scholarly journals High blood flow shear stress values are associated with circulating tumor cells cluster disaggregation in a multi-channel microfluidic device

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245536
Author(s):  
Alessandra Marrella ◽  
Arianna Fedi ◽  
Gabriele Varani ◽  
Ivan Vaccari ◽  
Marco Fato ◽  
...  
Keyword(s):  
Blood Flow ◽  
Shear Stress ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Microfluidic Device ◽  
Single Cells ◽  
Biological Significance ◽  
Circulatory System ◽  
Cfd Modeling

Metastasis represents a dynamic succession of events involving tumor cells which disseminate through the organism via the bloodstream. Circulating tumor cells (CTCs) can flow the bloodstream as single cells or as multicellular aggregates (clusters), which present a different potential to metastasize. The effects of the bloodstream-related physical constraints, such as hemodynamic wall shear stress (WSS), on CTC clusters are still unclear. Therefore, we developed, upon theoretical and CFD modeling, a new multichannel microfluidic device able to simultaneously reproduce different WSS characterizing the human circulatory system, where to analyze the correlation between SS and CTC clusters behavior. Three physiological WSS levels (i.e. 2, 5, 20 dyn/cm2) were generated, reproducing values typical of capillaries, veins and arteries. As first validation, triple-negative breast cancer cells (MDA-MB-231) were injected as single CTCs showing that higher values of WSS are correlated with a decreased viability. Next, the SS-mediated disaggregation of CTC clusters was computationally investigated in a vessels-mimicking domain. Finally, CTC clusters were injected within the three different circuits and subjected to the three different WSS, revealing that increasing WSS levels are associated with a raising clusters disaggregation after 6 hours of circulation. These results suggest that our device may represent a valid in vitro tool to carry out systematic studies on the biological significance of blood flow mechanical forces and eventually to promote new strategies for anticancer therapy.

scholarly journals Relevance of Circulating Tumor Cells as Predictive Markers for Cancer Incidence and Relapse

2022 ◽  
Vol 15 (1) ◽  
pp. 75
Author(s):  
Chaithanya Chelakkot ◽  
Hobin Yang ◽  
Young Kee Shin
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Progression ◽  
Cancer Incidence ◽  
Single Cells ◽  
Circulatory System ◽  
Predictive Marker ◽  
Response To Therapy ◽  
Cancer Prognosis ◽  
Novel Technologies

Shedding of cancer cells from the primary site or undetectable bone marrow region into the circulatory system, resulting in clinically overt metastasis or dissemination, is the hallmark of unfavorable invasive cancers. The shed cells remain in circulation until they extravasate to form a secondary metastatic lesion or undergo anoikis. The circulating tumor cells (CTCs) found as single cells or clusters carry a plethora of information, are acknowledged as potential biomarkers for predicting cancer prognosis and cancer progression, and are supposed to play key roles in determining tailored therapies for advanced diseases. With the advent of novel technologies that allow the precise isolation of CTCs, more and more clinical trials are focusing on the prognostic and predictive potential of CTCs. In this review, we summarize the role of CTCs as a predictive marker for cancer incidence, relapse, and response to therapy.

scholarly journals Circulating Tumor Cells: Technologies and Their Clinical Potential in Cancer Metastasis

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1111
Author(s):  
Jerry Xiao ◽  
Paula R. Pohlmann ◽  
Claudine Isaacs ◽  
Benjamin A. Weinberg ◽  
Aiwu R. He ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Single Cells ◽  
Circulatory System ◽  
Clinical Importance ◽  
Progression Free Survival ◽  
Primary Tumors ◽  
Isolation Techniques

Circulating tumor cells (CTCs) are single cells or clusters of cells within the circulatory system of a cancer patient. While most CTCs will perish, a small proportion will proceed to colonize the metastatic niche. The clinical importance of CTCs was reaffirmed by the 2008 FDA approval of CellSearch®, a platform that could extract EpCAM-positive, CD45-negative cells from whole blood samples. Many further studies have demonstrated the presence of CTCs to stratify patients based on overall and progression-free survival, among other clinical indices. Given their unique role in metastasis, CTCs could also offer a glimpse into the genetic drivers of metastasis. Investigation of CTCs has already led to groundbreaking discoveries such as receptor switching between primary tumors and metastatic nodules in breast cancer, which could greatly affect disease management, as well as CTC-immune cell interactions that enhance colonization. In this review, we will highlight the growing variety of isolation techniques for investigating CTCs. Next, we will provide clinically relevant context for CTCs, discussing key clinical trials involving CTCs. Finally, we will provide insight into the future of CTC studies and some questions that CTCs are primed to answer.

