Chemotherapy Impedes In Vitro Microcirculation and Promotes Migration of Leukemic Cells with Impact on Metastasis

Prathivadhi-Bhayankaram, Sruti; Ning, Jianhao; Mimlitz, Michael; Taylor, Craig; Gross, Erin M.; Nichols, Michael G.; Guck, Jochen; Ekpenyong, Andrew

doi:10.1016/j.bpj.2016.11.691

Cited by 5 publications

(6 citation statements)

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“…We also mimicked treatment conditions by treating sRBC of patients with hydroxyurea (HU), an FDA-approved drug whose clinical benefit varies between patients and whose mode mechanism of action in the case of SCD is not completely understood [25], [30]. Detailed descriptions of the MMM can be found in previous work where it has been used to study various cell types in health and diseases including macrophages [5], neutrophils [6], [7], leukemia cells [8], mesenchymal stromal cells [9]. Briefly, following conceptualization, AutoCAD software was used to design three variants of the MMM: one without constrictions (constant width of 15μm) and the others with 5 and 7μm as the smallest constriction widths (maximum width 15μm).…”

Section: Microfluidic Microcirculation Mimeticmentioning

confidence: 99%

Microfluidic Microcirculation Mimetic as a Tool for the Study of Rheological Characteristics of Red Cells in Patients With Sickle Cell Anaemia

Asuquo¹,

Effa²,

Gbotosho³

et al. 2022

Preprint

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Sickle cell disorder (SCD) is a multisystem disease with heterogeneous phenotypes. Although all patients have the mutated haemoglobin (Hb) in the SS phenotype, the severity and frequency of complications are variable. When exposed to low oxygen tension, the Hb molecule becomes dense and, forms tactoids which, lead to the peculiar sickled shapes of the affected red blood cells, giving the disorder its name. This sickle cell morphology is responsible for the profound and widespread pathologies associated with this disorder, such as vaso-occlusive crisis, (VOC). How much of the clinical manifestation is due to sickled erythrocytes and what is due to the relative contributions of other elements in the blood, especially in the microcapillary circulation, is usually not visualized and quantified for each patient during clinical management. Here, we used a microfluidic microcirculation mimetic (MMM) which has 187 capillary-like constrictions to impose deformations on erythrocytes of SCD patients, visualizing and characterizing the morpho-rheological properties of the cells in normoxic, hypoxic (using of sodium meta-bisulfite) and in treatment conditions (using hydroxyurea). The MMM enabled a patient-specific quantification of shape descriptors (circularity and roundness) and transit time through the capillary constrictions, which are readouts for morphorheological properties implicated in VOC. Our results demonstrate the feasibility of microfluidics-based monitoring of individual patients for personalized care in the context of SCD complications such as VOC, even in re-source-challenged settings.

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Section: Microfluidic Microcirculation Mimeticmentioning

confidence: 99%

Microfluidic Microcirculation Mimetic as a Tool for the Study of Rheological Characteristics of Red Cells in Patients With Sickle Cell Anaemia

Asuquo¹,

Effa²,

Gbotosho³

et al. 2022

Preprint

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“…However, no differences were observed between cKO P2 and WT neutrophils under any of the conditions tested (supplemental Figure 2B). Likewise, a microcapillary microcirculation mimetic (MMM) assay 42,43 using peritonitis neutrophils showed no difference in their ability to passively navigate through multiple constrictions at high speed (supplemental Figure 2C). Taken together, these assays strongly suggest that loss of PHD2 does not affect neutrophil deformability under externally applied stress without confinement.…”

Section: Phd2-deficient Neutrophils Display Enhanced Non-directed Motmentioning

confidence: 99%

HIF2α is a direct regulator of neutrophil motility

Sormendi

Deygas

Sinha

et al. 2021

Blood

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Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2α) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2α-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes.

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“…neoplastic states are frequently characterized by hypoxic conditions, tumour‐associated microenvironments might utilize the same mechanisms to recruit circulating cancer cells to O 2 ‐deprived niches, thereby potentially providing a sanctuary to facilitate the development of drug resistance and disease relapse 83,84 . Intriguingly, the chemotactic migration of leukemic cancer cells was significantly enhanced when treated with doxorubicin and daunorubicin in a microfluidic microcirculation mimetic device 85 . Overall, the concept of O 2 gradient‐directed migration is highly relevant from a clinical and translational standpoint as current strategies to decrease tumour vascularity augment tumour hypoxia with the associated risk of promoting tumour cell survival.…”

Section: Pathophysiological Effects Of Oxygen Gradientsmentioning

confidence: 99%

Engineering Tools for Regulating Hypoxia in Tumour Models

Kim

Green

Lin

et al. 2021

J Cellular Molecular Medi

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Major advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain incurable due to the development of drug resistance, minimal residual disease (MRD) and disease relapse, highlighting an incomplete understanding of the mechanisms underlying these processes. In recent years, the impact of non‐genetic factors on neoplastic transformations has increasingly been acknowledged, and growing evidence suggests that low oxygen (O2) levels (ie hypoxia) in the tumour microenvironment play a critical role in the development and treatment of cancer. As a result, there is a growing need to develop research tools capable of reproducing physiologically relevant O2 conditions encountered by cancer cells in their natural environments in order to gain in‐depth insight into tumour cell metabolism and function. In this review, the authors highlight the importance of hypoxia in the pathogenesis of malignant diseases and provide an overview of novel engineering tools that have the potential to further drive this evolving, yet technically challenging, field of cancer research.

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Chemotherapy Impedes In Vitro Microcirculation and Promotes Migration of Leukemic Cells with Impact on Metastasis

Cited by 5 publications

References 0 publications

Microfluidic Microcirculation Mimetic as a Tool for the Study of Rheological Characteristics of Red Cells in Patients With Sickle Cell Anaemia

Microfluidic Microcirculation Mimetic as a Tool for the Study of Rheological Characteristics of Red Cells in Patients With Sickle Cell Anaemia

HIF2α is a direct regulator of neutrophil motility

Engineering Tools for Regulating Hypoxia in Tumour Models

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