scholarly journals The Cancer Microenvironment: Mechanical Challenges of the Metastatic Cascade

2021 ◽  
Vol 9 ◽  
Author(s):  
Sebastian E. Amos ◽  
Yu Suk Choi
Keyword(s):  
Basic Research ◽  
Circulating Tumor Cell ◽  
Secondary Site ◽  
Cell Phenotype ◽  
Adherent Cell ◽  
Mechanical Stimuli ◽  
Cellular Mechanics ◽  
Metastatic Cascade ◽  
Submicron Scale

The metastatic cascade presents a significant challenge to patient survival in the fight against cancer. As metastatic cells disseminate and colonize a secondary site, stepwise exposure to microenvironment-specific mechanical stimuli influences and protects successful metastasis. Following cancerous transformation and associated cell recruitment, the tumor microenvironment (TME) becomes a mechanically complex niche, owing to changes in extracellular matrix (ECM) stiffness and architecture. The ECM mechanically reprograms the cancer cell phenotype, priming cells for invasion. 2D and 3D hydrogel-based culture platforms approximate these environmental variables and permit investigations into tumor-dependent shifts in malignancy. Following TME modification, malignant cells must invade the local ECM, driven toward blood, and lymph vessels by sensing biochemical and biophysical gradients. Microfluidic chips recreate cancer-modified ECM tracks, empowering studies into modes of confined motility. Intravasation and extravasation consist of complex cancer-endothelial interactions that modify an otherwise submicron-scale migration. Perfused microfluidic platforms facilitate the physiological culture of endothelial cells and thus enhance the translatability of basic research into metastatic transendothelial migration. These platforms also shed light on the poorly understood circulating tumor cell, which defies adherent cell norms by surviving the shear stress of blood flow and avoiding anoikis. Metastatic cancers possess the plasticity to adapt to new mechanical conditions, permitting their invasiveness, and ensuring their survival against anomalous stimuli. Here, we review the cellular mechanics of metastasis in the context of current in vitro approaches. Advances that further expose the mechanisms underpinning the phenotypic fluidity of metastatic cancers remain central to the development of novel interventions targeting cancer.

scholarly journals 3D Perfusable Hydrogel Recapitulating the Cancer Dynamic Environment to in Vitro Investigate Metastatic Colonization

Polymers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 2467
Author(s):  
Chiara Vitale ◽  
Arianna Fedi ◽  
Alessandra Marrella ◽  
Gabriele Varani ◽  
Marco Fato ◽  
...  
Keyword(s):  
Single Channel ◽  
Fluid Dynamic ◽  
Dynamic Environment ◽  
Metastatic Breast ◽  
Polymeric Matrix ◽  
The Body ◽  
Secondary Site ◽  
Circulation System ◽  
Metastatic Cascade

Metastasis is a dynamic process involving the dissemination of circulating tumor cells (CTCs) through blood flow to distant tissues within the body. Nevertheless, the development of an in vitro platform that dissects the crucial steps of metastatic cascade still remains a challenge. We here developed an in vitro model of extravasation composed of (i) a single channel-based 3D cell laden hydrogel representative of the metastatic site, (ii) a circulation system recapitulating the bloodstream where CTCs can flow. Two polymers (i.e., fibrin and alginate) were tested and compared in terms of mechanical and biochemical proprieties. Computational fluid-dynamic (CFD) simulations were also performed to predict the fluid dynamics within the polymeric matrix and, consequently, the optimal culture conditions. Next, once the platform was validated through perfusion tests by fluidically connecting the hydrogels with the external circuit, highly metastatic breast cancer cells (MDA-MB-231) were injected and exposed to physiological wall shear stress (WSS) conditions (5 Dyn/cm2) to assess their migration toward the hydrogel. Results indicated that CTCs arrested and colonized the polymeric matrix, showing that this platform can be an effective fluidic system to model the first steps occurring during the metastatic cascade as well as a potential tool to in vitro elucidate the contribution of hemodynamics on cancer dissemination to a secondary site.

