Mechanisms of tumour invasion and metastasis : emerging targets for therapy

The progression of a tumour from one of benign and delimited growth to one that is invasive and metastatic is the major cause of poor clinical outcome in cancer patients. The invasion and metastasis of tumours is a highly complex and multistep process that requires a tumour cell to modulate its ability to adhere, degrade the surrounding extracellular matrix, migrate, proliferate at a secondary site and stimulate angiogenesis. Knowledge of the process has greatly increased and this has resulted in the identification of a number of molecules that are fundamental to the process. The involvement of these molecules has been shown to relate not only to the survival and proliferation of the tumour cell but, also to the processes of tumour cell adhesion, migration, and the tumour cells ability to degrade and escape the primary site as well as play a role in angiogenesis. These molecules may provide important therapeutic targets that represent the ability to target specific steps in the process of invasion and metastasis and provide additional therapies. The review focuses on representative key targets in each of these processes and summarises the state of play in each case.

Assessment of angiogenic potential--the use of AIDS-KS cell supernatants as an in vitro model

Metastasis, the passage of primary tumour cells throughout the body via the vascular system and their subsequent proliferation into secondary lesions in distant organs, represents a poor prognosis and therefore an understandably feared event for cancer patients. Despite considerable advances in cancer diagnosis and treatment, most deaths are the result of metastases resistant to conventional treatment [1]. Rather than being a random process, metastasis involves a series of organised steps leading to the growth of a secondary tumour. Malignant tumours stimulate the production of new vessels by the host, and this process is a prerequisite for the increase in size of a new tumour [2]. Angiogenesis, not only permits tumour expansion but also allows the entry of tumour cells into the circulation and is probably the most vital event for the metastatic process [3]. Metastasis and angiogenesis [4] have received much attention in recent years. A biological understanding of both phenomena seems to be an urgent priority towards the search for an effective prevention and treatment of tumour progression. Studies in vitro and in vivo have shown that one of the most important barriers to the passage of malignant cells is the basement membrane. The crossing of such barriers is a vital step in the formation of a metastasis [5].

The impact of a congestion charging exemption on the demand for new low‐emission vehicles

