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This work presents measurements of the local H  ii environment metallicities of core-collapse supernovae (SNe) within a luminosity distance of 30 Mpc. 76 targets were observed at the Isaac Newton Telescope and environment metallicities could be measured for 65 targets using the N2 and O3N2 strong emission line method. The cumulative distribution functions (CDFs) of the environment metallicities of Type Ib and Ic SNe tend to higher metallicity than Type IIP, however Type Ic are also present at lower metallicities whereas Type Ib are not. The Type Ib frequency distribution is narrower (standard deviation ∼0.06 dex) than the Ic and IIP distributions (∼0.15 dex) giving some evidence for a significant fraction of single massive progenitor stars; the low metallicity of Type Ic suggests a significant fraction of compact binary progenitors. However, both the Kolmogorov–Smirnov test and the Anderson–Darling test indicate no statistical significance for a difference in the local metallicities of the three SN types. Monte Carlo simulations reveal a strong sensitivity of these tests to the uncertainties of the derived metallicities. Given the uncertainties of the strong emission methods, the applicability of the tests seems limited. We extended our analysis with the data of the Type Ib/Ic/IIP SN sample from Galbany et al. The CDFs created with their sample confirm our CDFs very well. The statistical tests, combining our sample and the Galbany et al. sample, indicate a significant difference between Type Ib and Type IIP with <5 per cent probability that they are drawn from the same parent population. [ABSTRACT FROM AUTHOR]

Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD). EC deletion of TRAIL in vivo or in vitro inhibited neo-angiogenesis, pericyte recruitment, and vessel stabilization, resulting in reduced lower-limb blood perfusion with ischemia. Activation of the TRAIL receptor (TRAIL-R) restored blood perfusion and stable blood vessel networks in mice. Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD.

Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.

Improving tumor access for drug delivery is challenging, particularly in poorly perfused tumors. The availability of functional tumor blood vessels for systemic access is vital to allow drugs or imaging agents to accumulate in the tumor parenchyma. We subjected mice engineered to develop hepatocellular carcinoma (HCC), to treatment with tumor necrosis factor alpha (TNFα) conjugated to a CSG peptide (CSGRRSSKC). CSG binds to the laminin-nidogen-1 complex of the extracellular matrix (ECM) in HCC. When produced as a recombinant fusion protein, the TNFα-CSG functions as an ECM depletion agent via an immune-mediated mechanism to improve tumor perfusion. Tumor perfusion in HCC was dramatically improved after daily intravenous (i.v.) injection of 5 µg TNFα-CSG for five consecutive days. Following treatment, we assessed the tumor accessibility to accumulate an imaging agent, superparamagnetic iron-oxide nanoparticles (IO-NP). Here, we compared the passive delivery of an i.v. dose of IO-NP in HCC following ECM depletion after TNFα-CSG treatment, to the intratumoral accumulation of a comparable dose of CSG-targeted IO-NP in HCC with intact ECM. Magnetic resonance imaging (MRI) T 2 -weighted scans and T 2 relaxation times indicate that when the tumor ECM is intact, HCC was resistant to the intratumoral uptake of IO-NP, even when the particles were tagged with CSG peptide. In contrast, pre-treatment with TNFα-CSG resulted in the highest IO-NP accumulation in tumors. These findings suggest poorly perfused HCC may be resistant to molecular-targeted imaging agents including CSG-IO-NP. We demonstrate that specific ECM depletion using TNFα-CSG improves nanoparticle delivery into poorly perfused tumors such as HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yeow, Wu, Wang, Winteringham, Feindel, Tirnitz-Parker, Leedman, Ganss and Hamzah.)

