tumorigenicity. Our results support the increased efficacy of combination approaches to antiangiogenic therapy.

Animals↗
PubMed2005

The realisation of targeted antitumour therapy.

Better understanding of the pathways regulating proliferation and metastasis of cancer cells has led to the development of novel molecular-targeted therapies. The number of molecular-targeted agents approved for use in the clinic is growing, with many more in clinical trials. Most of these compounds can be broadly classified into two main categories: monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The pathological processes targeted include vascular endothelial growth factor-dependent tumour angiogenesis and epidermal growth factor receptor-dependent tumour cell proliferation and survival. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. Recent progress in targeted antitumour therapy is discussed, with a focus on antiangiogenesis.

Antibodies, Monoclonal↗
PubMed2003

Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer.

Adrenomedullin (ADM) is an angiogenic factor that has also been shown to be a mitogen and a hypoxia survival factor for tumour cells. These properties point to ADM as a potential promoter of human malignancies, but little data are available concerning the expression of ADM in human breast cancer. In the present work, we have examined ADM peptide expression in a series of malignant breast tumours by immunohistochemistry using a newly developed anti-ADM monoclonal antibody. In addition, ADM plasma concentrations in breast cancer patients and healthy controls were determined by radioimmunoassay. Of the examined breast cancer samples, 27/33 (82%) showed a moderate to strong staining intensity. ADM-peptide expression in breast tumours was significantly correlated with axillary lymph node metastasis (P=0.030). Analysis of ADM plasma concentrations showed no significant difference between the circulating ADM levels of breast cancer patients and healthy controls. However, a significant positive correlation was found between tumour size and plasma ADM levels (r=0.641, P=0.017). Moreover, ADM levels in breast cancer patients correlated with the presence of lymph node metastasis (P=0.002). In conclusion, we have shown for the first time that ADM peptide is widely expressed in breast cancer and that the degree of expression is associated with lymph node metastasis. ADM peptide in plasma of breast cancer patients reflects the size of the primary tumour, but is unlikely to be a useful tumour marker for the detection of breast cancer. Plasma ADM might represent an independent predictor of lymph node metastasis. The clinical implications of these findings remain to be evaluated.

Adrenomedullin↗
PubMed2003

New molecular pathways in angiogenesis.

Angiogenesis has developed into a major area of cancer research. Recently, several newly identified signalling pathways have been shown to play a role in both normal and pathological (including tumour) angiogenesis. Several of the molecules involved in these pathways have potential as novel anti-cancer therapeutic targets including members of the ephrin/Eph receptor, Notch/delta, sprouty, hedgehog and roundabout/slit families. These developments are reviewed.

Ephrins↗
PubMed2002

Wnt-7a is upregulated by norethisterone in human endometrial epithelial cells: a possible mechanism by which progestogens reduce the risk of estrogen-induced endometrial neoplasia.

Progestogens are added to oestrogen in hormone replacement therapy regimens to reduce the risk of endometrial cancer. We have performed in vitro studies analysing gene expression of isolated normal endometrial epithelia cells (NEE) treated with estradiol and the progestogen norethisterone acetate (NETA). We report here for the first time upregulation of the Wnt-7a gene by NETA in estrogen treated NEE. Wnt genes are a large family of developmental genes associated with cellular responses such as oncogenesis. We therefore suggest that upregulation of Wnt-7a may be associated with the antineoplastic effects of progestogens on the endometrium.

Cells, Cultured↗
PubMed2002

Tamoxifen induction of angiogenic factor expression in endometrium.

Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre- and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre- but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

Adrenomedullin↗
PubMed2002

Protease activated receptor-1 is down regulated by levonorgestrel in endometrial stromal cells.

