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.

scholarly journals Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation

2020 ◽  
Vol 117 (45) ◽  
pp. 27811-27819 ◽  
Author(s):  
Miguel O. Bernabeu ◽  
Jakub Köry ◽  
James A. Grogan ◽  
Bostjan Markelc ◽  
Albert Beardo ◽  
...  
Keyword(s):  
Network Effects ◽  
Tumor Tissue ◽  
Transport Theory ◽  
Substantial Reduction ◽  
Limiting Factor ◽  
Antiangiogenic Agents ◽  
Vascular Networks ◽  
Antiangiogenic Treatment ◽  
Proxy Measure ◽  
Cancer Agent

Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumor, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that red blood cell (RBC) transport plays in establishing oxygen heterogeneity in tumor 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 calculated average vessel lengthsL¯and diametersd¯from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratioλ=L¯/d¯compared to physiological conditions. Mathematical modeling reveals that small values of the ratio λ (i.e.,λ<6) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of λ in tumor vascular networks following treatment with the antiangiogenic 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 tumor tissue undergoing antiangiogenic treatment.

Is oxygen supply a limiting factor for survival during rewarming from profound hypothermia?

2006 ◽  
Vol 291 (1) ◽  
pp. H441-H450 ◽  
Author(s):  
Timofei V. Kondratiev ◽  
Kristina Flemming ◽  
Eivind S. P. Myhre ◽  
Mikhail A. Sovershaev ◽  
Torkjel Tveita
Keyword(s):  
Blood Volume ◽  
Tissue Oxygenation ◽  
Limiting Factor ◽  
Myocardial Tissue ◽  
Circulating Blood Volume ◽  
Profound Hypothermia ◽  
Group 3 ◽  
Vascular Beds ◽  
Group 2 ◽  
Group 1

It has been postulated that unsuccessful resuscitation of victims of accidental hypothermia is caused by insufficient tissue oxygenation. The aim of this study was to test whether inadequate O2supply and/or malfunctioning O2extraction occur during rewarming from deep/profound hypothermia of different duration. Three groups of rats ( n = 7 each) were used: group 1 served as normothermic control for 5 h; groups 2 and 3 were core cooled to 15°C, kept at 15°C for 1 and 5 h, respectively, and then rewarmed. In both hypothermic groups, cardiac output (CO) decreased spontaneously by >50% in response to cooling. O2consumption fell to less than one-third during cooling but recovered completely in both groups during rewarming. During hypothermia, circulating blood volume in both groups was reduced to approximately one-third of baseline, indicating that some vascular beds were critically perfused during hypothermia. CO recovered completely in animals rewarmed after 1 h ( group 2) but recovered to only 60% in those rewarmed after 5 h ( group 3), whereas blood volume increased to approximately three-fourths of baseline in both groups. Metabolic acidosis was observed only after 5 h of hypothermia (15°C). A significant increase in myocardial tissue heat shock protein 70 after rewarming in group 3, but not in group 2, indicates an association with the duration of hypothermia. Thus mechanisms facilitating O2extraction function well during deep/profound hypothermia, and, despite low CO, O2supply was not a limiting factor for survival in the present experiments.

Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications

2016 ◽  
Vol 397 (12) ◽  
pp. 1217-1222 ◽  
Author(s):  
Dorinne Desposito ◽  
Ludovic Waeckel ◽  
Louis Potier ◽  
Christine Richer ◽  
Ronan Roussel ◽  
...  
Keyword(s):  
Ace Inhibitors ◽  
Therapeutic Efficacy ◽  
Organ Damage ◽  
Clinical Development ◽  
Limiting Factor ◽  
Therapeutic Implications ◽  
Kinin Receptors ◽  
Pharmacological Studies ◽  
Kinin Receptor ◽  
Primary Activation

Abstract Genetic and pharmacological studies, clinical and experimental, focused on kallikrein-K1, kinin receptors and ACE/kininase II suggest that kinin release in the settings of ischemia or diabetes reduces organ damage, especially in the heart and kidney. Kinin bioavailability may be a limiting factor for efficacy of current kinin-potentiating drugs, like ACE inhibitors. Primary activation of kinin receptors by prototypic pharmacological agonists, peptidase-resistant, selective B1 or B2, displays therapeutic efficacy in experimental cardiac and peripheral ischemic and diabetic diseases. B1R agonism was especially efficient in diabetic animals and had no unwanted effects. Clinical development of kinin receptor agonists may be warranted.

scholarly journals Assessing the Concordance of Genomic Alterations between Circulating-Free DNA and Tumour Tissue in Cancer Patients

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1938 ◽  
Author(s):  
Leila Jahangiri ◽  
Tara Hurst
Keyword(s):  
Clonal Evolution ◽  
Solid Tumours ◽  
Tumour Tissue ◽  
Genomic Alterations ◽  
Circulating Free Dna ◽  
Free Dna ◽  
Longitudinal Tracking ◽  
Invasive Method ◽  
Somatic Alterations ◽  
Laboratory Tool

Somatic alterations to the genomes of solid tumours, which in some cases represent actionable drivers, provide diagnostic and prognostic insight into these complex diseases. Spatial and longitudinal tracking of somatic genomic alterations (SGAs) in patient tumours has emerged as a new avenue of investigation, not only as a disease monitoring strategy, but also to improve our understanding of heterogeneity and clonal evolution from diagnosis through disease progression. Furthermore, analysis of circulating-free DNA (cfDNA) in the so-called “liquid biopsy” has emerged as a non-invasive method to identify genomic information to inform targeted therapy and may also capture the heterogeneity of the primary and metastatic tumours. Considering the potential of cfDNA analysis as a translational laboratory tool in clinical practice, establishing the extent to which cfDNA represents the SGAs of tumours, particularly actionable driver alterations, becomes a matter of importance, warranting standardisation of methods and practices. Here, we assess the utilisation of cfDNA for molecular profiling of SGAs in tumour tissue across a broad range of solid tumours. Moreover, we examine the underlying factors contributing to discordance of detected SGAs between cfDNA and tumour tissue.

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.

BW12C perturbs normal and tumour tissue oxygenation and blood flow in man

1994 ◽  
Vol 32 (3) ◽  
pp. 210-217 ◽  
Author(s):  
S.J. Falk ◽  
J.R. Ramsay ◽  
R. Ward ◽  
K. Miles ◽  
A.K. Dixon ◽  
...  
Keyword(s):  
Blood Flow ◽  
Tissue Oxygenation ◽  
Tumour Tissue

scholarly journals PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Lavinia Morosi ◽  
Marina Meroni ◽  
Paolo Ubezio ◽  
Ilaria Fuso Nerini ◽  
Lucia Minoli ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Anticancer Drugs ◽  
Therapeutic Efficacy ◽  
Lymphatic Vessels ◽  
Tumour Microenvironment ◽  
Tumour Tissue ◽  
Tissue Architecture ◽  
Tumour Model ◽  
Pre Treatment ◽  
Recombinant Human Hyaluronidase

Abstract Background Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs. Methods We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry. Results Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model. Conclusion Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.

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