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 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 The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila

2019 ◽  
Author(s):  
Jean-Philippe Parvy ◽  
Yachuan Yu ◽  
Anna Dostalova ◽  
Shu Kondo ◽  
Alina Kurjan ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumour Necrosis Factor ◽  
Tumour Cell ◽  
Tumour Necrosis ◽  
Tumour Progression ◽  
Tumour Cells ◽  
Tumour Regression ◽  
Necrosis Factor

AbstractAntimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs’ capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

scholarly journals Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Antonietta Rosella Farina ◽  
Lucia Cappabianca ◽  
Michela Sebastiano ◽  
Veronica Zelli ◽  
Stefano Guadagni ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Tumour Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Protein Isoforms ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Cell Immortalization ◽  
Oncogene Activation ◽  
The Many

Abstract Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.

scholarly journals Novel functions for Rab GTPases in multiple aspects of tumour progression

2012 ◽  
Vol 40 (6) ◽  
pp. 1398-1403 ◽  
Author(s):  
Chiara Recchi ◽  
Miguel C. Seabra
Keyword(s):  
Drug Resistance ◽  
Cell Migration ◽  
Anticancer Drugs ◽  
Tumour Cell ◽  
Stromal Cells ◽  
Intracellular Trafficking ◽  
Tumour Progression ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Master Regulators

Rab GTPases are master regulators of intracellular trafficking and, in recent years, their role in the control of different aspects of tumour progression has emerged. In the present review, we show that Rab GTPases are disregulated in many cancers and have central roles in tumour cell migration, invasion, proliferation, communication with stromal cells and the development of drug resistance. As a consequence, Rab proteins may be novel potential candidates for the development of anticancer drugs and, in this context, the preliminary results obtained with an inhibitor of Rab function are also discussed.

scholarly journals Roles of Rho GTPases in leucocyte and leukaemia cell transendothelial migration

2013 ◽  
Vol 368 (1629) ◽  
pp. 20130013 ◽  
Author(s):  
Elvira Infante ◽  
Anne J. Ridley
Keyword(s):  
Cell Migration ◽  
Blood Vessels ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Immune Surveillance ◽  
Transendothelial Migration ◽  
Cell Entry ◽  
Leukaemia Cell ◽  
Multiple Points ◽  
Cytoskeletal Dynamics

Leucocytes migrate into and out of blood vessels at multiple points during their development and maturation, and during immune surveillance. In response to tissue damage and infection, they are rapidly recruited through the endothelium lining blood vessels into the tissues. Leukaemia cells also move in and out of the bloodstream during leukaemia progression. Rho GTPases are intracellular signalling proteins that regulate cytoskeletal dynamics and are key coordinators of cell migration. Here, we describe how different members of the Rho GTPase family act in leucocytes and leukaemia cells to regulate steps of transendothelial migration. We discuss how inhibitors of Rho signalling could be used to reduce leucocyte or leukaemia cell entry into tissues.

scholarly journals The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jean-Philippe Parvy ◽  
Yachuan Yu ◽  
Anna Dostalova ◽  
Shu Kondo ◽  
Alina Kurjan ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumour Necrosis Factor ◽  
Tumour Cell ◽  
Tumour Necrosis ◽  
Tumour Progression ◽  
Tumour Cells ◽  
Tumour Regression ◽  
Necrosis Factor

Antimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs’ capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals Long non-coding RNA ARHGAP5-AS1 inhibits migration of breast cancer cell via stabilizing SMAD7 protein

2021 ◽  
Author(s):  
Chen-Long Wang ◽  
Jing-Chi Li ◽  
Ci-Xiang Zhou ◽  
Cheng-Ning Ma ◽  
Di-Fei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Rho Gtpase ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Breast Cancer Cell Lines ◽  
Smad7 Protein

Abstract Purpose Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. Methods RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-β signaling. Results We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-β signaling pathway due to its inhibitory role on SMAD7. Conclusion ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future.

Tumour cell migration in adamantinomatous craniopharyngiomas is promoted by activated Wnt-signalling

2010 ◽  
Vol 119 (5) ◽  
pp. 631-639 ◽  
Author(s):  
Annett Hölsken ◽  
Michael Buchfelder ◽  
Rudolf Fahlbusch ◽  
Ingmar Blümcke ◽  
Rolf Buslei
Keyword(s):  
Cell Migration ◽  
Tumour Cell ◽  
Wnt Signalling
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