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

Risk and prognostic factors for endometrial carcinoma after diagnosis of breast or Lynch‐associated cancers—A population‐based analysis

We hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis, after accounting for EC arising after tamoxifen‐treated prior breast carcinoma, are more likely to have an underlying genetic basis. We used information from a population‐based study to compare measured risk factors, tumor characteristics, survival, and known mismatch repair (MMR) pathogenic variant status for EC subgroups according to prior diagnosis of cancer (none, breast cancer tamoxifen‐treated or not, Lynch Syndrome (LS)‐associated cancer). Family history of any cancer was increased for EC cases with prior breast cancer, both tamoxifen treated (P = 0.005) and untreated (P = 0.01). EC cases with prior LS‐associated cancer more often reported family history of LS‐associated cancer (P = 0.04) and breast cancer (P = 0.05). EC patients with a germline pathogenic MMR gene variant were more likely to report a prior cancer than cases with a MMR proficient tumor (P = 0.0001), but more than half (54.5%) of MMR carriers reported no prior cancer. Women developing EC after tamoxifen treatment for breast cancer were significantly more likely to develop EC of malignant mixed mullerian tumor subtype (13.2% vs 2.6%, P = 1.3 × 10^{-6}), present with stage IV disease (8.8% vs 1.2%, P = 1.6 × 10^{-6}), and have poorer survival (HR_{adj} 1.96; P = 0.001). While report of prior cancer is an indicator of MMR pathogenic variant status, molecular analysis of all ECs at diagnosis is warranted to detect all patients with LS. Results also indicate the importance of longer‐term monitoring of women treated with tamoxifen for symptoms of EC, and the need for studies assessing the biological mechanism underlying the poorer prognosis of this subset of EC patients

Interaction of the tetracyclines with double-stranded RNAs of random base sequence: new perspectives on the target and mechanism of action

The 16S rRNA binding mechanism proposed for the antibacterial action of the tetracyclines does not explain their mechanism of action against non-bacterial pathogens. In addition, several contradictory base pairs have been proposed as their binding sites on the 16S rRNA. This study investigated the binding of minocycline and doxycycline to short double-stranded RNAs (dsRNAs) of random base sequences. These tetracyclines caused a dose-dependent decrease in the fluorescence intensities of 6-carboxyfluorescein (FAM)-labelled dsRNA and ethidium bromide (EtBr)-stained dsRNA, indicating that both drugs bind to dsRNA of random base sequence in a manner that is competitive with the binding of EtBr and other nucleic acid ligands often used as stains. This effect was observable in the presence of Mg2+. The binding of the tetracyclines to dsRNA changed features of the fluorescence emission spectra of the drugs and the CD spectra of the RNA, and inhibited RNase III cleavage of the dsRNA. These results indicate that the double-stranded structures of RNAs may have a more important role in their interaction with the tetracyclines than the specific base pairs, which had hitherto been the subject of much investigation. Given the diverse functions of cellular RNAs, the binding of the tetracyclines to their double-stranded helixes may alter the normal processing and functioning of the various biological processes they regulate. This could help to explain the wide range of action of the tetracyclines against various pathogens and disease condition

The ADMR Receptor Mediates the Effects of Adrenomedullin on Pancreatic Cancer Cells and on Cells of the Tumor Microenvironment

Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC).AM receptors ADMR and CRLR were present in HPSC, HUVEC and MLECs while PDAC cells possessed only ADMR receptors as assessed by RT-PCR and western blotting. All cell lines expressed and secreted AM as indicated by ELISA. The growth of each of the cell lines was stimulated by exogenous AM and inhibited by the antagonist AMA. AM also stimulated in vitro angiogenesis assessed by polygon formation of endothelial cell lines. SiRNA-mediated silencing of ADMR, but not CRLR, reduced basal growth of all cells examined and reduced polygon formation of endothelial cells in vitro. Orthotopic tumors developed with shADMR bearing cancer cells had dramatically reduced primary tumor volume (>90%) and lung and liver metastasis compared to shControl bearing cells. To validate ADMR as a potential therapeutic target, in vivo studies were conducted using neutral nanoliposomes to systemically deliver human siRNA to ADMR to silence human cancer cells and mouse siRNA to ADMR to silence mouse tumor stromal cells. Systemic silencing of both human and mouse ADMR had no obvious adverse effects but strongly reduced tumor development.ADMR mediates the stimulatory effects of AM on cancer cells and on endothelial and stellate cells within the tumor microenvironment. These data support the further development of ADMR as a useful target treatment of pancreatic cancer

Comparative Analysis of Dengue and Zika Outbreaks Reveals Differences by Setting and Virus.

