scholarly journals CD99 regulates cancer cell transendothelial migration and endothelial cell function via CDC42 and actin remodelling

2019 ◽  
Author(s):  
Aarren J. Mannion ◽  
Adam F. Odell ◽  
Alison Taylor ◽  
Pamela F. Jones ◽  
Graham P Cook
Keyword(s):  
Endothelial Cell ◽  
Cancer Cell ◽  
Tumour Cell ◽  
Xenograft Model ◽  
Transendothelial Migration ◽  
Tumour Cells ◽  
Cell Surface Receptor ◽  
Endothelial Barrier ◽  
Functional Link ◽  
Endothelial Cell Function

AbstractMetastasis requires tumour cells to cross endothelial cell (EC) barriers and this occurs using mechanisms similar to those used by extravasating leucocytes during inflammation. The cell surface receptor CD99 is expressed by leucocytes and EC and participates in inflammatory transendothelial migration (TEM). CD99 is also expressed by tumour cells and we have analysed its role in tumour progression and cancer cell TEM. In a xenograft model, CD99 expression inhibited the metastatic progression of human breast cancer. In vitro, tumour cell CD99 was required for adhesion to ECs. However, tumour cell CD99 inhibited the invasion of the endothelial barrier by breast and prostate cancer cells and TEM itself. Furthermore, tumour cell CD99 depletion was associated with cytoskeletal remodelling. Loss of EC CD99 enhanced endothelial barrier function and reduced tumour cell TEM. Mechanistically, CD99 loss enhanced the expression and activity of CDC42, a known cytoskeletal organiser. CDC42 positively regulates EC angiogenic activity and the enhanced CDC42 activity resulting from loss of EC CD99 increased angiogenesis. As a signal transduction hub, CDC42 activity impacts upon many of the hallmarks of cancer. The functional link between CD99 and CDC42 identified here implicates CD99 in regulating these diverse pathways by modulation of CDC42 activity.

scholarly journals Tumour cell CD99 regulates transendothelial migration via CDC42 and actin remodelling

2021 ◽  
Author(s):  
Aarren J. Mannion ◽  
Adam F. Odell ◽  
Alison Taylor ◽  
Pamela F. Jones ◽  
Graham P Cook
Keyword(s):  
Cell Migration ◽  
Tumour Cell ◽  
Rho Gtpase ◽  
Tumour Progression ◽  
Xenograft Model ◽  
Transendothelial Migration ◽  
Tumour Cells ◽  
Metastatic Progression ◽  
Migratory Activity ◽  
Actin Remodelling

Metastasis requires tumour cells to cross endothelial cell (EC) barriers using pathways similar to those used by leucocytes during inflammation. Cell surface CD99 is expressed by healthy leucocytes and EC and participates in inflammatory transendothelial migration (TEM). Tumour cells also express CD99 and we have analysed its role in tumour progression and cancer cell TEM. Tumour cell CD99 was required for adhesion to ECs, but inhibited invasion of the endothelial barrier and migratory activity. Furthermore, CD99 depletion in tumour cells caused redistribution of the actin cytoskeleton and increased activity of the Rho GTPase CDC42, known for its role in actin remodelling and cell migration. In a xenograft model of breast cancer, tumour cell CD99 expression inhibited metastatic progression and patient samples showed reduced expression of the CD99 gene in brain metastases compared to matched primary breast tumours. We conclude that CD99 negatively regulates CDC42 and cell migration. However, CD99 has both pro- and anti-tumour activity and our data suggests that this results in part from its functional linkage to CDC42 and the diverse signalling pathways downstream of this Rho GTPase.

scholarly journals Differences of the tumour cell glycocalyx affect binding of capsaicin-loaded chitosan nanocapsules

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lydia von Palubitzki ◽  
Yuanyuan Wang ◽  
Stefan Hoffmann ◽  
Sabine Vidal-y-Sy ◽  
Bernd Zobiak ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Tumour Cell ◽  
Mammalian Cells ◽  
Heparan Sulphate ◽  
Tumour Cells ◽  
Counterion Condensation ◽  
Sequencing Data ◽  
Binding Rate

AbstractThe glycocalyx regulates the interaction of mammalian cells with extracellular molecules, such as cytokines. However, it is unknown to which extend the glycocalyx of distinct cancer cells control the binding and uptake of nanoparticles. In the present study, exome sequencing data of cancer patients and analysis of distinct melanoma and bladder cancer cell lines suggested differences in cancer cell-exposed glycocalyx components such as heparan sulphate. Our data indicate that glycocalyx differences affected the binding of cationic chitosan nanocapsules (Chi-NCs). The pronounced glycocalyx of bladder cancer cells enhanced the internalisation of nanoencapsulated capsaicin. Consequently, capsaicin induced apoptosis in the cancer cells, but not in the less glycosylated benign urothelial cells. Moreover, we measured counterion condensation on highly negatively charged heparan sulphate chains. Counterion condensation triggered a cooperative binding of Chi-NCs, characterised by a weak binding rate at low Chi-NC doses and a strongly increased binding rate at high Chi-NC concentrations. Our results indicate that the glycocalyx of tumour cells controls the binding and biological activity of nanoparticles. This has to be considered for the design of tumour cell directed nanocarriers to improve the delivery of cytotoxic drugs. Differential nanoparticle binding may also be useful to discriminate tumour cells from healthy cells.

