scholarly journals Rho GTPase signalling networks in cancer cell transendothelial migration

2021 ◽  
Author(s):  
Wessel Rodenburg ◽  
Jaap van Buul
Keyword(s):  
Endothelial Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Point Of View ◽  
Endothelial Barrier Function ◽  
Metastatic Cascade ◽  
Essential Step ◽  
Cytoskeleton Dynamics

Extravasation, the process by which tumor cells leave the circulation by transmigrating through the endothelium that lines blood vessel walls, is an essential step for metastasis towards distant organs. As such, reducing extravasation of cancer cells is a potential approach to inhibit metastasis. Rho GTPases are small signalling G-proteins that are central regulators of cytoskeleton dynamics, and thereby mediate several steps of the metastatic cascade, including invasion, migration, and extravasation of cancer cells. Additionally, RhoGTPase signalling networks regulate cancer cell-endothelial cell interactions and are involved in the disruption of the endothelial barrier function, allowing cancer cells to extravasate the underlying tissue. Thus, targeting Rho GTPase signalling networks may be an effective approach to inhibit extravasation and metastasis. In this review, the roles and regulation of Rho GTPase signalling networks in cancer cell extravasation will be discussed, both from a cancer cell and endothelial cell point of view.

scholarly journals The RhoA dependent anti-metastatic function of RKIP in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gardiyawasam Kalpana ◽  
Christopher Figy ◽  
Jingwei Feng ◽  
Claire Tipton ◽  
Julius N. De Castro ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Invasion ◽  
Rho Gtpases ◽  
Kinase Inhibitor ◽  
Cell Movement ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Cancer Cell Invasion ◽  
Invasion And Metastasis ◽  
Cytoskeleton Dynamics

AbstractRaf-1 kinase inhibitor protein was initially discovered as a physiological kinase inhibitor of the MAPK signaling pathway and was later shown to suppress cancer cell invasion and metastasis. Yet, the molecular mechanism through which RKIP executes its effects is not completely defined. RhoA has both a pro- and anti-metastatic cell-context dependent functions. Given that Rho GTPases primarily function on actin cytoskeleton dynamics and cell movement regulation, it is possible that one way RKIP hinders cancer cell invasion/metastasis is by targeting these proteins. Here we show that RKIP inhibits cancer cell invasion and metastasis by stimulating RhoA anti-tumorigenic functions. Mechanistically, RKIP activates RhoA in an Erk2 and GEF-H1 dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression.

Development of a novel method for the bioanalysis of benfotiamine and sulbutiamine in cancer cells

2016 ◽  
Vol 8 (28) ◽  
pp. 5596-5603 ◽  
Author(s):  
Jaeah Kim ◽  
Christopher P. Hopper ◽  
Kelsey H. Connell ◽  
Parisa Darkhal ◽  
Jason A. Zastre ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Biological Samples ◽  
Cancer Cell Proliferation ◽  
Essential Step ◽  
Novel Method

Quantification of benfotiamine and sulbutiamine, synthetic thiamine analogs, in biological samples is an essential step toward understanding the role of these thiamine analogs on cancer cell proliferation.

scholarly journals Driving Rho GTPase activity in endothelial cells regulates barrier integrity

2010 ◽  
Vol 103 (01) ◽  
pp. 40-55 ◽  
Author(s):  
Cora Beckers ◽  
Victor van Hinsbergh ◽  
Geerten van Nieuw Amerongen
Keyword(s):  
Barrier Function ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Three Dimensional ◽  
Regulatory Proteins ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Barrier Dysfunction ◽  
Gtpase Activation ◽  
The Individual