Numerous initiatives have been employed around the world in order to address rising greenhouse gas (GHG) emissions originating from the transport sector. These measures include: travel demand management (congestion‐charging), increased fuel taxes, alternative fuel subsidies and low‐emission vehicle (LEV) rebates. Incentivizing the purchase of LEVs has been one of the more prevalent approaches in attempting to tackle this global issue. LEVs, whilst having the advantage of lower emissions and, in some cases, more efficient fuel consumption, also bring the downsides of increased purchase cost, reduced convenience of vehicle fuelling, and operational uncertainty. To stimulate demand in the face of these challenges, various incentive‐based policies, such as toll exemptions, have been used by national and local governments to encourage the purchase of these types of vehicles. In order to address rising GHG emissions in Stockholm, and in line with the Swedish Government’s ambition to operate a fossil free fleet by 2030, a number of policies were implemented targeting the transport sector. Foremost amongst these was the combination of a congestion charge – initiated to discourage emissions‐intensive travel – and an exemption from this charge for some LEVs, established to encourage a transition towards a ‘green’ vehicle fleet. Although both policies shared the aim of reducing GHG emissions, the exemption for LEVs carried the risk of diminishing the effectiveness of the congestion charging scheme. As the number of vehicle owners choosing to transition to an eligible LEV increased, the congestion‐reduction effectiveness of the charging scheme weakened. In fact, policy makers quickly recognized this potential issue and consequently phased out the LEV exemption less than 18 months after its introduction (1). Several studies have investigated the demand for LEVs through stated‐preference (SP) surveys across multiple countries, including: Denmark (2), Germany (3, 4), UK (5), Canada (6), USA (7, 8) and Australia (9). Although each of these studies differed in approach, all involved SP surveys where differing characteristics between various types of vehicles, including LEVs, were presented to respondents and these respondents in turn made hypothetical decisions about which vehicle they would be most likely to purchase. Although these studies revealed a number of interesting findings in regards to the potential demand for LEVs, they relied on SP data. In contrast, this paper employs an approach where LEV choice is modelled by taking a retrospective view and by using revealed preference (RP) data. By examining the revealed preferences of vehicle owners in Stockholm, this study overcomes one of the principal limitations of SP data, namely that stated preferences may not in fact reflect individuals’ actual choices, such as when cost, time, and inconvenience factors are real rather than hypothetical. This paper’s RP approach involves modelling the characteristics of individuals who purchased new LEVs, whilst estimating the effect of the congestion charging exemption upon choice probabilities and subsequent aggregate demand. The paper contributes to the current literature by examining the effectiveness of a toll exemption under revealed preference conditions, and by assessing the total effect of the policy based on key indicators for policy makers, including: vehicle owner home location, commuting patterns, number of children, age, gender and income. Extended Abstract Submission for Kuhmo Nectar Conference 2014 2 The two main research questions motivating this study were:  Which individuals chose to purchase a new LEV in Stockholm in 2008?; and,  How did the congestion charging exemption affect the aggregate demand for new LEVs in Stockholm in 2008? In order to answer these research questions the analysis was split into two stages. Firstly, a multinomial logit (MNL) model was used to identify which demographic characteristics were most significantly related to the purchase of an LEV over a conventional vehicle. The three most significant variables were found to be: intra‐cordon residency (positive); commuting across the cordon (positive); and distance of residence from the cordon (negative). In order to estimate the effect of the exemption policy on vehicle purchase choice, the model included variables to control for geographic differences in preferences, based on the location of the vehicle owners’ homes and workplaces in relation to the congestion‐charging cordon boundary. These variables included one indicator representing commutes across the cordon and another indicator representing intra‐cordon residency. The effect of the exemption policy on the probability of purchasing LEVs was estimated in the second stage of the analysis by focusing on the groups of vehicle owners that were most likely to have been affected by the policy i.e. those commuting across the cordon boundary (in both directions). Given the inclusion of the indicator variable representing commutes across the cordon, it is assumed that the estimated coefficient of this variable captures the effect of the exemption policy on the utility of choosing to purchase an exempt LEV for these two groups of vehicle owners. The intra‐cordon residency indicator variable also controls for differences between the two groups, based upon direction of travel across the cordon boundary. A counter‐hypothesis to this assumption is that the coefficient of the variable representing commuting across the cordon boundary instead only captures geo‐demographic differences that lead to variations in LEV ownership across the different groups of vehicle owners in relation to the cordon boundary. In order to address this counter‐hypothesis, an additional analysis was performed on data from a city with a similar geodemographic pattern to Stockholm, Gothenburg ‐ Sweden’s second largest city. The results of this analysis provided evidence to support the argument that the coefficient of the variable representing commutes across the cordon was capturing the effect of the exemption policy. Based upon this framework, the predicted vehicle type shares were calculated using the estimated coefficients of the MNL model and compared with predicted vehicle type shares from a simulated scenario where the exemption policy was inactive. This simulated scenario was constructed by setting the coefficient for the variable representing commutes across the cordon boundary to zero for all observations to remove the utility benefit of the exemption policy. Overall, the procedure of this second stage of the analysis led to results showing that the exemption had a substantial effect upon the probability of purchasing and aggregate demand for exempt LEVs in Stockholm during 2008. By making use of unique evidence of revealed preferences of LEV owners, this study identifies the common characteristics of new LEV owners and estimates the effect of Stockholm's congestion charging exemption upon the demand for new LEVs during 2008. It was found that the variables that had the greatest effect upon the choice of purchasing an exempt LEV included intra‐cordon residency (positive), distance of home from the cordon (negative), and commuting across the cordon (positive). It was also determined that owners under the age of 30 years preferred non‐exempt LEVs (low CO2 LEVs), whilst those over the age of 30 years preferred electric vehicles. In terms of electric vehicles, it was apparent that those individuals living within the city had the highest propensity towards purchasing this vehicle type. A negative relationship between choosing an electric vehicle and the distance of an individuals’ residency from the cordon was also evident. Overall, the congestion charging exemption was found to have increased the share of exempt LEVs in Stockholm by 1.9%, with, as expected, a much stronger effect on those commuting across the boundary, with those living inside the cordon having a 13.1% increase, and those owners living outside the cordon having a 5.0% increase. This increase in demand corresponded to an additional 538 (+/‐ 93; 95% C.I.) new exempt LEVs purchased in Stockholm during 2008 (out of a total of 5 427; 9.9%). Policy makers can take note that an incentive‐based policy can increase the demand for LEVs and appears to be an appropriate approach to adopt when attempting to reduce transport emissions through encouraging a transition towards a ‘green’ vehicle fleet.