scholarly journals A Hydrodynamic Approach To Cancer

2015 ◽  
Author(s):  
Alexander Pinkowski ◽  
Walter Lilienblum
Keyword(s):  
Mass Transfer ◽  
Blood Flow ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Apparent Viscosity ◽  
Food Supply ◽  
Circulatory System ◽  
Nutrient Supply ◽  
Hydrodynamic Approach

Abstract This is the pre-print version of a paper submitted to Technische Mechanik (ISSN 0232-3869) Hydrodynamic analysis suggests that the injection of drag-reducing agents (DRA) in nanomolar concentrations may hinder metastasizing of circulating tumor cells and serve this way as a complementary post-operative treatment for cancer patients. Our conclusion is based on the following considerations: - Tumor cells need an extra nutrient supply in order to survive and grow. - The attachment of circulating tumor cells therefore tends to occur at sites in the human circulatory system characterized by localized turbulence, which enhances the mass transfer of nutrients, e.g., at sites of vessel branching and bending with plasma skimming. - Also obstacles to blood flow, such as plaques (atherosclerosis), tumors, and red blood cell (RBC) rouleaux, produce local vortices that increase mass transfer, i.e., food supply. - DRA have the ability to smooth (laminarise) localized turbulence in the circulatory system and to reduce mass transfer. - Depriving tumor cells of their required nutrient levels will reduce the probability of creating metastatic tumors, and may lead to their starvation-induced death. In the first part of our essay we demonstrate how flow constrictions decrease mean blood flow velocity, wall shear rates, and Reynolds numbers respectively, and increase the friction factor. Experimentally derived apparent viscosity data from literature will be used to determine the probability of RBC rouleaux formation. This is of importance since RBC rouleaux are typically associated with turbulent blood flow patterns. An increase in apparent viscosity at low flow rates will be attributed to the formation of RBC rouleaux. In part two we discuss the application of the Lockhart/Martinelli method to determine the pressure drop in blood vessels. The objective is to determine a mass transfer coefficient characterizing the mass transfer between the center and the wall of both healthy and cancerous blood vessels. This coefficient indicates the nutrient supply available to tumor cells under different flow conditions and shows the effect of DRA. Our hydrodynamic approach contrasts with previous studies of the possible benefits of DRA injection, which were focused on improving blood supply. We emphasize the reduction of the mass transfer rate as a tool to withhold turbulence induced supplementary food supply to tumor cells. Due to the possibility of unexpected side effects when using DRA (including their mechanical degradation products) animal models are indispensable before clinical trials.

scholarly journals Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gautier Follain ◽  
Naël Osmani ◽  
Valentin Gensbittel ◽  
Nandini Asokan ◽  
Annabel Larnicol ◽  
...  
Keyword(s):  
Blood Flow ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Metastatic Progression ◽  
Metastatic Dissemination ◽  
Secondary Tumors ◽  
Flow Profiles ◽  
Endothelial Response ◽  
Life Threatening

AbstractTumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.

scholarly journals Mitotic arrest affects clustering of tumor cells

2021 ◽  
Author(s):  
Julia Bonnet ◽  
Lise Rigal ◽  
Odile Mondesert ◽  
Renaud Morin ◽  
Gaelle Corsaut ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Cell ◽  
Cell Aggregation ◽  
Metastatic Potential ◽  
Mitotic Arrest ◽  
Chemotherapeutic Agents ◽  
The Impact ◽  
Mcf 7

Abstract Background Cancer cell aggregation is a key process involved in the formation of tumor cell clusters. It has recently been shown that clusters of circulating tumor cells (CTCs) have an increased metastatic potential compared to isolated circulating tumor cells. Several widely used chemotherapeutic agents that target the cytoskeleton microtubules and cause cell cycle arrest at mitosis have been reported to modulate CTC number or the size of CTC clusters. Results In this study, we investigated in vitro the impact of mitotic arrest on the ability of breast tumor cells to form clusters. By using live imaging and quantitative image analysis, we found that MCF-7 cancer cell aggregation is compromised upon incubation with paclitaxel or vinorelbine, two chemotherapeutic drugs that target microtubules. In line with these results, we observed that MCF-7 breast cancer cells experimentally synchronized and blocked in metaphase aggregated poorly and formed loose clusters. To monitor clustering at the single-cell scale, we next developed and validated an in vitro assay based on live video-microscopy and custom-designed micro-devices. The study of cluster formation from MCF-7 cells that express the fluorescent marker LifeAct-mCherry using this new assay allowed showing that substrate anchorage-independent clustering of MCF-7 cells was associated with the formation of actin-dependent highly dynamic cell protrusions. Metaphase-synchronized and blocked cells did not display such protrusions, and formed very loose clusters that failed to compact. Conclusions Altogether, our results suggest that mitotic arrest induced by microtubule-targeting anticancer drugs prevents cancer cell clustering and therefore, could reduce the metastatic potential of circulating tumor cells.

Sign in / Sign up

Export Citation Format

Share Document