scholarly journals The Tumour Vasculature as a Target to Modulate Leucocyte Trafficking

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1724
Author(s):  
Yang Zhao ◽  
Ka Ka Ting ◽  
Paul Coleman ◽  
Yanfei Qi ◽  
Jinbiao Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transendothelial Migration ◽  
Tumour Microenvironment ◽  
Solid Tumours ◽  
Recruitment Process ◽  
Vascular Abnormalities ◽  
Tumour Vasculature ◽  
Underlying Mechanisms ◽  
Leucocyte Recruitment

The effectiveness of immunotherapy against solid tumours is dependent on the appropriate leucocyte subsets trafficking and accumulating in the tumour microenvironment (TME) with recruitment occurring at the endothelium. Such recruitment involves interactions between the leucocytes and the endothelial cells (ECs) of the vessel and occurs through a series of steps including leucocyte capture, their rolling, adhesion, and intraluminal crawling, and finally leucocyte transendothelial migration across the endothelium. The tumour vasculature can curb the trafficking of leucocytes through influencing each step of the leucocyte recruitment process, ultimately producing an immunoresistant microenvironment. Modulation of the tumour vasculature by strategies such as vascular normalisation have proven to be efficient in facilitating leucocyte trafficking into tumours and enhancing immunotherapy. In this review, we discuss the underlying mechanisms of abnormal tumour vasculature and its impact on leucocyte trafficking, and potential strategies for overcoming the tumour vascular abnormalities to boost immunotherapy via increasing leucocyte recruitment.

Oxygen and cancer

2019 ◽  
pp. 255-269
Author(s):  
Adrian L. Harris ◽  
Margaret Ashcroft
Keyword(s):  
Cellular Response ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Solid Tumours ◽  
Adaptive Responses ◽  
Tumour Vasculature ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Different Cell Types ◽  
The Impact

Oxygen is required for most multicellular, aerobic organisms to survive and function. The vasculature provides the conduit for delivering oxygen via haemoglobin in the blood to organs, tissues, and cells. In diseases such as cancer, low tissue oxygenation or hypoxia occurs in solid tumours because of an inadequate supply of oxygen due to aberrant tumour vasculature. Hypoxia is a key feature of most solid tumours and underlies many of the processes associated with how cancer progresses; including tumour cell survival and proliferation, genetic instability, immune responses, angiogenesis, invasion and metastasis, and metabolic adaptive responses. Solid tumours contain several different cell types that respond to hypoxia within the tumour microenvironment. Hypoxia-inducible factors (HIFs) are a highly evolutionarily conserved family of dimeric transcription factors that are central to mediating the cellular response to hypoxia by regulating the expression of a diverse array of targets. Hypoxia and HIF activation is associated with treatment failure, resistance, and poor clinical outcomes. This chapter will provide an overview of the role of hypoxia in cancer, outline the methods used to measure hypoxia clinically, and discuss the impact of hypoxia on current front-line therapies being used to treat cancer.

scholarly journals Homocysteine Induces Apoptosis of Human Umbilical Vein Endothelial Cells via Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Zhimin Zhang ◽  
Congying Wei ◽  
Yanfen Zhou ◽  
Tao Yan ◽  
Zhengqiang Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Umbilical Vein ◽  
Dependent Manner ◽  
Human Umbilical Vein ◽  
Homologous Protein ◽  
Intracellular Ros ◽  
Underlying Mechanisms ◽  
Umbilical Vein Endothelial Cells

Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-κb. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy-induced HUVEC apoptosis and the activation of NF-κb. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-κb.

scholarly journals Clostridial Spores for Cancer Therapy: Targeting Solid Tumour Microenvironment

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Brittany Umer ◽  
David Good ◽  
Jozef Anné ◽  
Wei Duan ◽  
Ming Q. Wei
Keyword(s):  
Cancer Therapy ◽  
Solid Tumour ◽  
Early Stage ◽  
Treatment Options ◽  
Anaerobic Bacteria ◽  
Past Research ◽  
Tumour Microenvironment ◽  
The Body ◽  
Solid Tumours ◽  
Current Status

Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it’s differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobicClostridiumhas shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumourin situ. Various strategies utilizingClostridiumare currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies.