Diagnostic imaging of aggressive cancer with a high stroma content may benefit from the use of imaging contrast agents targeted with peptides that have high binding affinity to the extracellular matrix (ECM). In this study, we report the use of superparamagnetic iron-oxide nanoparticles (IO-NP) conjugated to a nonapeptide, CSGRRSSKC (CSG), which specifically binds to the laminin-nidogen-1 complex in tumours. We show that CSG-IO-NP accumulate in tumours, predominantly in the tumour ECM, following intravenous injection into a murine model of pancreatic neuroendocrine tumour (PNET). In contrast, a control untargeted IO-NP consistently show poor tumour uptake, and IO-NP conjugated to a pentapeptide. CREKA that bind fibrin clots in blood vessels show restricted uptake in the angiogenic vessels of the tumours. CSG-IO-NP show three-fold higher intratumoral accumulation compared to CREKA-IO-NP. Magnetic resonance imaging (MRI) T 2 -weighted scans and T 2 relaxation times indicate significant uptake of CSG-IO-NP irrespective of tumour size, whereas the uptake of CREKA-IO-NP is only consistent in small tumours of less than 3 mm in diameter. Larger tumours with significantly reduced tumour blood vessels show a lack of CREKA-IO-NP uptake. Our data suggest CSG-IO-NP are particularly useful for detecting stroma in early and advanced solid tumours.

Improving the effectiveness of anti-cancer immunotherapy remains a major clinical challenge. Cytotoxic T cell infiltration is crucial for immune-mediated tumor rejection, however, the suppressive tumor microenvironment impedes their recruitment, activation, maturation and function. Nevertheless, solid tumors can harbor specialized lymph node vasculature and immune cell clusters that are organized into tertiary lymphoid structures (TLS). These TLS support naïve T cell infiltration and intratumoral priming. In many human cancers, their presence is a positive prognostic factor, and importantly, predictive for responsiveness to immune checkpoint blockade. Thus, therapeutic induction of TLS is an attractive concept to boost anti-cancer immunotherapy. However, our understanding of how cancer-associated TLS could be initiated is rudimentary. Exciting new reagents which induce TLS in preclinical cancer models provide mechanistic insights into the exquisite stromal orchestration of TLS formation, a process often associated with a more functional or "normalized" tumor vasculature and fueled by LIGHT/LTα/LTβ, TNFα and CC/CXC chemokine signaling. These emerging insights provide innovative opportunities to induce and shape TLS in the tumor microenvironment to improve immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Johansson-Percival and Ganss.)

Advanced metastatic cancer is rarely curable. While immunotherapy has changed the oncological landscape profoundly, cure in metastatic disease remains the exception. Tumor blood vessels are crucial regulators of tumor perfusion, immune cell influx and metastatic dissemination. Indeed, vascular hyperpermeability is a key feature of primary tumors, the pre-metastatic niche in host tissue and overt metastases at secondary sites. Combining anti-angiogenesis and immune therapies may therefore unlock synergistic effects by inducing a stabilized vascular network permissive for effector T cell trafficking and function. However, anti-angiogenesis therapies, as currently applied, are hampered by intrinsic or adaptive resistance mechanisms at primary and distant tumor sites. In particular, heterogeneous vascular and immune environments which can arise in metastatic lesions of the same individual pose significant challenges for currently approved drugs. Thus, more consideration needs to be given to tailoring new combinations of vascular and immunotherapies, including dosage and timing regimens to specific disease microenvironments.

Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy., (Copyright © 2020 Brown, Richardson, Kabir, Trinder, Ganss and Leedman.)

Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the pre-metastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intra-metastatic blood vessels and increases GrzB + effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to anti-PD-1 checkpoint inhibitors. These findings demonstrate an important application for LIGHT-VTP therapy in preventing metastatic development as well as exerting anti-tumor effects in established metastases., Competing Interests: Declaration of Interests R.G. and A.J.-P. hold a patent related to this work., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tumour growth critically depends on a supportive microenvironment, including the tumour vasculature. Tumour blood vessels are structurally abnormal and functionally anergic which limits drug access and immune responses in solid cancers. Thus, tumour vasculature has been considered an attractive therapeutic target for decades. However, with time, anti-angiogenic therapy has evolved from destruction to structural and functional rehabilitation as understanding of tumour vascular biology became more refined. Vessel remodelling or normalisation strategies which alleviate hypoxia are now coming of age having been shown to have profound effects on the tumour microenvironment. This includes improved tumour perfusion, release from immune suppression and lower metastasis rates. Nevertheless, clinical translation has been slow due to challenges such as the transient nature of current normalisation strategies, limited in vivo monitoring and the heterogeneity of primary and/or metastatic tumour environments, calling for more tailored approaches to vascular remodelling. Despite these setbacks, harnessing vascular plasticity provides unique opportunities for anti-cancer combination therapies in particular anti-angiogenic immunotherapy which are yet to reach their full potential., Competing Interests: The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review., (© 2020 The authors.)