Lithium release from ß-tricalcium phosphate inducing cementogenic and osteogenic differentiation for both hPDLCs and hBMSCs

It is accepted that the accelerated differentiation of tissue cells on bioactive materials is of great importance to regenerate the lost tissues. It was previously reported that lithium (Li) ions could enhance the in vitro proliferation and differentiation of retinoblastoma cells and endometrium epithelia by activating the Wnt canonical signalling pathway. It is interesting to incorporate Li ions into bioactive ceramics, such as β-tricalcium phosphate (Li-β-TCP), in order to stimulate both osteogenic and cementogenic differentiation of different stem cells for the regeneration of bone/periodontal tissues. Therefore, the aim of this study was to investigate the interactions of human periodontal ligament cells (hPDLCs) and human bone marrow stromal cells (hBMSCs) with Li-β-TCP bioceramic bulks and their ionic extracts, and further explore the osteogenic and cementogenic stimulation of Li-β-TCP bioceramics and the possible molecular mechanisms. The results showed that Li-β-TCP bioceramic disks supported the cell attachment and proliferation, and significantly enhanced bone/cementum-related gene expression, Wnt canonical signalling pathway activation for both hPDLCs and hBMSCs, compared to conventional β-TCP bioceramic disks without Li. The release of Li from Li-β-TCP powders could significantly promote the bone/cementum-related gene expression for both hPDLCs and hBMSCs compared to pure β-TCP extracts without Li release. Our results suggest that the combination of Li with β-TCP bioceramics may be a promising method to enhance bone/cementum regeneration as Li-β-TCP possesses excellent in vitro osteogenic and cementogenic stimulation properties by inducing bone/cementum-related gene expression in both hPDLCs and hBMSCs.

Analysis of the needs of the East Coast cluster regional natural resource management bodies in relation to planning for climate change adaptation