SummaryIn the past decade understanding of the role of the Rho GTPases RhoA, Rac1 and Cdc42 has been developed from regulatory proteins that regulate specific actin cytoskeletal structures – stress fibers, lamellipodia and filopodia – to complex integrators of cytoskeletal structures that can exert multiple functions depending on the cellular context. Fundamental to these functions are three-dimensional complexes between the individual Rho GTPases, their specific activators (GEFs) and inhibitors (GDIs and GAPs), which greatly outnumber the Rho GTPases themselves, and additional regulatory proteins. By this complexity of regulation different vasoactive mediators can induce various cytoskeletal structures that enable the endothelial cell (EC) to respond adequately. In this review we have focused on this complexity and the consequences of Rho GTPase regulation for endothelial barrier function. The permeability inducers thrombin and VEGF are presented as examples of G-protein coupled receptor- and tyrosine kinase receptormediated Rho GTPase activation, respectively. These mediators induce complex but markedly different networks of activators, inhibitors and effectors of Rho GTPases, which alter the endothelial barrier function. An interesting feature in this regulation is that Rho GTPases often have both barrier-protecting and barrier-disturbing functions. While Rac1 enforces the endothelial junctions, it becomes part of a barrier-disturbing mechanism as activator of reactive oxygen species generating NADPH oxidase. Similarly RhoA is protective under basal conditions, but becomes involved in barrier dysfunction after activation of ECs by thrombin. The challenge and promise lies in unfolding this complex regulation, as this will provide leads for new therapeutic opportunities.

scholarly journals The Complexities of Metastasis

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1575 ◽  
Author(s):  
San Juan ◽  
Garcia-Leon ◽  
Rangel ◽  
Goetz ◽  
Chaffer
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Patient Survival ◽  
Phenotypic Heterogeneity ◽  
Mechanical Forces ◽  
Metastatic Dissemination ◽  
Metastatic Cascade ◽  
Functional Capacities

Therapies that prevent metastatic dissemination and tumor growth in secondary organs are severely lacking. A better understanding of the mechanisms that drive metastasis will lead to improved therapies that increase patient survival. Within a tumor, cancer cells are equipped with different phenotypic and functional capacities that can impact their ability to complete the metastatic cascade. That phenotypic heterogeneity can be derived from a combination of factors, in which the genetic make-up, interaction with the environment, and ability of cells to adapt to evolving microenvironments and mechanical forces play a major role. In this review, we discuss the specific properties of those cancer cell subgroups and the mechanisms that confer or restrict their capacity to metastasize.

scholarly journals Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1292 ◽  
Author(s):  
Pavol Zubor ◽  
Zuzana Dankova ◽  
Zuzana Kolkova ◽  
Veronika Holubekova ◽  
Dusan Brany ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Cell Cycle Control ◽  
Solid Malignancies ◽  
Depth Analysis ◽  
Preventive And Personalized Medicine ◽  
Novel Biomarkers ◽  
Cytoskeleton Dynamics

Rho guanosine triphospatases (GTPases) resemble a conserved family of GTP-binding proteins regulating actin cytoskeleton dynamics and several signaling pathways central for the cell. Rho GTPases create a so-called Ras-superfamily of GTPases subdivided into subgroups comprising at least 20 members. Rho GTPases play a key regulatory role in gene expression, cell cycle control and proliferation, epithelial cell polarity, cell migration, survival, and apoptosis, among others. They also have tissue-related functions including angiogenesis being involved in inflammatory and wound healing processes. Contextually, any abnormality in the Rho GTPase function may result in severe consequences at molecular, cellular, and tissue levels. Rho GTPases also play a key role in tumorigenesis and metastatic disease. Corresponding mechanisms include a number of targets such as kinases and scaffold/adaptor-like proteins initiating GTPases-related signaling cascades. The accumulated evidence demonstrates the oncogenic relevance of Rho GTPases for several solid malignancies including breast, liver, bladder, melanoma, testicular, lung, central nervous system (CNS), head and neck, cervical, and ovarian cancers. Furthermore, Rho GTPases play a crucial role in the development of radio- and chemoresistance e.g. under cisplatin-based cancer treatment. This article provides an in-depth overview on the role of Rho GTPases in gynecological cancers, highlights relevant signaling pathways and pathomechanisms, and sheds light on their involvement in tumor progression, metastatic spread, and radio/chemo resistance. In addition, insights into a spectrum of novel biomarkers and innovative approaches based on the paradigm shift from reactive to predictive, preventive, and personalized medicine are provided.

Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 1950-1955 ◽  
Author(s):  
Xavier Cullere ◽  
Sunil K. Shaw ◽  
Lorna Andersson ◽  
Junichi Hirahashi ◽  
Francis W. Luscinskas ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Barrier Function ◽  
Rho Gtpase ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Cortical Actin ◽  
Cell Contacts ◽  
Exchange Factor ◽  
Gtpase Activation ◽  
Cell Cell

Abstract Endothelial cell-cell junctional proteins and cortical actin are of central importance for regulating vascular permeability. Rap1, a member of the Ras family of GTPases, is enriched at endothelial cell-cell contacts and activated by cyclic AMP (cAMP) through a PKA-independent pathway. Activation of a cAMP-inducible guanine-exchange factor for Rap, Epac, results in markedly enhanced basal endothelial barrier function by increasing cortical actin and subsequent redistribution of adherens and tight junctional molecules to cell-cell contacts. Activation of Epac also counteracts thrombin-induced hyperpermeability through down-regulation of Rho GTPase activation, suggesting cross-talk between Rap and Rho GT-Pases. Thus, Epac/Rap activation represents a new pathway for regulating endothelial cell barrier function.

scholarly journals Inhibition of Tunneling Nanotubes between Cancer Cell and the Endothelium Alters the Metastatic Phenotype

2021 ◽  
Vol 22 (11) ◽  
pp. 6161
Author(s):  
Chinmayee Dash ◽  
Tanmoy Saha ◽  
Shiladitya Sengupta ◽  
Hae Lin Jang
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Rho Gtpase ◽  
Metastatic Cancer ◽  
Tunneling Nanotubes ◽  
Invasive Phenotype ◽  
Exocyst Complex ◽  
Cellular Aggregates ◽  
Phenotypic State ◽  
Metastatic Cancer Cells

The interaction of tumor cells with blood vessels is one of the key steps during cancer metastasis. Metastatic cancer cells exhibit phenotypic state changes during this interaction: (1) they form tunneling nanotubes (TNTs) with endothelial cells, which act as a conduit for intercellular communication; and (2) metastatic cancer cells change in order to acquire an elongated phenotype, instead of the classical cellular aggregates or mammosphere-like structures, which it forms in three-dimensional cultures. Here, we demonstrate mechanistically that a siRNA-based knockdown of the exocyst complex protein Sec3 inhibits TNT formation. Furthermore, a set of pharmacological inhibitors for Rho GTPase–exocyst complex-mediated cytoskeletal remodeling is introduced, which inhibits TNT formation, and induces the reversal of the more invasive phenotype of cancer cell (spindle-like) into a less invasive phenotype (cellular aggregates or mammosphere). Our results offer mechanistic insights into this nanoscale communication and shift of phenotypic state during cancer–endothelial interactions.

scholarly journals RhoBTB1 interacts with ROCKs and inhibits invasion

2019 ◽  
Vol 476 (17) ◽  
pp. 2499-2514 ◽  
Author(s):  
Raquel B. Haga ◽  
Ritu Garg ◽  
Francesca Collu ◽  
Bárbara Borda D'Agua ◽  
Sofia T. Menéndez ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Invasion ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Coiled Coil ◽  
Kinase Domain ◽  
Cancer Cell Invasion ◽  
Coiled Coil Region ◽  
Cytoskeletal Dynamics ◽  
Actin Cytoskeletal Dynamics

Abstract RhoBTB1 is an atypical Rho GTPase with two BTB domains in addition to its Rho domain. Although most Rho GTPases regulate actin cytoskeletal dynamics, RhoBTB1 is not known to affect cell shape or motility. We report that RhoBTB1 depletion increases prostate cancer cell invasion and induces elongation in Matrigel, a phenotype similar to that induced by depletion of ROCK1 and ROCK2. We demonstrate that RhoBTB1 associates with ROCK1 and ROCK2 and its association with ROCK1 is via its Rho domain. The Rho domain binds to the coiled-coil region of ROCK1 close to its kinase domain. We identify two amino acids within the Rho domain that alter RhoBTB1 association with ROCK1. RhoBTB1 is a substrate for ROCK1, and mutation of putative phosphorylation sites reduces its association with Cullin3, a scaffold for ubiquitin ligases. We propose that RhoBTB1 suppresses cancer cell invasion through interacting with ROCKs, which in turn regulate its association with Cullin3. Via Cullin3, RhoBTB1 has the potential to affect protein degradation.

Cancer Cells Cause Vascular Endothelial Cell (vEC) Retraction via 12(S)HETE Secretion; The Possible Role of Cancer Cell Derived Microparticle

2006 ◽  
Vol 14 (2) ◽  
pp. 862-868 ◽  
Author(s):  
Keiji Uchide ◽  
Masato Sakon ◽  
Hideo Ariyoshi ◽  
Syouji Nakamori ◽  
Masaru Tokunaga ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial
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