scholarly journals Fluid shear stress coupled with narrow constrictions induce cell type-dependent morphological and molecular changes in circulating tumor cells

2019 ◽  
Author(s):  
Hamizah Ahmad Cognart ◽  
Jean-Louis Viovy ◽  
Catherine Villard
Keyword(s):  
Shear Stress ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Fluid Shear Stress ◽  
Dynamical Behavior ◽  
Metastatic Breast ◽  
Microfluidic Channels ◽  
Mechanical Stimuli ◽  
Fluid Shear ◽  
Mesenchymal Transition

AbstractCancer mortality mainly arises from metastases, due to cells that escape from a primary tumor, circulate in the blood as circulating tumor cells (CTCs), permeate across blood vessels and nest in distant organs. It is still unclear how CTCs overcome the harsh conditions of fluid shear stress and mechanical constraints within the microcirculation. Here, a model of the blood microcirculation was established through the fabrication of microfluidic channels comprising constrictions. Metastatic breast cancer cells of epithelial-like and mesenchymal-like phenotypes were flowed into the microfluidic device. These cells were visualized during circulation, analyzed for their dynamical behavior and retrieved post-circulation. γ-H2AX staining showed significant increase of DNA damage response in epithelial-like SK-BR-3 cells, while gene expression analysis of key regulators of epithelial-to-mesenchymal transition revealed significant increase of Twist2 relative expression in mesenchymal-like MDA-MB-231 cells post-circulation. This work documents first results of the changes at the cellular, subcellular and molecular scales induced by the two main mechanical stimuli arising from circulatory conditions.

scholarly journals Fluid Shear Stress Induces EMT of Circulating Tumor Cells via JNK Signaling in Favor of Their Survival during Hematogenous Dissemination

2020 ◽  
Vol 21 (21) ◽  
pp. 8115
Author(s):  
Ying Xin ◽  
Keming Li ◽  
Mo Yang ◽  
Youhua Tan
Keyword(s):  
Shear Stress ◽  
Shear Flow ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Tumor Metastasis ◽  
Fluid Shear Stress ◽  
Fluid Shear ◽  
Jnk Signaling ◽  
Hematogenous Dissemination

Tumor cells metastasize to distal organs mainly through hematogenous dissemination, where they experience considerable levels of fluid shear stress. Epithelial–mesenchymal transition (EMT) plays a critical role in tumor metastasis. However, how fluid shear stress influences the EMT phenotype of circulating tumor cells (CTCs) in suspension has not been fully understood. The role of shear-induced EMT in cell survival under blood shear flow remains unclear. This study shows that the majority of breast CTCs underwent apoptosis under shear flow and the surviving cells exhibited mesenchymal phenotype, suggesting that fluid shear stress induces EMT. Mechanistically, fluid shear stress-activated Jun N-terminal kinase (JNK) signaling, inhibition/activation of which suppressed/promoted the EMT phenotype. In particular, shear flow facilitated the JNK-dependent transition of epithelial CTCs into the mesenchymal status and maintained the pre-existing mesenchymal cells. Importantly, the induction of EMT suppressed the pro-apoptosis gene p53 upregulated modulator of apoptosis (PUMA) and enhanced the survival of suspended CTCs in fluid shear stress, which was rescued by overexpressing PUMA or silencing JNK signaling, suggesting that shear-induced EMT promotes CTC survival through PUMA downregulation and JNK activation. Further, the expressions of EMT markers and JUN were correlated with poor patient survival. In summary, our findings have demonstrated that fluid shear stress induces EMT in suspended CTCs via JNK signaling that promotes their survival in shear flow. This study thus unveils a new role of blood shear stress in CTC survival and facilitates the development of novel therapeutics against tumor metastasis.

scholarly journals Abstract 3152: RhoA-myosinII axis protects circulating tumor cells from fluid shear stress-induced damage