The Climate Change Adaptation for Natural Resource Management (NRM) in East Coast Australia Project aims to foster and support an effective “community of practice” for climate change adaptation within the East Coast Cluster NRM regions that will increase the capacity for adaptation to climate change through enhancements in knowledge and skills and through the establishment of long‐term collaborations. It is being delivered by six consortium research partners: * The University of Queensland (project lead) * Griffith University * University of the Sunshine Coast * CSIRO * New South Wales Office of Environment and Heritage * Queensland Department of Science, IT, Innovation and the Arts (Queensland Herbarium). The project relates to the East Coast Cluster, comprising the six coastal NRM regions and regional bodies between Rockhampton and Sydney: * Fitzroy Basin Association (FBA) * Burnett‐Mary Regional Group (BMRG) * SEQ Catchments (SEQC) * Northern Rivers Catchment Management Authority (CMA) (NRCMA) * Hunter‐Central Rivers CMA (HCRCMA) * Hawkesbury Nepean CMA (HNCMA). The aims of this report are to summarise the needs of the regional bodies in relation to NRM planning for climate change adaptation, and provide a basis for developing the detailed work plan for the research consortium. Two primary methods were used to identify the needs of the regional bodies: (1) document analysis of the existing NRM/ Catchment Action Plans (CAPs) and applications by the regional bodies for funding under Stream 1 of the Regional NRM Planning for Climate Change Fund, and; (2) a needs analysis workshop, held in May 2013 involving representatives from the research consortium partners and the regional bodies. The East Coast Cluster includes five of the ten largest significant urban areas in Australia, world heritage listed natural environments, significant agriculture, mining and extensive grazing. The three NSW CMAs have recently completed strategic level CAPs, with implementation plans to be finalised in 2014/2015. SEQC and FBA are beginning a review of their existing NRM Plans, to be completed in 2014 and 2015 respectively; while BMRG is aiming to produce a NRM and Climate Variability Action Strategy. The regional bodies will receive funding from the Australian Government through the Regional NRM Planning for Climate Change Fund (NRM Fund) to improve regional planning for climate change and help guide the location of carbon and biodiversity activities, including wildlife corridors. The bulk of the funding will be available for activities in 2013/2014, with smaller amounts available in subsequent years. Most regional bodies aim to have a large proportion of the planning work complete by the end of 2014. In addition, NSW CMAs are undergoing major structural change and will be incorporated into semi‐autonomous statutory Local Land Services bodies from 2014. Boundaries will align with local government boundaries and there will be significant change in staff and structures. The regional bodies in the cluster have a varying degree of climate knowledge. All plans recognise climate change as a key driver of change, but there are few specific actions or targets addressing climate change. Regional bodies also have varying capacity to analyse large volumes of spatial or modelling data. Due to the complex nature of natural resource management, all regional bodies work with key stakeholders (e.g. local government, industry groups, and community groups) to deliver NRM outcomes. Regional bodies therefore require project outputs that can be used directly in stakeholder engagement activities, and are likely to require some form of capacity building associated with each of the outputs to maximise uptake. Some of the immediate needs of the regional bodies are a summary of information or tools that are able to be used immediately; and a summary of the key outputs and milestone dates for the project, to facilitate alignment of planning activities with research outputs. A project framework is useful to show the linkages between research elements and the relevance of the research to the adaptive management cycle for NRM planning in which the regional bodies are engaged. A draft framework is proposed to stimulate and promote discussion on research elements and linkages; this will be refined during and following the development of the detailed project work plan. The regional bodies strongly emphasised the need to incorporate a shift to a systems based resilience approach to NRM planning, and that approach is included in the framework. The regional bodies identified that information on climate projections would be most useful at regional and subregional scale, to feed into scenario planning and impact analysis. Outputs should be ‘engagement ready’ and there is a need for capacity building to enable regional bodies to understand and use the projections in stakeholder engagement. There was interest in understanding the impacts of climate change projections on ecosystems (e.g. ecosystem shift), and the consequent impacts on the production of ecosystem services. It was emphasised that any modelling should be able to be used by the regional bodies with their stakeholders to allow for community input (i.e. no black box models). The online regrowth benefits tool was of great interest to the regional bodies, as spatial mapping of carbon farming opportunities would be relevant to their funding requirements. The NSW CMAs identified an interest in development of the tool for NSW vegetation types. Needs relating to socio‐economic information included understanding the socio‐economic determinants of carbon farming uptake and managing community expectations. A need was also identified to understand the vulnerability of industry groups as well as community to climate change impacts, and in particular understanding how changes in the flow of ecosystem services would interact with the vulnerability of these groups to impact on the linked ecologicalsocio‐economic system. Responses to disasters (particularly flooding and storm surge) and recovery responses were also identified as being of interest. An ecosystem services framework was highlighted as a useful approach to synthesising biophysical and socioeconomic information in the context of a systems based, resilience approach to NRM planning. A need was identified to develop processes to move towards such an approach to NRM planning from the current asset management approach. Examples of best practice in incorporating climate science into planning, using scenarios for stakeholder engagement in planning and processes for institutionalising learning were also identified as cross‐cutting needs. The over‐arching theme identified was the need for capacity building for the NRM bodies to best use the information available at any point in time. To this end a planners working group has been established to support the building of a network of informed and articulate NRM agents with knowledge of current climate science and capacity to use current tools to engage stakeholders in NRM planning for climate change adaptation. The planners working group would form the core group of the community of practice, with the broader group of stakeholders participating when activities aligned with their interests. In this way, it is anticipated that the Project will contribute to building capacity within the wider community to effectively plan for climate change adaptation.

Emergency healthcare of the future

Emergency healthcare is a high profile component of modern healthcare systems, which over the past three decades has fundamentally transformed in many countries. However, despite this rapid development, and associated investments in service standards, there is a high level of concern with the performance of emergency health services relating principally to system wide congestion. The factors driving this problem are complex but relate largely to the combined impact of growing demand, expanded scope of care and blocked access to inpatient beds. These factors are unlikely to disappear in the medium term despite the National Emergency Access Target. The aim of this article is to stimulate a conversation about the future design and functioning of emergency healthcare systems; examining what we understand about the problem and proposing a rationale that may underpin future strategic approaches. This is also an invitation to join the conversation.

Benchmarking potential factors leading to education quality : a study of Cambodian higher education

Purpose To study the quality in higher education in Cambodia and explore the potential factors leading to quality in Cambodian higher education. Design/methodology/approach Five main factors that were deemed relevant in providing quality in Cambodian higher education were proposed: academic curriculum and extra-curricular activities, teachers' qualification and methods, funding and tuition, school facilities, and interactive network. These five propositions were used to compare Shu-Te University, Taiwan with the top five universities in Cambodia. The data came in the forms of questionnaire and desk research. Descriptive analytical approach is then carried out to describe these five factors. Findings Only 6 per cent of lecturers hold PhD degree and about 85 per cent never published any papers; some private universities charge as low as USD200 per academic year, there is almost no donation from international organizations, and annual government funding on higher education sector nationwide in 2005 was only about USD3.67 million; even though there is a library at each university, books, study materials etc. are not up-to-date and inadequate; 90 per cent of the lecturers never have technical discussion or meeting and about 60 per cent of students felt that their teachers did not have time for them to consult with. Originality/value A useful insight was gained into the perceived importance of quality in higher education that can stimulate debate and discussion on the role of government in building the standard quality in higher education. Also, the findings from this research can assist in the development of a framework of developing human resource.