The Rac activator Tiam1 controls efficient T-cell trafficking and route of transendothelial migration

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6138-6147 ◽  
Author(s):  
Audrey Gérard ◽  
Rob A. van der Kammen ◽  
Hans Janssen ◽  
Saskia I. Ellenbroek ◽  
John G. Collard
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Transendothelial Migration ◽  
Contact Hypersensitivity ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Cell Arrest

Abstract Migration toward chemoattractants is a hallmark of T-cell trafficking and is essential to produce an efficient immune response. Here, we have analyzed the function of the Rac activator Tiam1 in the control of T-cell trafficking and transendothelial migration. We found that Tiam1 is required for chemokine- and S1P-induced Rac activation and subsequent cell migration. As a result, Tiam1-deficient T cells show reduced chemotaxis in vitro, and impaired homing, egress, and contact hypersensitivity in vivo. Analysis of the T-cell transendothelial migration cascade revealed that PKCζ/Tiam1/Rac signaling is dispensable for T-cell arrest but is essential for the stabilization of polarization and efficient crawling of T cells on endothelial cells. T cells that lack Tiam1 predominantly transmigrate through individual endothelial cells (transcellular migration) rather than at endothelial junctions (paracellular migration), suggesting that T cells are able to change their route of transendothelial migration according to their polarization status and crawling capacity.

Abstract 74: The Inflammatory Phenotype Of Mesenchymal Fibroblasts And Its Role In Aging Dependent Cardiac Fibrosis- A Target For Statins?

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Katarzyna A Cieslik ◽  
JoAnn Trial ◽  
Mark L Entman
Keyword(s):  
Endothelial Cells ◽  
Myeloid Cell ◽  
Transendothelial Migration ◽  
Mouse Heart ◽  
Type I ◽  
Aged Mouse ◽  
Vitro Assay ◽  
Procollagen Type ◽  
Procollagen Type I ◽  
Inflammatory Phenotype

In the aging mouse (C57BL/6) myocardium fibrosis steadily increases after 14 months of age and is accompanied by elevated numbers of myeloid derived fibroblasts. Recently, we proposed a mechanism by which inflammatory mesenchymal fibroblasts (IMF) derived from mesenchymal stem cells secrete monocyte chemoattractant protein-1 (MCP-1) necessary for myeloid fibroblast induction in the aging heart. The current study extends the characterization of this inflammatory phenotype by describing elevated interleukin-6 (IL-6) secretion and increased expression of IL-6 receptor (IL-6R) in IMF. Since IL-6R lacks an intracellular domain it requires a co-receptor gp130 (generally expressed) to induce an intracellular signal. Thus, generation of an IL-6R soluble receptor allows IL-6 signaling on cells that do not express IL-6R (or expression is low), such as endothelial cells. We investigate the function of IL-6 and IL-6R in the promotion of transendothelial migration of monocytes through cardiac endothelium and their maturation into myeloid fibroblasts in in vitro assay. Treatments with IL-6 and more extensively IL-6+IL-6R resulted in a 3-5 fold increase (above the control level) in myeloid cell migration and maturation into myeloid fibroblasts. Thus IMF can contribute both IL-6 and IL-6R to endothelial cells and facilitate myeloid cell transendothelial migration. In agreement with these data, analysis of the aged mouse heart revealed the presence of fibroblasts expressing IL-6 (procollagen type I + IL-6 + cells), M1 macrophages (CD86 + cells) and M2 macrophages (CD301 + procollagen type I + cells) that were absent in hearts from young mice. The mechanisms by which expression of these factors is upregulated in IMF are being investigated; our data suggest that MCP-1 and IL-6 expression are controlled by the farnesyltransferase (FTase)-Ras-Erk1/2 pathway. Interestingly, since atorvastatin interferes with farnesyl synthesis it also reduced MCP-1 and IL-6 expression in IMF. These data may introduce a new use of this class of drugs in the prevention of the age-related fibrosis.