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

The density of intratumoral CD8 + T cells predicts patient survival and responsiveness to immunotherapy. Effector T cell infiltration in turn is controlled by the tumor vasculature which co-evolves together with an immune-suppressive environment. At the T cell-vascular interface, endothelial cells actively suppress T cell trafficking and function. Conversely, forced activation, normalization, and differentiation of tumor vessels into high endothelial venule entrance portals for lymphocytes can facilitate T cell extravasation. Emerging evidence demonstrates that this process is not exclusively controlled by the endothelium. Indeed, tumor vasculature and CD4 + and/or CD8 + T cells may regulate each other: increasing local effector T cell numbers or re-invigorating pre-existing T cells via immune checkpoint blockade can directly affect the vasculature. A deeper understanding of the orchestration and duration of this reciprocal relationship may help shape the design of future immunotherapies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Cellular-scale imaging of the mechanical properties of tissue has helped to reveal the origins of disease; however, cellular-scale resolution is not readily achievable in intact tissue volumes. Here, we demonstrate volumetric imaging of Young's modulus using ultrahigh-resolution optical coherence elastography, and apply it to characterizing the stiffness of mouse aortas. We achieve isotropic resolution of better than 15 μm over a 1-mm lateral field of view through the entire depth of an intact aortic wall. We employ a method of quasi-static compression elastography that measures volumetric axial strain and uses a compliant, transparent layer to measure surface axial stress. This combination is used to estimate Young's modulus throughout the volume. We demonstrate differentiation by stiffness of individual elastic lamellae and vascular smooth muscle. We observe stiffening of the aorta in regulator of G protein signaling 5-deficient mice, a model that is linked to vascular remodeling and fibrosis. We observe increased stiffness with proximity to the heart, as well as regions with micro-structural and micro-mechanical signatures characteristic of fibrous and lipid-rich tissue. High-resolution imaging of Young's modulus with optical coherence elastography may become an important tool in vascular biology and in other fields concerned with understanding the role of mechanics within the complex three-dimensional architecture of tissue., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

In this paper, we describe a technique capable of visualizing mechanical properties at the cellular scale deep in living tissue, by incorporating a gradient-index (GRIN)-lens micro-endoscope into an ultrahigh-resolution optical coherence elastography system. The optical system, after the endoscope, has a lateral resolution of 1.6 µ m and an axial resolution of 2.2 µ m. Bessel beam illumination and Gaussian mode detection are used to provide an extended depth-of-field of 80 µ m, which is a 4-fold improvement over a fully Gaussian beam case with the same lateral resolution. Using this system, we demonstrate quantitative elasticity imaging of a soft silicone phantom containing a stiff inclusion and a freshly excised malignant murine pancreatic tumor. We also demonstrate qualitative strain imaging below the tissue surface on in situ murine muscle. The approach we introduce here can provide high-quality extended-focus images through a micro-endoscope with potential to measure cellular-scale mechanics deep in tissue. We believe this tool is promising for studying biological processes and disease progression in vivo ., Competing Interests: BFK: OncoRes Medical (F,I), AC and DDS: OncoRes Medical (I). The other authors declare that there are no conflicts of interest related to this article.