The role of customer gratitude in making relationship marketing investments successful

This paper recognises that customer loyalty is important for many competitive organisations, and that retail firms make investments to build and maintain loyal relationships with their existing and potential customers (e.g. loyalty programs). However, there has been little focus on the mechanisms by which these relationship investments operate to achieve customer loyalty. This paper examines one mechanism, namely customer gratitude, which works to make a firm’s relationship marketing investment a success or a failure. Using data from 1600 undergraduate students, this study empirically confirms the mediating role of customer gratitude between the customers’ perceptions a firm’s relationship marketing investments and customers’ perceptions of the value of the relationship with the firm. Further, a significant moderating effect of perceived benevolence on the relationship between customers’ perceptions a firm’s relationship marketing investments and customer gratitude was identified. For theorists, this customer gratitude model offers a better psychological explanation of how relationship marketing investments operate to improve the value that customers place on their relationships with retailers. Our research suggests that managers should invest resources to stimulate customer gratitude in order to build strong customer–seller relationships.

Differential subcellular and extracellular localisations of proteins required for insulin-like growth factor- and extracellular matrix-induced signalling events in breast cancer progression

Background: Cancer metastasis is the main contributor to breast cancer fatalities as women with the metastatic disease have poorer survival outcomes than women with localised breast cancers. There is an urgent need to develop appropriate prognostic methods to stratify patients based on the propensities of their cancers to metastasise. The insulin-like growth factor (IGF)-I:IGF binding protein (IGFBP):vitronectin complexes have been shown to stimulate changes in gene expression favouring increased breast cancer cell survival and a migratory phenotype. We therefore investigated the prognostic potential of these IGF- and extracellular matrix (ECM) interaction-induced proteins in the early identification of breast cancers with a propensity to metastasise using patient-derived tissue microarrays. Methods: Semiquantitative immunohistochemistry analyses were performed to compare the extracellular and subcellular distribution of IGF- and ECM-induced signalling proteins among matched normal, primary cancer and metastatic cancer formalin-fixed paraffin-embedded breast tissue samples. Results: The IGF- and ECM-induced signalling proteins were differentially expressed between subcellular and extracellular localisations. Vitronectin and IGFBP-5 immunoreactivity was lower while β1 integrin immunoreactivity was higher in the stroma surrounding metastatic cancer tissues, as compared to normal breast and primary cancer stromal tissues. Similarly, immunoreactive stratifin was found to be increased in the stroma of primary as well as metastatic breast tissues. Immunoreactive fibronectin and β1 integrin was found to be highly expressed at the leading edge of tumours. Based on the immunoreactivity it was apparent that the cell signalling proteins AKT1 and ERK1/2 shuffled from the nucleus to the cytoplasm with tumour progression. Conclusion: This is the first in-depth, compartmentalised analysis of the distribution of IGF- and ECM-induced signalling proteins in metastatic breast cancers. This study has provided insights into the changing pattern of cellular localisation and expression of IGF- and ECM-induced signalling proteins in different stages of breast cancer. The differential distribution of these biomarkers could provide important prognostic and predictive indicators that may assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy.

Sitooter-i

As part of the process of renewing its City Centre Master Plan, Brisbane City Council and its CBD are hosting an Ideas Fiesta between April 11th- 3rd May 2013. It hopes to generate new ideas, showcase design concepts, and stimulate interest in imagining the future of the city centre. Events will be held in a variety of city outdoor spaces, streets, laneways and venues to identify catalyst projects and explore design ideas for the city centre. In the City Botanic Gardens ‘Sunday reserved for you’ on 21st April and ‘A shot of green’ on Wednesday 24th April are some of the events planned and are the setting for innovative items of park furniture and other activities. A sitooterie (Scottish) is an outdoor space to sit… a place to enjoy nature. This Sitooter-i has been digitally designed for CNC fabrication with the ergonomics of reclining, lounging, just sitting or jumping around in mind. It was assembled by staff and students from Queensland University of Technology and is made from locally sourced plywood components which are easily dismantled for re-use elsewhere. But this Sitooter-i inspired by natural forms is also both physically and technologically interactive. Sensors record sound, light and temperature in their interactions with users. This data may be relayed as LED lights played in rhythm along frame edges or used by Brisbane City Council to assess frequency and style of use, perhaps revealing the effectiveness of its performance and the preferences of its users. See: http://sitooteri.wordpress.com/

