Papel de CXCR4 en la diseminación hematógena y intraperitoneal en el cáncer de ovario

El término cáncer de ovario se utiliza para definir todas aquellas neoplasias malignas que crecen en el ovario. Debido a esta definición meramente por su localización, este tipo de cáncer engloba a diferentes tipos de tumores, con características fisiopatológicas y moleculares muy dispares. El 90% de los tumores de ovario tienen un origen epitelial (EOC) y se clasifican siguiendo criterios histológicos y genéticos en cinco grandes grupos: serosos de alto grado (80% de los diagnósticos y de características más agresivas, responsables del 80% de las muertes debidas al cáncer de ovario), serosos de bajo grado (<5%), endometroides (15%), mucinosos (<5%) y tumores de célula clara (<5%)(Bast, 2009; Bowtell 2010)

Banker plants and landscape composition influence colonisation precocity of tomato greenhouses by mirid predators

Conservation biological control involves manipulation of the environment to enhance the effectiveness of natural enemies in controlling crop pests. In this study, we combined historical data, sticky trap sampling of tomato greenhouses and beat sampling of adjacent vegetation to identify which greenhouse characteristics, habitat management practices and landscape features favour an early colonisation of tomato greenhouses by the key mirid predator Macrolophus pygmaeus and its establishment in NE Spain. Results show that landscape composition and the use of Calendula officinalis banker plants inside the greenhouse are key factors. In general, greater amounts of herbaceous semi-natural cover at the landscape scale promoted M. pygmaeus colonisation, while the use of C. officinalis banker plants encouraged M. pygmaeus colonisation independently of the landscape context. We identified host plants adjacent to tomato greenhouses that sustain M. pygmaeus populations; however, they did not have a major effect on M. pygmaeus colonisation compared to larger landscape and banker plant effects. Early colonisation of greenhouses by this predator species also translated into lower accumulated incidence of pests at the end of the sampling period. This study demonstrates the importance of active habitat management practices in promoting the early arrival of M. pygmaeus in greenhouses with delayed spontaneous colonisation.info:eu-repo/semantics/acceptedVersio

PI3K (Phosphatidylinositol 3-Kinase) activation and endothelial cell proliferation in patients with hemorrhagic hereditary telangiectasia type 1

Hemorrhagic hereditary telangiectasia (HHT) type 2 patients have increased activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in telangiectasia. The main objective is to evaluate the activation of the PI3K pathway in cutaneous telangiectasia of HHT1 patients. A cutaneous biopsy of a digital hand telangiectasia was performed in seven HHT1 and eight HHT2 patients and compared with six controls. The study was approved by the Clinical Research Ethics Committee of our center. A histopathological pattern with more dilated and superficial vessels that pushed up the epidermis was identified in HHT patients regardless of the type of mutation and was associated with older age, as opposed to the common telangiectasia pattern. The mean proliferation index (Ki-67) was statistically higher in endothelial cells (EC) from HHT1 than in controls. The percentage of positive EC for pNDRG1, pAKT, and pS6 in HHT1 patients versus controls resulted in higher values, statistically significant for pNDRG1 and pS6. In conclusion, we detected an increase in EC proliferation linked to overactivation of the PI3K pathway in cutaneous telangiectasia biopsies from HHT1 patients. Our results suggest that PI3K inhibitors could be used as novel therapeutic agents for HHT