scholarly journals Elevated expression of the adhesion GPCR ADGRL4/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David M. Favara ◽  
Ines Liebscher ◽  
Ali Jazayeri ◽  
Madhulika Nambiar ◽  
Helen Sheldon ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Gc Content ◽  
Luciferase Reporter ◽  
Cell Phenotype ◽  
Beta Catenin ◽  
Sprouting Angiogenesis ◽  
Proteolytic Site ◽  
Elevated Expression ◽  
Adhesion Gpcr

AbstractADGRL4/ELTD1 is an orphan adhesion GPCR (aGPCR) expressed in endothelial cells that regulates tumour angiogenesis. The majority of aGPCRs are orphan receptors. The Stachel Hypothesis proposes a mechanism for aGPCR activation, in which aGPCRs contain a tethered agonist (termed Stachel) C-terminal to the GPCR-proteolytic site (GPS) cleavage point which, when exposed, initiates canonical GPCR signalling. This has been shown in a growing number of aGPCRs. We tested this hypothesis on ADGRL4/ELTD1 by designing full length (FL) and C-terminal fragment (CTF) ADGRL4/ELTD1 constructs, and a range of potential Stachel peptides. Constructs were transfected into HEK293T cells and HTRF FRET, luciferase-reporter and Alphascreen GPCR signalling assays were performed. A stable ADGRL4/ELTD1 overexpressing HUVEC line was additionally generated and angiogenesis assays, signalling assays and transcriptional profiling were performed. ADGRL4/ELTD1 has the lowest GC content in the aGPCR family and codon optimisation significantly increased its expression. FL and CTF ADGRL4/ELTD1 constructs, as well as Stachel peptides, did not activate canonical GPCR signalling. Furthermore, stable overexpression of ADGRL4/ELTD1 in HUVECs induced sprouting angiogenesis, lowered in vitro anastomoses, and decreased proliferation, without activating canonical GPCR signalling or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta catenin or STAT3 pathways. Overexpression upregulated ANTXR1, SLC39A6, HBB, CHRNA, ELMOD1, JAG1 and downregulated DLL4, KIT, CCL15, CYP26B1. ADGRL4/ELTD1 specifically regulates the endothelial tip-cell phenotype through yet undefined signalling pathways.

scholarly journals Mechanical Strain-Enabled Reconstitution of Dynamic Environment in Organ-on-a-Chip Platforms: A Review

Micromachines ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 765
Author(s):  
Qianbin Zhao ◽  
Tim Cole ◽  
Yuxin Zhang ◽  
Shi-Yang Tang
Keyword(s):  
Cell Culture ◽  
Shear Stress ◽  
Cultured Cells ◽  
Mechanical Strain ◽  
3D Cell Culture ◽  
Small Scale ◽  
Mechanical Stimuli ◽  
Human Organ ◽  
Organ On A Chip

Organ-on-a-chip (OOC) uses the microfluidic 3D cell culture principle to reproduce organ- or tissue-level functionality at a small scale instead of replicating the entire human organ. This provides an alternative to animal models for drug development and environmental toxicology screening. In addition to the biomimetic 3D microarchitecture and cell–cell interactions, it has been demonstrated that mechanical stimuli such as shear stress and mechanical strain significantly influence cell behavior and their response to pharmaceuticals. Microfluidics is capable of precisely manipulating the fluid of a microenvironment within a 3D cell culture platform. As a result, many OOC prototypes leverage microfluidic technology to reproduce the mechanically dynamic microenvironment on-chip and achieve enhanced in vitro functional organ models. Unlike shear stress that can be readily generated and precisely controlled using commercial pumping systems, dynamic systems for generating proper levels of mechanical strains are more complicated, and often require miniaturization and specialized designs. As such, this review proposes to summarize innovative microfluidic OOC platforms utilizing mechanical actuators that induce deflection of cultured cells/tissues for replicating the dynamic microenvironment of human organs.

scholarly journals Academic collaborative models fostering the translation of physiological in vitro systems from basic research into drug discovery