The pacific islands of Micronesia have experienced several outbreaks of mosquito-borne diseases over the past decade. In outbreaks on small islands, the susceptible population is usually well defined, and there is no co-circulation of pathogens. Because of this, analysing such outbreaks can be useful for understanding the transmission dynamics of the pathogens involved, and particularly so for yet understudied pathogens such as Zika virus. Here, we compared three outbreaks of dengue and Zika virus in two different island settings in Micronesia, the Yap Main Islands and Fais, using a mathematical model of transmission dynamics and making full use of commonalities in disease and setting between the outbreaks. We found that the estimated reproduction numbers for Zika and dengue were similar when considered in the same setting, but that, conversely, reproduction number for the same disease can vary considerably by setting. On the Yap Main Islands, we estimated a reproduction number of 8.0-16 (95% Credible Interval (CI)) for the dengue outbreak and 4.8-14 (95% CI) for the Zika outbreak, whereas for the dengue outbreak on Fais our estimate was 28-102 (95% CI). We further found that the proportion of cases of Zika reported was smaller (95% CI 1.4%-1.9%) than that of dengue (95% CI: 47%-61%). We confirmed these results in extensive sensitivity analysis. They suggest that models for dengue transmission can be useful for estimating the predicted dynamics of Zika transmission, but care must be taken when extrapolating findings from one setting to another

Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells

BACKGROUND: Deregulation of the Wnt/ β-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in β-catenin stabilization and accumulation, and the aberrant modulation of β-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells. METHODS: Gene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of β-catenin was used to identify target genes of this pathway. RESULTS: The differential expression in response to ΔNβ-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/β-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon ΔNβ-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue. CONCLUSIONS: HIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer

Effect of a farnesyl transferase inhibitor (R115777) on ductal carcinoma in situ of the breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo

INTRODUCTION: The ras pathway is essential for cell growth and proliferation. The effects of R115777, a farnesyl transferase inhibitor, were investigated in cancer cell lines expressing varying levels of growth factor receptors and with differing ras status. Effects on tumour xenografts and human ductal carcinoma in situ (DCIS) of the breast in a xenograft mouse model were also tested. METHOD: In vitro, the concentrations required to reduce cell numbers by 50% (50% inhibitory concentration) were established (MDA-MB231, MCF-7, MCF-7/HER2-18, BT-474, SK-BR3 and SKOV3). Human DCIS was implanted in nude mice or, in separate experiments, cultured cells were injected (MDA-MB231, MCF-7/HER2-18, SKOV3) and allowed to form tumours. Proliferation and apoptosis were determined by immunohistochemistry in xenografts and cell tumours. RESULTS: The 50% inhibitory concentrations varied a hundred-fold, from 39 nmol/l (± 26 nmol/l) for SKBR3 to 5.9 μmol/l(± 0.8 μmol/l) for MDA-MB231. In MCF-7/HER2-18 and SKOV3 cells the levels of tumour growth inhibition were approximately 85% and 40%, respectively. There was a significant decrease in the cell turnover index (CTI; proliferation/apoptosis). In MDA-MB 231 with activated k-ras no inhibition was observed. In treated DCIS xenografts proliferation decreased and apoptosis increased. The CTI ratio between the start and 1 and 2 weeks of treatment were 1.99 and 1.50, respectively, for controls and 0.85 (P = 0.005) and 0.75 (P = 0.08) for treated xenografts. CONCLUSION: Treatment with the farnesyl transferase inhibitor reduced cell growth in vitro and cell tumour growth in vivo. In DCIS treatment resulted in a reduced CTI. R115777 is a promising treatment for breast cancer but the relation between effect and growth factor receptor and ras status has to be established

Ovarian carcinoma associated with pregnancy: A clinicopathologic analysis of 23 cases and review of the literature

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to analyze and describe cases of ovarian cancer in pregnant women treated at our center and to review the literature concerned, and to discuss the rationale for therapy.</p> <p>Methods</p> <p>Twenty-Three patients of ovarian malignancies during pregnancy were treated at Vali- Asr Hospital between 1991 and 2002. Data on treatment and follow-up were evaluated.</p> <p>Results</p> <p>The incidence of ovarian carcinoma associated with pregnancy in our series was 0.083/1000 deliveries. Eleven (47.8%) were found with ovarian malignant germ cell tumors, five (21.7%) with low malignant potential tumors, four (17.4%) with invasive epithelial tumors, and three (13%) with sex cord stromal tumors. Seventeen (73.9%) of the patients were diagnosed in stage I and had complete remission. Five of the six in advanced stage died. The mean follow-up was 36.3 months. The prognosis was significantly related with stage and histological type (<it>P </it>< 0.05). Sixteen healthy live babies were recorded in this group, and two premature newborn died of respiratory distress syndrome. Chemotherapy was administered to 44% of the patients, in two cases during pregnancy. Overall survival at 5 years was 61%. In most of case conservative surgical treatment could be performed with adequate staging and debulking.</p> <p>Conclusion</p> <p>Early finding of ascitis by ultrasound and persistent large ovarian mass during pregnancy may be related to malignancy and advanced stage. Pregnant women in advanced stage of ovarian cancer seem to have poor prognosis.</p