T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8 + T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell-specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8 + T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature. Cancer Res; 77(16); 4434-47. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Current therapies for pregnancy-related hypertension and its complications remain inadequate, although an increasing role for maternal susceptibility is becoming evident. Systemic vascular dysfunction in response to imbalances in angiogenic, inflammatory, and constricting factors is implicated in the pathogenesis of gestational hypertension, and growing evidence now links these factors with maternal metabolism. In particular, the crucial role of peroxisome proliferator-activated receptors (PPARs) in maternal vascular adaptation provides further insights into how obesity and gestational diabetes may be linked to pregnancy-induced hypertension and preeclampsia. This is especially important given the rapidly growing prevalence of obesity during pregnancy, and highlights a new approach to treat pregnancy-related hypertension and its complications., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The use of hair ethyl glucuronide (EtG) levels as a biomarker for chronic high intake of ethanol (EtOH) is increasing, and misclassification of alcohol consumption may have large implications for the patient. The aim of this study was to compare levels of hair EtG in patients with reduced kidney function to levels seen in a comparable control group and to investigate whether the hair EtG levels among kidney failure patients who are social drinkers may lead to a false-positive diagnosis of heavy drinking., Methods: A total of 41 patients with reduced kidney function and 42 healthy volunteers were included in the study. Both patients and the healthy volunteers reported moderate alcohol intake. The levels of EtG in hair (corrected for estimated daily intake of EtOH [EDI]) were compared between the 2 groups., Results: There was no significant difference between the groups regarding EDI. Despite this, there were significant higher levels of hair EtG (corrected for EDI) in the patient group compared to the control group (p < 0.001). Eight subjects (20%) in the patient group showed EtG levels in hair above 30 pg/mg, in contrast to no subjects among healthy volunteers (p = 0.002). In the patient group, there was significant correlation between levels of EtG in hair and both estimated glomerulus filtration rate and serum creatinine levels., Conclusions: This study documents an increased risk of obtaining a false-positive diagnosis of heavy drinking among renal disease patients who are social drinkers. Interpretation of EtG levels in hair among patients with reduced kidney function must be performed with caution., (Copyright © 2016 by the Research Society on Alcoholism.)

Current clinical success with anti-cancer immunotherapy provides exciting new treatment opportunities. While encouraging, more needs to be done to induce durable effects in a higher proportion of patients. Increasing anti-tumor effector T cell quantity or quality alone does not necessarily correlate with therapeutic outcome. Instead, the tumor microenvironment is a critical determinant of anti-cancer responsiveness to immunotherapy and can confer profound resistance. Yet, the tumor-promoting environment - due to its enormous plasticity - also delivers the best opportunities for adjuvant therapy aiming at recruiting, priming and sustaining anti-tumor cytotoxicity. While the tumor environment as an entity is increasingly well understood, current interventions are still broad and often systemic. In contrast, tumors grow in a highly compartmentalized environment which includes the vascular/perivascular niche, extracellular matrix components and in some tumors lymph node aggregates; all of these structures harbor and instruct subsets of immune cells. Targeting and re-programming specific compartments may provide better opportunities for adjuvant immunotherapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Normalization of the tumor vasculature is an emerging concept shown to improve anti-cancer therapy. However, there are currently no clinical interventions that effect long-lasting normalization. Here, we have developed a strategy for normalization by specific intratumoral delivery of LIGHT/TNFSF14. Importantly, normalization occurs by induced expression of contractile markers in intratumoral pericytes, which in turn re-establishes tight pericyte-vessel alignment. Restoring vessel integrity improves tumor perfusion and acts as adjuvant to chemo- and immunotherapy. Mechanistically, intratumoral LIGHT induces pericyte differentiation and normalization via Rho kinase signaling. Minute amounts of LIGHT act in a paracrine fashion to trigger an amplifying cascade involving transforming growth factor β (TGF-β) from peri-vascular macrophages. That these effects can be reproduced by adoptive transfer of LIGHT-stimulated macrophages alone demonstrates their central role in regulating pericyte differentiation. Our findings highlight a crucial role of pericyte contractile properties in vascular normalization, effected by macrophage signaling, thus providing so far unexplored anti-cancer opportunities., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Liver progenitor cells (LPCs) are necessary for repair in chronic liver disease because the remaining hepatocytes cannot replicate. However, LPC numbers also correlate with disease severity and hepatocellular carcinoma risk. Thus, the progenitor cell response in diseased liver may be regulated to optimize liver regeneration and minimize the likelihood of tumorigenesis. How this is achieved is currently unknown. Human and mouse diseased liver contain two subpopulations of macrophages with different ontogenetic origins: prenatal yolk sac-derived Kupffer cells and peripheral blood monocyte-derived macrophages. We examined the individual role(s) of Kupffer cells and monocyte-derived macrophages in the induction of LPC proliferation using clodronate liposome deletion of Kupffer cells and adoptive transfer of monocytes, respectively, in the choline-deficient, ethionine-supplemented diet model of liver injury and regeneration. Clodronate liposome treatment reduced initial liver monocyte numbers together with the induction of injury and LPC proliferation. Adoptive transfer of monocytes increased the induction of liver injury, LPC proliferation, and tumor necrosis factor-α production., Conclusion: Kupffer cells control the initial accumulation of monocyte-derived macrophages. These infiltrating monocytes are in turn responsible for the induction of liver injury, the increase in tumor necrosis factor-α, and the subsequent proliferation of LPCs., (© 2015 by the American Association for the Study of Liver Diseases.)