Progestogens are used clinically for contraception, to control excessive menstrual bleeding and to oppose oestrogen in hormone replacement therapy. The use of intrauterine levonorgestrel (LNG) is however, associated with endometrial atrophy and decidualisation of the stroma. In this study, we aimed to identify genes whose expression is modulated by LNG either alone or in combination with progesterone. Thus endometrial stromal cells were stimulated with progesterone, LNG or LNG and progesterone. Poly-A RNA was isolated and used to probe expression arrays. The expression of a number of genes was altered on exposure to LNG or LNG and progesterone. Alteration of expression patterns was confirmed using semi-quantitative RT-PCR and western blot analysis. In particular, the protease activated receptor-1 (PAR-1) gene that encodes a receptor for thrombin was down regulated. This is the first demonstration that PAR-1 is down regulated by the progestogen LNG in human endometrium. Alteration in the expression levels of this receptor may affect both growth and haemostatic activity within the endometrium and may account for the observed morphological effects seen in users of intrauterine LNG delivery devices.

Down-Regulation↗
PubMed2002

In-vivo angiogenesis and progestogens.

BACKGROUND: Progestogens are used clinically for contraception, to control excessive menstrual bleeding, and to prevent estrogen-induced endometrial hyperplasia. A significant problem with progestogen-only methods of contraception is the induction of breakthrough bleeding. METHODS: The effects of different progestogens on angiogenesis were examined using two approaches. The mouse sponge angiogenesis assay employed direct delivery of the dose ranges achieved therapeutically. The angiogenic response to long-term intrauterine levonorgestrel exposure, compared with unexposed premenopausal endometrium, was also studied. RESULTS: In the mouse sponge assay, norethisterone and medroxyprogesterone acetate stimulated angiogenesis at all doses, but was dose-dependent for levonorgestrel and nomegestrol. Levonorgestrel stimulated angiogenesis in the dose range 100 pmol/l to 10 nmol/l, but not at higher doses. In contrast, nomegestrol acetate stimulated angiogenesis at high, but not low, doses. Expression of acidic and basic fibroblast growth factors, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin were unaltered in levonorgestrel-exposed endometrium compared with premenopausal controls. Vascular density was increased but endothelial proliferation reduced in levonorgestrel-exposed endometrium. CONCLUSIONS: This is the first report of the direct effects of a wide range of doses of different progestogens on angiogenesis; results suggest that vascular targeting may be an effective strategy to deal with progestogen-induced abnormal bleeding.

Administration, Intravaginal↗
PubMed2001

Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer.

Reactive oxygen species (ROS) damage DNA, but the role of ROS in breast carcinoma may not be limited to the mutagenic activity that drives carcinoma initiation and progression. Carcinoma cells in vitro and in vivo are frequently under persistent oxidative stress. In the present review, we outline potential causes of oxygen radical generation within carcinoma cells and explore the possible impact of oxidative stress on the clinical outcome of breast carcinoma.

Breast↗
PubMed2001

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth.

Regions of hypoxia are a common feature of solid tumours. When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is initiated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated gene. ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with specificity being conferred by the receptor associated modifying protein 2 (RAMP2). Here we report for the first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis. These cells also show an upregulation of the oncoprotein Bcl-2, which is protective against hypoxic cell death when transiently transfected into Ishikawa cells. Since Ishikawa cells express the putative ADM-receptor CRLR-RAMP2 the production and secretion of ADM with the consecutive upregulation of Bcl-2 could establish an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death. These results, taken together with our previous findings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies.

Adrenomedullin↗
PubMed2001

Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis.

Delta-Notch signalling regulates cell-fate choices in a variety of tissues during development. We report the expression of Delta4 (D14) in arterial endothelium during mouse embryogenesis and in the endothelium of tumor blood vessels. The expression of D14 in the mouse begins at 8 dpc in the dorsal aortae, umbilical artery and the heart. Subsequent expression is restricted to smaller vessels and capillaries and is reduced in most adult tissues. However, it is high in the vasculature of xenograft human tumors in the mouse, in endogenous human tumors and is regulated by hypoxia. These data implicate D14 and the Notch signalling pathway in angiogenesis and suggest possible new targets for antiangiogenic tumor therapy.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Human bladder cancer invasion model using rat bladder in vitro and its use to test mechanisms and therapeutic inhibitors of invasion.