Equally engaged : demystifying tertiary study in the creative arts to equity communities

The participation rate of students from low socio-economic (SES) backgrounds into Australian universities remains low. A nationwide initiative to raise participation rates aims to stimulate interest, highlight career possibilities and enhance understanding of university. The program also aims to improve retention and completion rates of those students. This paper provides a case study and preliminary evaluation of QUT’s Creative Industries Faculty’s (CIF) outreach programs to low SES school students, operating since 2012. Programs are conducted across the disciplines of Dance, Drama, Media, Digitalstorytelling, Music and Entertainment. Presenting the arts and creative industries as a viable study / career pathway is particularly challenging to low SES groups. However, the focus on the creative industries aims to broaden understanding of arts and creativity, emphasising the significance of digital technology in the transformation of the workforce, providing new career opportunities in the creative and non-creative sectors. CIF’s outreach programs have been delivered to hundreds of students and this paper presents a case study and evaluation of several programs.

The aerospace engineering challenge

Integrating Science, Technology, and Engineering in Mathematics authors share ideas and activities that stimulate student interest in the integrated fields of science, technology, engineering, and mathematics (STEM) in K–grade 6 classrooms. This article describes an activity that introduced fourth-grade students to the work of aerospace engineers and to the science, technology, and mathematics principles associated with flight.

Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A

We show that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, downregulates the cGMP-specific phosphodiesterase PDE5A. Although PDE5A downregulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A downregulation leads to an increase in cGMP, which induces an increase in cytosolic Ca2+, stimulating increased contractility and inducing invasion. PDE5A downregulation also this leads to an increase in short-term and long-term colonization of the lungs by melanoma cells. We do not observe this pathway in NRAS mutant melanoma or BRAF mutant colorectal cells. Thus, we show that in melanoma cells oncogenic BRAF induces invasion through downregulation of PDE5A.

Virulence properties of asymptomatic bacteriuria Escherichia coli

In asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract without provoking symptoms. Here, we compared the virulence properties of a collection of ABU Escherichia coli strains to cystitis and pyelonephritis strains. Specific urinary tract infection (UTI)-associated virulence genes, hemagglutination characteristics, siderophore production, hemolysis, biofilm formation, and the ability of strains to adhere to and induce cytokine responses in epithelial cells were analyzed. ABU strains were phylogenetically related to strains that cause symptomatic UTI. However, the virulence properties of the ABU strains were variable and dependent on a combination of genotypic and phenotypic factors. Most ABU strains adhered poorly to epithelial cells; however, we also identified a subgroup of strongly adherent strains that were unable to stimulate an epithelial cell IL-6 cytokine response. Poor immune activation may represent one mechanism whereby ABU E. coli evade immune detection after the establishment of bacteriuria.

NADPH oxidases as regulators of tumor angiogenesis : current and emerging concepts

Significance Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and peroxynitrite are generated ubiquitously by all mammalian cells and have been understood for many decades as inflicting cell damage and as causing cancer by oxidation and nitration of macromolecules, including DNA, RNA, proteins, and lipids. Recent Advances A current concept suggests that ROS can also promote cell signaling pathways triggered by growth factors and transcription factors that ultimately regulate cell proliferation, differentiation, and apoptosis, all of which are important hallmarks of tumor cell proliferation and angiogenesis. Moreover, an emerging concept indicates that ROS regulate the functions of immune cells that infiltrate the tumor environment and stimulate angiogenesis, such as macrophages and specific regulatory T cells. Critical Issues In this article, we highlight that the NADPH oxidase family of ROS-generating enzymes are the key sources of ROS and, thus, play an important role in redox signaling within tumor, endothelial, and immune cells thereby promoting tumor angiogenesis. Future Directions Knowledge of these intricate ROS signaling pathways and identification of the culprit NADPH oxidases is likely to reveal novel therapeutic opportunities to prevent angiogenesis that occurs during cancer and which is responsible for the revascularization after current antiangiogenic treatment.