2018 ◽  
Author(s):  
Devon L. Moose ◽  
Ben L. Krog ◽  
Gretchen Burke ◽  
Lei Zhao ◽  
Lillian Rhodes ◽  
...  
Keyword(s):  
Shear Stress ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Fluid Shear Stress ◽  
Fluid Shear

scholarly journals Fluid shear stress induces epithelial-mesenchymal transition (EMT) in Hep-2 cells

Oncotarget ◽  
2016 ◽  
Vol 7 (22) ◽  
pp. 32876-32892 ◽  
Author(s):  
Shuangfeng Liu ◽  
Fating Zhou ◽  
Yang Shen ◽  
Yingying Zhang ◽  
Hongmei Yin ◽  
...  
Keyword(s):  
Shear Stress ◽  
Fluid Shear Stress ◽  
Epithelial Mesenchymal Transition ◽  
Fluid Shear ◽  
Mesenchymal Transition

scholarly journals Inflammation-Based Scores Increase the Prognostic Value of Circulating Tumor Cells in Primary Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1134 ◽  
Author(s):  
Svetlana Miklikova ◽  
Gabriel Minarik ◽  
Tatiana Sedlackova ◽  
Jana Plava ◽  
Marina Cihova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Mononuclear Cells ◽  
Complete Blood Count ◽  
Metastatic Breast ◽  
Disease Recurrence ◽  
Mesenchymal Transition ◽  
Lymphocyte Ratio ◽  
Increased Risk

A correlation between circulating tumor cells (CTCs) and monocytes in metastatic breast cancer (BC), where CTCs and monocyte-to-lymphocyte ratio (MLR) were predictors of overall survival (OS), was recently shown. Herein, we aimed to assess the association between CTCs and the complete blood count (CBC)-derived inflammation-based scores in 284 primary BC patients. CTCs were determined in CD45-depleted peripheral blood mononuclear cells by real time-PCR. This method allowed us to detect a subset of CTCs with an epithelial-to-mesenchymal transition phenotype (CTC EMT), previously associated with inferior outcomes in primary BC. In the present study, CTC EMT positivity (hazard ratio (HR) = 2.4; 95% CI 1.20–4.66, p = 0.013) and elevated neutrophil-to-lymphocyte ratio (NLR) (HR = 2.20; 95% CI 1.07–4.55; p = 0.033) were associated with shorter progression-free survival (PFS) in primary BC patients. Multivariate analysis showed that CTC EMT-positive patients with NLR ≥ 3 had 8.6 times increased risk of disease recurrence (95% CI 2.35–31.48, p = 0.001) compared with CTC EMT-negative patients with NLR < 3. Similarly, disease recurrence was 13.14 times more likely in CTC EMT-positive patients with MLR ≥ 0.34 (95% CI 4.35–39.67, p < 0.001). Given its low methodological and financial demands, the CBC-derived inflammation-based score determination could, after broader validation, significantly improve the prognostication of BC patients.

scholarly journals Expression of Stem Cell and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells of Breast Cancer Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Natalia Krawczyk ◽  
Franziska Meier-Stiegen ◽  
Malgorzata Banys ◽  
Hans Neubauer ◽  
Eugen Ruckhaeberle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Current Data ◽  
Stem Cell Markers ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

Evaluation and characterization of circulating tumor cells (CTCs) have become a major focus of translational cancer research. Presence of CTCs predicts worse clinical outcome in early and metastatic breast cancer. Whether all cells from the primary tumor have potential to disseminate and form subsequent metastasis remains unclear. As part of the metastatic cascade, tumor cells lose their cell-to-cell adhesion and undergo epithelial-mesenchymal transition (EMT) in order to enter blood circulation. During EMT epithelial antigens are downregulated; thus, such tumor cells might elude classical epithelial marker-based detection. Several researchers postulated that some CTCs express stem cell-like phenotype; this might lead to chemoresistance and enhanced metastatic potential of such cells. In the present review, we discuss current data on EMT and stem cell markers in CTCs of breast cancer and their clinical significance.

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