Targeting Microenvironment of Melanoma and Head and Neck Cancers in Photodynamic Therapy

2021 ◽  
Vol 28 ◽  
Author(s):  
Ivana Ratkaj ◽  
Martina Mušković ◽  
Nela Malatesti
Keyword(s):  
Photodynamic Therapy ◽  
Head And Neck ◽  
Tumour Progression ◽  
Neck Region ◽  
Angiogenesis Inhibitors ◽  
Tumour Microenvironment ◽  
Head And Neck Cancers ◽  
Skin Cancers ◽  
Tumour Vasculature ◽  
Optimal Drug

Background: Photodynamic therapy (PDT), in comparison to other skin cancers, is still far less effective for melanoma, due to the strong absorbance and the role of melanin in cytoprotection. The tumour microenvironment (TME) has a significant role in tumour progression, and the hypoxic TME is one of the main reasons for melanoma progression to metastasis and its resistance to PDT. Hypoxia is also a feature of solid tumours in the head and neck region that indicates a negative prognosis. Objective: The aim of this study was to individuate and describe systematically the main strategiesthe main strategies systematically in targeting the TME, especially hypoxia, in PDT against melanoma and head and neck cancers (HNC), and assess the current success in their application. Methods: PubMed, was used for searching, in MEDLINE and other databases were used for searching, for the most recent publications on PDT against melanoma and HNC in combination with the TME targeting and hypoxia. Results: In PDT for melanoma and HNC, it is very important to control hypoxia levels, and, amongst the different approaches, oxygen self-supply systems are often applied. Vascular targeting is promising, but to improve it, optimal drug-light interval, and formulation to increase the accumulation of the photosensitiser in the tumour vasculature, have to be established. On the other side, the use of angiogenesis inhibitors, such as those interfering with VEGF signalling are somewhat less successful than expected and need to be further investigated. Conclusion: Combination The combination of PDT with immunotherapy by using multifunctional nanoparticles continues to develop and seems to be the most promising for achieving a complete and lasting antitumour effect.

scholarly journals Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation

2019 ◽  
Author(s):  
Miguel O. Bernabeu ◽  
Jakub Köry ◽  
James A. Grogan ◽  
Bostjan Markelc ◽  
Albert Beardo ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Tissue Oxygenation ◽  
Solid Tumours ◽  
Tumour Tissue ◽  
Limiting Factor ◽  
Antiangiogenic Agents ◽  
Vascular Structure ◽  
Vascular Networks ◽  
Tumour Vasculature ◽  
Proxy Measure

AbstractOxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumour, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that RBC transport plays in establishing oxygen heterogeneity in tumour tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculate average vessel lengths and diameters from tumour allografts of three cancer cell lines and observe a substantial reduction in the ratio compared to physiological conditions. Mathematical modelling reveals that small values of the ratio λ (i.e. λ < 6) can bias haematocrit distribution in tumour vascular networks and drive heterogeneous oxygenation of tumour tissue. Finally, we show an increase in the value of λ in tumour vascular networks following treatment with the anti-angiogenic cancer agent DC101. Based on our findings, we propose λ as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumour tissue undergoing anti-angiogenic treatment.Significance statementOxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal tumour vascular structure. We investigate the role that anomalies in RBC transport play in establishing oxygen heterogeneity in tumour tissue. We introduce a metric to characterise tumour vasculature (mean vessel length-to-diameter ratio, λ) and demonstrate how it predicts tissue oxygen heterogeneity. We also report an increase in λ following treatment with the antiangiogenic agent DC101. Together, we propose λ as an effective way of monitoring the action of anti-angiogenic agents and a proxy measure of oxygen heterogeneity in tumour tissue. Unravelling the causal relationship between tumour vascular structure and tissue oxygenation will pave the way for new personalised therapeutic approaches.

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