As well as being a passive support, the extracellular matrix also regulates key biological processes such as invasion, differentiation and angiogenesis. We have therefore developed an in vitro model of bladder cancer invasion using de-epithelialized rat bladder to allow for tumour cell-extracellular matrix interactions. Onto this we have seeded a panel of human bladder cancer cell lines (RT4, RT112, 253J and EJ28 (T24)) representing progression from well to poorly differentiated phenotypes and used as models of superficial to invasive bladder cancer. The better differentiated cell lines RT4 and RT112 reproducibly grew as stratified epithelium, whereas poorly differentiated EJ28 cells invaded across a broad front. Invasion was not simply related to proliferation rate, measured either as doubling time on plastic (non-invasive 253J and invasive EJ28 having the same doubling time) or by Ki-67 proliferation index within the model. We used the model to test the ability of 4 compounds that interfere with tumour cell-extracellular matrix interactions (suramin, N-acetylcysteine and the urokinase plasminogen activator pathway antagonists A5 compound and monoclonal antibody Mab 3936) to inhibit invasion. At non-toxic concentrations, all significantly inhibited invasion (P< 0.05), although to varying degrees, suramin and A5 almost completely and N-acetylcysteine the least. In conclusion, this model shows the urokinase system is important for bladder invasion and can be used to investigate other mechanisms of bladder cancer invasion and also for the testing of intravesical drugs.

Acetylcysteine↗
PubMed2001

Vascular endothelial growth factor transgenic mice exhibit reduced male fertility and placental rejection.

Recent evidence points to the involvement of vascular endothelial growth factor (VEGF) in mammalian reproductive physiology. Transgenic mice expressing VEGF (121 isoform) under the control of the polyepithelial mucin-1 (muc-1) promoter showed a reduction in male fertility due to impaired spermiogenesis, and aberrant placentation leading to preferential rejection of male embryos. A skew in the sex ratio of the litters was seen (three females to two males), independently of whether the transgene was carried by the male or female parent. In-situ hybridization permitted distinction of expression of the human VEGF transgene from endogenous mouse VEGF, and confirmed expression of the transgene in a wide range of epithelial tissues. Expression of the transgene in spermatocytes and in the embryonic portion of placenta is thought to be responsible for the reduced fertility and embryonic resorptions respectively. Males showed either complete sperm maturation arrest or various gradations of partial fertility. Abnormally high or low VEGF in human semen has been reported to be correlated with a lack of pregnancy success following IVF. The muc1-VEGF (121 isoform) transgenic mouse provides an animal model with which to further study this VEGF-induced pathology.

Animals↗
PubMed2001

Differential and cell-specific expression of calcitonin receptor-like receptor and receptor activity modifying proteins in the human uterus.

The calcitonin receptor-like receptor (CRLR) can function as a receptor for either calcitonin gene-related peptide (CGRP) or adrenomedullin (AM), depending upon co-expression with members of a novel family of receptor activity-modifying proteins (RAMP). RAMP1 presents the CRLR at the cell surface as a CGRP/AM receptor. RAMP2- and RAMP3-transported CRLR receptors act as AM-specific receptors. However, it is still unknown if this signalling system operates in vivo. Of particular interest is the uterus, where both peptides and their binding sites are known to be present and where both mitogenic and vasodilatory responses to AM and CGRP have been demonstrated. In this study, we examined whether CRLR and RAMP are co-expressed in the same populations of cells in human uterine tissue. Analysis by in-situ hybridization and immunocytochemistry revealed a heterogeneous and cell type-specific distribution of components of this AM/CGRP signalling system. Adrenomedullin mRNA was expressed and evenly distributed across all cell types. CRLR mRNA was predominantly found in blood vessels. RAMP1 expression was specific to myometrial myocytes and vascular smooth muscle cells in uterine arteries. RAMP2 and RAMP3 mRNA were not detectable by in-situ hybridization. The pattern of differential and cell-specific expression of CRLR and RAMP suggests the involvement of CRLR/RAMP1 in the processes of vasodilation, smooth muscle relaxation and angiogenesis in response to AM and CGRP in the human uterus, but also indicates that other receptors may be implicated.

Adrenomedullin↗