TNF-induced endothelial barrier disruption: beyond actin and Rho

2014 ◽  
Vol 112 (12) ◽  
pp. 1088-1102 ◽  
Author(s):  
Beatriz Marcos-Ramiro ◽  
Diego García-Weber ◽  
Jaime Millán
Keyword(s):  
Endothelial Cell ◽  
Barrier Function ◽  
Endothelial Permeability ◽  
Transendothelial Migration ◽  
Cell Junctions ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Adhesion Receptors ◽  
Barrier Disruption ◽  
Leukocyte Transendothelial Migration

SummaryThe decrease of endothelial barrier function is central to the long-term inflammatory response. A pathological alteration of the ability of endothelial cells to modulate the passage of cells and solutes across the vessel underlies the development of inflammatory diseases such as atherosclerosis and multiple sclerosis. The inflammatory cytokine tumour necrosis factor (TNF) mediates changes in the barrier properties of the endothelium. TNF activates different Rho GTPases, increases filamentous actin and remodels endothelial cell morphology. However, inhibition of actin-mediated remodelling is insufficient to prevent endothelial barrier disruption in response to TNF, suggesting that additional molecular mechanisms are involved. Here we discuss, first, the pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelial cell-cell junctions and, second, the ability of endothelial adhesion receptors such as ICAM-1, VCAM-1 and PECAM-1, involved in leukocyte transendothelial migration, to control endothelial permeability to small molecules, often through ROS generation. These adhesion receptors regulate endothelial barrier function in ways both dependent on and independent of their engagement by immune cells, and orchestrate the crosstalk between leukocyte transendothelial migration and endothelial permeability during inflammation.

Cancer Cell-Endothelial Reactions: The Microinjury Hypothesis and Localized thrombosis in the Formation of Micrometastases

1979 ◽  
Author(s):  
B. A. Warren
Keyword(s):  
Cancer Cell ◽  
Tumour Cell ◽  
Thrombus Formation ◽  
Blood Stream ◽  
Tumour Cells ◽  
Cell Junctions ◽  
Endothelial Lining ◽  
Initial Fixation ◽  
Injured Region ◽  
Circulating Tumour Cell

The two important cancer cell-endothelial reactions are the entrance of tumour cells into the blood stream and the exit of tumour cells from vessels, (i) In transplantable melanoma transplants in the hamster cheek poach, tumour cells were found to migrate activily througt the endothelial cell junctions and attenuated endothellunf “giant, capillaries” at the edge of the tumours as early as 3 days after transplantation, (ii) The outcome of multiple episodes of microembolism by tumour cell emboli is dependent, in part, upon the structure of the specific microcirculatory units involved, the state of their endothelial lining and the size and deformability of the tumour cell emboli themselves. The Kawaguchi-Nakamura microinjury hypothesis suggests that the waves of emboli reach a specific microcirculatory bed and result in damage at certain sites in the unit due to prolonged temporary blockage of flow through the unit. This depends upon the presence of tumour emboli of a certain size and stiffness. The damage of the unit causes localized thrombus formation-Subsequent flow over the damaged area brings fresh emboli into contact with the injured region which is then favourably altered for the attachment and initial fixation of the circulating tumour cell emboli. In experiments with Walker 256 carcinoma, mouse thymoma and Hela cells these tumour cells were found to attach more firmly to damaged vessel wall than to regions of intact endothelium.

Do DPP-4 inhibitors improve endothelial cell function?

2017 ◽  
Vol 01 (01) ◽  
Author(s):  
Hiroshi Nomoto ◽  
Hideaki Miyoshi ◽  
Akinobu Nakamura ◽  
Tatsuya Atsumi ◽  
Naoki Manda ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Endothelial Cell Function

CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/β -catenin Signaling

2020 ◽  
Vol 20 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Fang Peng ◽  
Chuansheng Yang ◽  
Yanan Kong ◽  
Xiaojia Huang ◽  
Yanyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Lung Metastasis ◽  
Xenograft Model ◽  
Breast Cancer Cell Lines ◽  
Cell Renewal ◽  
Cancer Stemness ◽  
Mesenchymal Transition ◽  
Potential Biomarker

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

Sign in / Sign up

Export Citation Format

Share Document