Analyzing the regulation of metabolic pathways in human breast cancer

<p>Abstract</p> <p>Background</p> <p>Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer.</p> <p>Methods</p> <p>For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors.</p> <p>Results</p> <p>Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway.</p> <p>Conclusion</p> <p>We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment.</p

Defining the Molecular Basis of Tumor Metabolism: a Continuing Challenge Since Warburg's Discovery

Cancer cells are the product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of cell survival, proliferation, differentiation and death mechanisms. the role of oncogene activation and tumor suppressor inhibition in the onset of cancer is well established. Traditional antitumor therapies target specific molecules, the action/expression of which is altered in cancer cells. However, since the physiology of normal cells involves the same signaling pathways that are disturbed in cancer cells, targeted therapies have to deal with side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal metabolism displayed by cancer cells has been highlighted by many studies. Recently, the study of tumor metabolism has received much attention because metabolic transformation is a crucial cancer hallmark and a direct consequence of disturbances in the activities of oncogenes and tumor suppressors. in this review we discuss tumor metabolism from the molecular perspective of oncogenes, tumor suppressors and protein signaling pathways relevant to metabolic transformation and tumorigenesis. We also identify the principal unanswered questions surrounding this issue and the attempts to relate these to their potential for future cancer treatment. As will be made clear, tumor metabolism is still only partly understood and the metabolic aspects of transformation constitute a major challenge for science. Nevertheless, cancer metabolism can be exploited to devise novel avenues for the rational treatment of this disease. Copyright (C) 2011 S. Karger AG, BaselFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed ABC UFABC, CCNH, Santo Andre, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Ciencias Biol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Bioquim, São Paulo, BrazilUniv Fed Sao Carlos UFSCar, DFQM, Sorocaba, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Ciencias Biol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Bioquim, São Paulo, BrazilFAPESP: 10/16050-9FAPESP: 10/11475-1FAPESP: 08/51116-0Web of Scienc

Time domains of the hypoxic ventilatory response in ectothermic vertebrates

Over a decade has passed since Powell et al. (Respir Physiol 112:123–134, 1998) described and defined the time domains of the hypoxic ventilatory response (HVR) in adult mammals. These time domains, however, have yet to receive much attention in other vertebrate groups. The initial, acute HVR of fish, amphibians and reptiles serves to minimize the imbalance between oxygen supply and demand. If the hypoxia is sustained, a suite of secondary adjustments occur giving rise to a more long-term balance (acclimatization) that allows the behaviors of normal life. These secondary responses can change over time as a function of the nature of the stimulus (the pattern and intensity of the hypoxic exposure). To add to the complexity of this process, hypoxia can also lead to metabolic suppression (the hypoxic metabolic response) and the magnitude of this is also time dependent. Unlike the original review of Powell et al. (Respir Physiol 112:123–134, 1998) that only considered the HVR in adult animals, we also consider relevant developmental time points where information is available. Finally, in amphibians and reptiles with incompletely divided hearts the magnitude of the ventilatory response will be modulated by hypoxia-induced changes in intra-cardiac shunting that also improve the match between O2 supply and demand, and these too change in a time-dependent fashion. While the current literature on this topic is reviewed here, it is noted that this area has received little attention. We attempt to redefine time domains in a more ‘holistic’ fashion that better accommodates research on ectotherms. If we are to distinguish between the genetic, developmental and environmental influences underlying the various ventilatory responses to hypoxia, however, we must design future experiments with time domains in mind

Barriers and facilitators to using NHS Direct: a qualitative study of ‘users’ and ‘non-users’