The impact of KRAS mutations on VEGF-A production and tumour vascular network

Background: The malignant potential of tumour cells may be influenced by the molecular nature of KRAS mutations being codon 13 mutations less aggressive than codon 12 ones. Their metabolic profile is also different, with an increased anaerobic glycolytic metabolism in cells harbouring codon 12 KRAS mutations compared with cells containing codon 13 mutations. We hypothesized that this distinct metabolic behaviour could be associated with different HIF-1α expression and a distinct angiogenic profile. Methods: Codon13 KRAS mutation (ASP13) or codon12 KRAS mutation (CYS12) NIH3T3 transfectants were analyzed in vitro and in vivo. Expression of HIF-1α, and VEGF-A was studied at RNA and protein levels. Regulation of VEGF-A promoter activity was assessed by means of luciferase assays using different plasmid constructs. Vascular network was assessed in tumors growing after subcutaneous inoculation. Non parametric statistics were used for analysis of results. Results: Our results show that in normoxic conditions ASP13 transfectants exhibited less HIF-1α protein levels and activity than CYS12. In contrast, codon 13 transfectants exhibited higher VEGF-A mRNA and protein levels and enhanced VEGF-A promoter activity. These differences were due to a differential activation of Sp1/AP2 transcription elements of the VEGF-A promoter associated with increased ERKs signalling in ASP13 transfectants. Subcutaneous CYS12 tumours expressed less VEGF-A and showed a higher microvessel density (MVD) than ASP13 tumours. In contrast, prominent vessels were only observed in the latter. Conclusion: Subtle changes in the molecular nature of KRAS oncogene activating mutations occurring in tumour cells have a major impact on the vascular strategy devised providing with new insights on the role of KRAS mutations on angiogenesis

Dibenzylxanthines as PPEPCK-M inhibitors for cancer therapy

Phosphoenolpyruvate carboxykinase (PEPCK) is the key enzyme in gluconeogenesis/glyceroneogenesis, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. In eukaryotes, there are two isozymes present either in the cytosol (PEPCKC, PCK1) or the mitochondria (PEPCK-M, PCK2). While PCK1 is found in gluconeogenic tissues and has a very clear metabolic function, PCK2 is expressed in non-gluconeogenic cell types, where its role remains largely unknown. For example, PCK2 is highly expressed in most cancer cells, where it provides a growth advantage to cancer cells in nutrient-poor environments

The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels

In a search for new therapeutic targets for treating epithelial ovarian cancer, we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition

Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2

The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53‐response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53‐MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets

Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model

Gemcitabine shows a marked antitumor effect as a result of its cytotoxic action toward proliferative cells. In this article, we aim to investigate the potential antitumor and antiangiogenic effect of gemcitabine following a metronomic schedule that involves the regular administration of cytotoxic drugs at doses lower than standard treatment. In vitro results showed that human endothelial cells are more sensitive to gemcitabine (IC50 3 nmol/L) than pancreatic tumor cells (IC50 20 nmol/L). For in vivo studies, we used an orthotopic implantation model of human pancreatic carcinoma in nude mice. Gemcitabine was administered i.p. following a low-dose schedule (1 mg/kg/d for a month) and compared with the conventional schedule (100 mg/kg days 0, 3, 6, and 9 postimplantation). Metronomic treatment effect on established tumor was equivalent to standard administration. The measure of CD31 endothelial marked area allowed us to show an in vivo antiangiogenic effect of this drug that was further enhanced by using metronomic administration. This effect correlated with an induction of thrombospondin-1, a natural inhibitor of angiogenesis. Our results allow us to hypothesize that, in addition to a direct antiproliferative or cytotoxic antiendothelial cell effect, a secondary effect involving thrombospondin-1 induction might provide an explanation for the specificity of the effects of metronomic gemcitabine treatment

Neurodevelopmental effects of undernutrition and placental underperfusion in fetal growth restriction rabbit models

Introduction: Chronic reduction of oxygen and nutrient delivery to the fetus has been related to neurodevelopmental problems. Placental underperfusion induces a significant reduction in oxygen and nutrient delivery, whereas maternal undernutrition causes mainly nutrient deficiency. A comparison of the neurodevelopmental effects of both situations in pregnant rabbits was performed. Materials and Methods: The placental underperfusion model was induced after uteroplacental vessel ligation at 25 days of pregnancy. The undernutrition model was induced after a reduction of 70% of the basal maternal intake at 22 days of pregnancy. Neurobehavioral tests were applied in the derived offspring at the neonatal period and over the long term. Structural brain differences were evaluated by brain networks obtained from diffusion magnetic resonance imaging. Results: Birth weight was significantly lower in both cases. However, stillbirth was only increased in the placental underperfusion model. Cases from both models presented poorer neurobehavioral performance and network infrastructure, being more pro-nounced in the placental underperfusion model. Discussion: Prenatal insults during the last third of gestation resulted in functional and structural disturbances. The degree of neurodevelopmental impairment and its association with structural brain reorganization seemed to be related to the type of the prenatal insult, showing stronger effects in the placental underperfusion model. (C) 2017 S. Karger AG, Base