2021 ◽  
Author(s):  
Alessandra Silvestri ◽  
Francisca Vicente ◽  
María J. Vicent ◽  
Bahne Stechmann ◽  
Wolfgang Fecke
Keyword(s):  
Drug Discovery ◽  
Basic Research ◽  
Collaborative Models ◽  
In Vitro Systems

scholarly journals A Novel Bioreactor for the Mechanical Stimulation of Clinically Relevant Scaffolds for Muscle Tissue Engineering Purposes

Processes ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 474
Author(s):  
Silvia Todros ◽  
Silvia Spadoni ◽  
Edoardo Maghin ◽  
Martina Piccoli ◽  
Piero G. Pavan
Keyword(s):  
Mechanical Stimulation ◽  
Strain Range ◽  
Tensile Tests ◽  
Muscular Tissue ◽  
Fe Model ◽  
Mechanical Stimuli ◽  
Physiological Strain ◽  
Cellular Alignment ◽  
Stimulation Of

Muscular tissue regeneration may be enhanced in vitro by means of mechanical stimulation, inducing cellular alignment and the growth of functional fibers. In this work, a novel bioreactor is designed for the radial stimulation of porcine-derived diaphragmatic scaffolds aiming at the development of clinically relevant tissue patches. A Finite Element (FE) model of the bioreactor membrane is developed, considering two different methods for gripping muscular tissue patch during the stimulation, i.e., suturing and clamping with pliers. Tensile tests are carried out on fresh and decellularized samples of porcine diaphragmatic tissue, and a fiber-reinforced hyperelastic constitutive model is assumed to describe the mechanical behavior of tissue patches. Numerical analyses are carried out by applying pressure to the bioreactor membrane and evaluating tissue strain during the stimulation phase. The bioreactor designed in this work allows one to mechanically stimulate tissue patches in a radial direction by uniformly applying up to 30% strain. This can be achieved by adopting pliers for tissue clamping. Contrarily, the use of sutures is not advisable, since high strain levels are reached in suturing points, exceeding the physiological strain range and possibly leading to tissue laceration. FE analysis allows the optimization of the bioreactor configuration in order to ensure an efficient transduction of mechanical stimuli while preventing tissue damage.

STRETCHABLE Lab-on-Chip Device With Impedance Spectroscopy Capability for Mammalian Cell Studies

2016 ◽  
Author(s):  
Xudong Zhang ◽  
Anis Nurashikin Nordin ◽  
Fang Li ◽  
Ioana Voiculescu
Keyword(s):  
Impedance Spectroscopy ◽  
Mammalian Cells ◽  
Dynamic Environment ◽  
Cyclic Strain ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Aortic Endothelial Cells ◽  
Lab On Chip

This paper presents the fabrication and testing of electric cell-substrate impedance spectroscopy (ECIS) electrodes on a stretchable membrane. This is the first time when ECIS electrodes were fabricated on a stretchable substrate and ECIS measurements on mammalian cells exposed to cyclic strain of 10% were successfully demonstrated. A chemical was used to form strong chemical bond between gold electrodes of ECIS sensor and polymer membrane, which enable the electrodes keep good conductive ability during cyclic stretch. The stretchable membrane integrated with the ECIS sensor can simulate and replicate the dynamic environment of organism and enable the analysis of the cells activity involved in cells attachment and proliferation in vitro. Bovine aortic endothelial cells (BAEC) were used to evaluate the endothelial function influenced by mechanical stimuli in this research because they undergo in vivo cyclic physiologic elongation produced by the blood circulation in the arteries.

scholarly journals Diabetic Cataract—Pathogenesis, Epidemiology and Treatment

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Andreas Pollreisz ◽  
Ursula Schmidt-Erfurth
Keyword(s):  
Experimental Studies ◽  
Disease Process ◽  
Basic Research ◽  
Polyol Pathway ◽  
Population Based ◽  
Diabetic Patients ◽  
Diabetic Cataract ◽  
Cataract Development

Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies. This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.

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