Rationale:The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin−knockout mice exhibit enhanced tumor growth and angiogenesis. However, as β3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of β3-integrin function.Objective: Our aim was to examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis. Methods and Results:We have crossed β3-integrin-floxed (β3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial β3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression. Conclusions:
Anti-angiogenic treatments against αvβ3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through αvβ3-integrin-independent mechanisms. Here, we show that suppression of β3-integrin in mice leads to the activation of a neuropilin-1 (NRP1)-dependent cell migration pathway in endothelial cells via a mechanism that depends on NRP1's mobilisation away from mature focal adhesions following VEGF-stimulation. The simultaneous genetic targeting of both molecules significantly impairs paxillin-1 activation and focal adhesion remodelling in endothelial cells, and therefore inhibits tumour angiogenesis and the growth of already established tumours. These findings provide a firm foundation for testing drugs against these molecules in combination to treat patients with advanced cancers.
For nearly two decades now, the RGD (Arg-Gly-Asp)-binding αvβ3-integrin has been a focus of anti-angiogenic drug design. These inhibitors are well-tolerated, but have shown only limited success in patients. Over the years, studies in β3-integrin-knockout mice have shed some light on possible explanations for disappointing clinical outcomes. However, studying angiogenesis in β3-integrin-knockout mice is a blunt tool to investigate β3-integrin's role in pathological angiogenesis. Since establishing our laboratory at University of East Anglia (UEA), we have adopted more refined models of genetically manipulating the expression of the β3-integrin subunit. The present review will highlight some of our findings from these models and describe how data from them have forced us to rethink how targeting αvβ3-integrin expression affects tumour angiogenesis and cancer progression. Revisiting the fundamental biology behind how this integrin regulates tumour growth and angiogenesis, we believe, is the key not only to understanding how angiogenesis is normally co-ordinated, but also in success with drugs directed against it.
Integrin β3 is seen as a key anti‐angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro‐ or anti‐angiogenic depends on the context in which it is expressed. To understand precisely β3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the β3‐dependent adhesome. We show that depletion of β3‐integrin in this cell type leads to changes in microtubule behaviour that control cell migration. β3‐integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2‐driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when β3‐integrin levels are reduced.
ObjectivesAcademical and not-for-profit research funders are increasingly requiring that the research they fund must be published open access, with some insisting on publishing with a Creative Commons Attribution (CC BY) licence to allow the broadest possible use. We aimed to clarify the open access variants provided by leading medical journals and record the availability of the CC BY licence for commercially funded research.MethodsWe identified medical journals with a 2015 impact factor of ≥15.0 on 24 May 2017, then excluded from the analysis journals that only publish review articles. Between 29 June 2017 and 26 July 2017, we collected information about each journal’s open access policies from their websites and/or by email contact. We contacted the journals by email again between 6 December 2017 and 2 January 2018 to confirm our findings.ResultsThirty-five medical journals publishing original research from 13 publishers were included in the analysis. All 35 journals offered some form of open access allowing articles to be free-to-read, either immediately on publication or after a delay of up to 12 months. Of these journals, 21 (60%) provided immediate open access with a CC BY licence under certain circumstances (eg, to specific research funders). Of these 21, 20 only offered a CC BY licence to authors funded by non-commercial organisations and one offered this option to any funder who required it.ConclusionsMost leading medical journals do not offer to authors reporting commercially funded research an open access licence that allows unrestricted sharing and adaptation of the published material. The journals’ policies are therefore not aligned with open access declarations and guidelines. Commercial research funders lag behind academical funders in the development of mandatory open access policies, and it is time for them to work with publishers to advance the dissemination of the research they fund.
Integrin β3 is seen as a key anti-angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro-or anti-angiogenic depends on the context in which it is expressed. To understand precisely β3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the β3-dependent adhesome. We show that depletion of β3-integrin in this cell type leads to changes in microtubule behaviour that control their migration. β3-integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2 driven control of Rac1 activity. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when β3-integrin levels are reduced. Affliations:1 School of Biological Sciences, University of East Anglia, Norwich, UK. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/145839 doi: bioRxiv preprint first posted online Jun. 3, 2017; 2 INTRODUCTIONAngiogenesis, the formation of new blood vessels from those that already exist, plays an essential role in tumour growth (Hanahan and Weinberg, 2011). As such, targeting angiogenesis is seen as crucial in many anti-cancer strategies (Zhao and Adjei, 2015).Therapies directed against vascular endothelial growth factor (VEGF) and its major receptor, VEGF-receptor-2 (VEGFR2), whilst effective in a number of cancers, are not without side-effects due to the role this signaling pathway plays in vascular homeostasis (Chen and Hung, 2013). Fibronectin (FN)-binding endothelial integrins, especially αvβ3-and α5β1-integrins, have emerged as alternative anti-angiogenic targets because of their expression in neovasculature (Brooks et al., 1994;Kim et al., 2000). However, neither global nor conditional knockouts of these integrins block tumour angiogenesis long-term (Murphy et al., 2015;Reynolds et al., 2002;Steri et al., 2014), and clinical trials of blocking antibodies and peptides directed against these extracellular matrix (ECM) receptors have been disappointing (Schaffner et al., 2013; Stupp et al., 2014).To gain novel insight into how αvβ3-integrin regulates outside-in signal transmission (Hynes, 2002), we have undertaken an unbiased analysis of the molecular composition of the mature endothelial adhesome (the network of structural and signaling proteins involved in regulating cell-matrix adhesions (Zaidel-Bar et al., 2007)), and profiled changes that occur when β3-integrin function or expression are manipulated. In so doing, we have uncovered β3-integrin dependent changes in microtubule behaviour that regulate cell migration. RESULTS AND DISCUSSIONThe isolation and analysis of integrin adhesion complexes (IACs) by massspectrometry (MS) is difficult because of the low affinity and transient nature of the molecular interactions occurring at these sites. However, usi...
Introduction We aim to provide guidance on outcomes and measures for use in patients with Alzheimer's clinical syndrome. Methods A consensus group of 20 voting members nominated by 10 professional societies, and a non‐voting chair, used a Delphi approach and modified GRADE criteria. Results Consensus was reached on priority outcomes (n = 66), measures (n = 49) and statements (n = 37) across nine domains. A number of outcomes and measurement instruments were ranked for: Cognitive abilities; Functional abilities/dependency; Behavioural and neuropsychiatric symptoms; Patient quality of life (QoL); Caregiver QoL; Healthcare and treatment‐related outcomes; Medical investigations; Disease‐related life events; and Global outcomes. Discussion This work provides indications on the domains and ideal pertinent measurement instruments that clinicians may wish to use to follow patients with cognitive impairment. More work is needed to develop instruments that are more feasible in the context of the constraints of clinical routine.
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