Background NHS Direct, introduced in 1998, has provided 24/7 telephone-based healthcare advice and information to the public in England and Wales. National studies have suggested variation in the uptake of this service amongst the UK¿s diverse population. This study provides the first exploration of the barriers and facilitators that impact upon the uptake of this service from the perspectives of both `users¿ and `non- users¿. Methods Focus groups were held with NHS Direct `users¿ (N?=?2) from Bedfordshire alongside `non-users¿ from Manchester (N?=?3) and Mendip, Somerset (N?=?4). Each focus group had between five to eight participants. A total of eighty one people aged between 21 and 94 years old (M: 58.90, SD: 22.70) took part in this research. Each focus group discussion lasted approximately 90 minutes and was audiotape-recorded with participants¿ permission. The recordings were transcribed verbatim. A framework approach was used to analyse the transcripts. Results The findings from this research uncovered a range of barriers and facilitators that impact upon the uptake of NHS Direct. `Non-users¿ were unaware of the range of services that NHS Direct provided. Furthermore, `non-users¿ highlighted a preference for face-to face communication, identifying a lack of confidence in discussing healthcare over the telephone. This was particularly evident among older people with cognitive difficulties. The cost to telephone a `0845¿ number from a mobile was also viewed to be a barrier to access NHS Direct, expressed more often by `non-users¿ from deprived communities. NHS Direct `users¿ identified that awareness, ease of use and convenience were facilitators which influenced their decision to use the service. Conclusions An understanding of the barriers and facilitators which impact on the access and uptake of telephone-based healthcare is essential to move patients towards the self-care model. This research has highlighted the need for telephone-based healthcare services to increase public awareness; through the delivery of more targeted advertising to promote the service provision availabl

Cancer stem cell metabolism

Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets

Data from an International Multi-Centre Study of Statistics and Mathematics Anxieties and Related Variables in University Students (the SMARVUS Dataset)

This large, international dataset contains survey responses from N = 12,570 students from 100 universities in 35 countries, collected in 21 languages. We measured anxieties (statistics, mathematics, test, trait, social interaction, performance, creativity, intolerance of uncertainty, and fear of negative evaluation), self-efficacy, persistence, and the cognitive reflection test, and collected demographics, previous mathematics grades, self-reported and official statistics grades, and statistics module details. Data reuse potential is broad, including testing links between anxieties and statistics/mathematics education factors, and examining instruments’ psychometric properties across different languages and contexts

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs. There are, however, two different aspects of the problem caused by tumor hypoxia when cancer therapy is concerned: One is due to the chemical reactions that molecular oxygen enters intoin therapeutically targeted cells. This results in a direct chemical protection against therapy by the hypoxic microenvironment which has little to do with cellular biological regulatory processes. This part of the protective effect of hypoxia has been known for more than half a century and has been studied extensively. However, in recent years more focus has been put into the other aspect of hypoxia, namely the effect of this microenvironmental condition on selecting cells with certain genetical pre-requisites that are negative with respect to patient prognosis. There are adaptive mechanisms, where hypoxia induces regulatory cascades in cells resulting in a changed metabolism or changes in extra cellular signalling. These processes may lead to changes in cellular intrinsic sensitivity to treatment irrespective of oxygenation and furthermore, may also have consequences for tissue organization. Thus, the adaptive mechanisms induced by hypoxia itself may have a selective effect on cells with a fine-tuned protection against damage and stress of many kinds. It therefore could be that the adaptive mechanisms may be taken advantage of for new tumor labelling/imaging and treatment strategies. One of the Achilles’ heels of hypoxia research has always been exact measurements of tissue oxygenation as well as control of oxygenation in biological tumor models. Thus, development of technology that can ease this control is vital in order to study mechanisms and perform drug development under relevant conditions. An integrated EU Framework project 2004-2009, termed Euroxy, demonstrates several pathways involved in transcription and translation control of the hypoxic cell phenotype and evidence of cross talk with responses to pH and redox changes. The carbon anhydrase isoenzyme CA IX was selected for further studies due to its expression on the surface of many types of hypoxic tumors. The effort has lead to marketable culture flaks with sensors and incubation equipment and the synthesis of new drug candidates against new molecular targets. New labelling/imaging methods for cancer diagnosing and imaging of hypoxic cancer tissue now are being tested in xeno-graft models and also are in early clinical testing while new potential anticancer drugs are undergoing tests using xenografted tumor cancers. The present paper describes the above results in individual consortium partner presentations