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia., (Copyright © 2015, American Association for the Advancement of Science.)

The cardiovascular system including the heart and intricate network of arteries, veins, and capillaries is essential for normal organ homeostasis and tightly controlled by G protein-coupled receptor (GPCR) signaling cascades. Imbalances of these signaling systems can manifest in cardiovascular disease. There has been a recent surge in studies on modulators of GPCR activity, so-called regulator of G protein signaling (RGS) molecules, due to their potential as pharmacological targets. Among RGS proteins, RGS5 is prominently expressed in arterial vascular smooth muscle cells (vSMC) suggesting an important role in vascular function. Although apparently dispensable for embryonic development, RGS5 has now emerged as a crucial regulator of adaptive cardiovascular processes, including remodeling of the vascular wall under stress. RGS5 has been shown to regulate signaling pathways which shape vSMC differentiation, migration, contraction, as well as tissue inflammation and fibrosis. Indeed, studies in RGS5 mutant mice have confirmed a crucial and nonredundant role as regulator of cardiac function, blood pressure homeostasis, and adult neovascularization such as angiogenesis and arteriogenesis. In response to environmental cues, RGS5 is dynamically controlled at both mRNA and protein levels. This enables direct, precise, and rapid modulation of Gαq- and Gαi-coupled GPCR signaling which also integrates receptor tyrosine kinases (RTK) and Gαs/Gα12/13-mediated GPCR signal transduction. Although RGS5's endogenous role in a spatiotemporal context is still largely unknown, its prominence in vascular tissue makes it an important molecule to study and a prime candidate for therapeutic intervention., (© 2015 Elsevier Inc. All rights reserved.)

Stroma is an integral part of solid tumors and plays a key role in growth promotion and immune suppression. Most current therapies focus on destroying tumors and/or abnormal vasculature. However, evidence is emerging that anticancer efficacy improves with vessel normalization rather than destruction. Specific targeting of cytokines into tumors provides proof-of-concept that tumor stroma is dynamic and can be remodeled to increase drug access and alleviate immune suppression. Changing the inflammatory milieu 'opens' tumors for therapy and thus provides a license for destruction. This involves reprogramming of paracrine signaling networks between multiple stromal components to break the vicious cycle of angiogenesis and immune suppression. With active immunotherapy rapidly moving into the clinic, local cytokine delivery emerges as an attractive adjuvant., (Copyright © 2013 Elsevier Ltd. All rights reserved.)