P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

Closures of regular languages for profinite topologies

The Pin-Reutenauer algorithm gives a method, that can be viewed as a descriptive procedure, to compute the closure in the free group of a regular language with respect to the Hall topology. A similar descriptive procedure is shown to hold for the pseudovariety A of aperiodic semigroups, where the closure is taken in the free aperiodic omega-semigroup. It is inherited by a subpseudovariety of a given pseudovariety if both of them enjoy the property of being full. The pseudovariety A, as well as some of its subpseudovarieties are shown to be full. The interest in such descriptions stems from the fact that, for each of the main pseudovarieties V in our examples, the closures of two regular languages are disjoint if and only if the languages can be separated by a language whose syntactic semigroup lies in V. In the cases of A and of the pseudovariety DA of semigroups in which all regular elements are idempotents, this is a new result.PESSOA French-Portuguese project Egide-Grices 11113YM, "Automata, profinite semigroups and symbolic dynamics".FCT -- Fundação para a Ciência e a Tecnologia, respectively under the projects PEst-C/MAT/UI0144/2011 and PEst-C/MAT/UI0013/2011.ANR 2010 BLAN 0202 01 FREC.AutoMathA programme of the European Science Foundation.FCT and the project PTDC/MAT/65481/2006 which was partly funded by the European Community Fund FEDER

Age-dependent changes in insulin-like immunoreactivity in rat submandibular salivary glands.

In recent years, a growing interest had arisen in hormonal factors in salivary glands. We have investigated the changes in the content of an insulin-like immunoreactive (ILI) compound in the submandibular salivary glands of Sprague Dawley rats during physiological aging, in the range 15 days-27 months. The amount of ILI in the submandibular glands of young adult rats was found to be doubled in the post-natal period until the age of puberty and was maintained in senescence. No significant correlation was found between age-dependent variations in ILI levels of submandibular salivary glands and circulating insulin concentrations, further supporting previous indications that ILI is being synthesized in situ. It is possible that ILI could exert paracrine effects within the glands, as regards the development of other glandular structures during the first months of life, as well as the preservation of glandular function in senescent animals as well

Anti-cancer drug validation: the contribution of tissue engineered models

Abstract Drug toxicity frequently goes concealed until clinical trials stage, which is the most challenging, dangerous and expensive stage of drug development. Both the cultures of cancer cells in traditional 2D assays and animal studies have limitations that cannot ever be unraveled by improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. Considering the NCI60, a panel of 60 cancer cell lines representative of 9 different cancer types: leukemia, lung, colorectal, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast, we propose to review current Bstate of art^ on the 9 cancer types specifically addressing the 3D tissue models that have been developed and used in drug discovery processes as an alternative to complement their studyThis article is a result of the project FROnTHERA (NORTE-01-0145-FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This article was also supported by the EU Framework Programme for Research and Innovation HORIZON 2020 (H2020) under grant agreement n° 668983 — FoReCaST. FCT distinction attributed to Joaquim M. Oliveira (IF/00423/2012) and Vitor M. Correlo (IF/01214/2014) under the Investigator FCT program is also greatly acknowledged.info:eu-repo/semantics/publishedVersio

Productivity links morphology, symbiont specificity, and bleaching in the evolution of Caribbean octocoral symbioses

Many cnidarians host endosymbiotic dinoflagellates from the genus Symbiodinium. It is generally assumed that the symbiosis is mutualistic, where the host benefits from symbiont photosynthesis while providing protection and photosynthetic substrates. Diverse assemblages of symbiotic gorgonian octocorals can be found in hard bottom communities throughout the Caribbean. While current research has focused on the phylo- and population genetics of gorgonian symbiont types and their photo-physiology, relatively less work has focused on biogeochemical benefits conferred to the host and how these benefits vary across host species. Here, we examine this symbiosis among 11 gorgonian species collected in Bocas del Toro, Panama. By coupling light and dark bottle incubations (P/R) with 13C-bicarbonate tracers, we quantified the link between holobiont oxygen metabolism with carbon assimilation and translocation from symbiont to host. Our data show that P/R varied among species, and was correlated with colony morphology and polyp size. Sea fans and sea plumes were net autotrophs (P/R > 1.5) while nine species of sea rods were net heterotrophs with most below compensation (P/R < 1.0). 13C assimilation corroborated the P/R results, and maximum δ13Chost values were strongly correlated with polyp size, indicating higher productivity by colonies with high polyp SA:V. A survey of gorgonian-Symbiodinium associations revealed that productive species maintain specialized, obligate symbioses and are more resistant to coral bleaching, whereas generalist and facultative associations are common among sea rods that have higher bleaching sensitivities. Overall, productivity and polyp size had strong phylogenetic signals with carbon fixation and polyp size showing evidence of trait covariance.published_or_final_versio

Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. © 2014 The Author(s)

Histidine-Rich Glycoprotein Can Prevent Development of Mouse Experimental Glioblastoma

Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma)

CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo

Thus far the clinical benefits seen in breast cancer patients treated with drugs targeting the vascular endothelial growth factor (VEGF) pathway are only modest. Consequently, additional antiangiogenic approaches for treatment of breast cancer need to be investigated. Thrombospondin-2 (TSP-2) has been shown to inhibit tumor growth and angiogenesis with a greater potency than the related molecule TSP-1. The systemic effects of TSP-2 on tumor metastasis and the underlying molecular mechanisms of the antiangiogenic activity of TSP-2 have remained poorly understood. We generated a recombinant fusion protein consisting of the N-terminal region of TSP-2 and the IgG-Fc1 fragment (N-TSP2-Fc) and could demonstrate that the antiangiogenic activity of N-TSP2-Fc is dependent on the CD36 receptor. We found that N-TSP2-Fc inhibited VEGF-induced tube formation of human dermal microvascular endothelial cells (HDMEC) on matrigel in vitro and that concurrent incubation of anti-CD36 antibody with N-TSP2-Fc resulted in tube formation that was comparable to untreated control. N-TSP2-Fc potently induced apoptosis of HDMEC in vitro in a CD36-dependent manner. Moreover, we could demonstrate a CD36 receptor-mediated loss of mitochondrial membrane potential and activation of caspase-3 in HDMEC in vitro. Daily intraperitoneal injections of N-TSP2-Fc resulted in a significant inhibition of the growth of human MDA-MB-435 and MDA-MB-231 tumor cells grown in the mammary gland of immunodeficient nude mice and in reduced tumor vascularization. Finally, increased serum concentrations of N-TSP2-Fc significantly inhibited regional metastasis to lymph nodes and distant metastasis to lung as shown by quantitative real-time alu PCR. These results identify N-TSP2-Fc as a potent systemic inhibitor of tumor metastasis and provide strong evidence for an important role of the CD36 receptor in mediating the antiangiogenic activity of TSP-2