interstitial_fluid_flow   9

Mechanical stretch and shear flow induced reorganization and recruitment of fibronectin in fibroblasts
shear flow induces FN reorganization by fibroblasts - maybe also by mesenchymal tumor cells?

It was our objective to study the role of mechanical stimulation on fibronectin (FN) reorganization and recruitment by exposing fibroblasts to shear fluid flow and equibiaxial stretch. Mechanical stimulation was also combined with a Rho inhibitor to probe their coupled effects on FN. Mechanically stimulated cells revealed a localization of FN around the cell periphery as well as an increase in FN fibril formation. Mechanical stimulation coupled with chemical stimulation also revealed an increase in FN fibrils around the cell periphery. Complimentary to this, fibroblasts exposed to fluid shear stress structurally rearranged pre-coated surface FN, but unstimulated and stretched cells did not. These results show that mechanical stimulation directly affected FN reorganization and recruitment, despite perturbation by chemical stimulation. Our findings will help elucidate the mechanisms of FN biosynthesis and organization by furthering the link of the role of mechanics with FN.
interstitial_fluid_flow  fibronectin  fibroblasts  fibril 
2 days ago by Segalllab
Competing tumor cell migration mechanisms caused by interstitial fluid flow - ScienceDirect
In the seminal work by Swartz and collaborators (Shields et al., 2007) it was discovered that autologously secreted or activated (ECM-bound) chemokine forms local pericellular diffusion gradients skewed by fluid convection, and the cells subsequently chemotact up the flow-directed gradient. However, in (Polacheck et al., 2011) Kamm and collaborators found that there is a competing downstream and upstream migration transport mechanism. Their study showed that both mechanisms are present at the same time and the relative strength of these two stimuli governs the directional bias in migration for a cell population and is a function of cell density, interstitial flow rate, and CCR7 receptor availability. The main objective of this work is to give a possible explanation of these two different concurrent cell migration mechanisms by means of a theoretical model. Relying on multiphase modelling, separate momentum balance equations are formulated, respectively, for the cell phase and the interstitial fluid (IF) phase. In order to represent proteolytic activity and autologous chemotaxis a non-moving ECM component is included, as well as proteases secreted by the cancer cells and chemokine that can be released from ECM. The cell and IF momentum balance equations include cell-ECM and fluid-ECM resistance force terms (i.e., classical Darcy’s equation terms), but also a cell-fluid interaction term that can account for a more indirect effect that fluid-generated stress may have on cancer cells. We illustrate how the cancer cells can work through this term and effectively avoid being pushed in the flow direction, and even create upstream migration by controlling its magnitude and sign. We think of this as the mathematical interpretation of the experimental observation by Kamm and collaborators that the fluid generated matrix adhesion tension on the upstream side of cells activates integrin adhesion complexes, resulting in activation of focal adhesion (FA) proteins. The model predicts that generally the strength of the upstream migration mechanism is sensitive to the cell volume fraction: a lower density of cells is subject to a weaker upstream migration effect; a higher density of cancer cells can more effectively generate upstream migration. This behavior is a result of the nonlinear coupling between cell-ECM, fluid-ECM, and cell-fluid interaction terms that naturally are involved in the mathematical expression for the net cell velocity.
interstitial_fluid_flow  microfluidics 
11 days ago by Segalllab
Mechano-Dependent Phosphorylation of the PDZ-Binding Motif of CD97/ADGRE5 Modulates Cellular Detachment: Cell Reports
possible mechanism of detecting shear stress at adherens junctions.

Cells respond to mechanical stimuli with altered signaling networks. Here, we show that mechanical forces rapidly induce phosphorylation of CD97/ADGRE5 (pCD97) at its intracellular C-terminal PDZ-binding motif (PBM). Biochemically, this phosphorylation disrupts CD97 binding to PDZ domains of the scaffold protein DLG1. In shear-stressed cells, pCD97 appears not only in junctions, retracting fibers, and the attachment area but also in lost membrane patches, demonstrating (intra)cellular detachment at the CD97 PBM. This motif is critical for the CD97-dependent mechanoresponse. Cells expressing CD97 without the PBM are more deformable, and under shear stress, these cells lose cell contacts faster and show changes in the actin cytoskeleton when compared with cells expressing full-length CD97. Our data indicate CD97 linkage to the cytoskeleton. Consistently, CD97 knockout phenocopies CD97 without the PBM, and membranous CD97 is organized in an F-actin-dependent manner. In summary, CD97 shapes the cellular mechanoresponse through signaling modulation via its PBM.
shear_stress  interstitial_fluid_flow  adherens_junctions 
june 2019 by Segalllab
Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival | Nature
stretching of endothelial cells induces HGF production - possible relevance for spheroid invasion activation? Is dependent on integrinb1 and vegfr3 in the endothelial cells HGF was originally known as 'scatter factor' and is an emt factor - possible the IF force on spheroids could be inducing HGF to lead to downregulated Ecadherin. HGF can downregulate Ecadherin in MDCK cells (Mol Biol Cell. 1998 Aug; 9(8): 2185–2200.), and HGF induced migration of MCF10A cells in the absence of AP1510 (Proc Natl Acad Sci U S A. 2004 Feb 3; 101(5): 1257–1262.)

Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1,2,3,4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1,2,3,4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates β1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both β1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.
HGF  stretch_activation  stress  strain_induced_motility  Integrins  interstitial_fluid_flow  interstitial_pressure  vegfr3  itgb1 
march 2019 by Segalllab
Interstitial flow promotes macrophage polarization toward an M2 phenotype | Molecular Biology of the Cell
In summary, we propose a new framework whereby interstitial flow contributes to tumor progression by promoting macrophage M2 polarization and recruitment toward tumor tissues. Interstitial flow, through β1 integrin/Src-mediated activation of STAT3/6, promotes macrophage transition to an M2 phenotype evident by flow-induced Arg I, TGFβ, CD206, TGM2, and CD163 expression. This flow-induced M2 polarization enhances macrophage migration, as well as the ability of macrophages to promote cancer cell motility (Figure 7A). Moreover, IF also induces the preferential migration of macrophages against the direction of flow. Since interstitial fluid flows from the tumor mass to the draining lymph nodes in tissues surrounding the tumor, macrophages in the surrounding stromal tissues could be directed by this flow to migrate upstream and infiltrate toward the tumor site. As interstitial flow induces macrophage M2 polarization, these macrophages could then produce chemical factors, such as TGFβ and Arg I, to promote EMT, immunosuppression, and cancer cell invasion (Figure 7B). Taken together, our findings provide novel insights into the mechanobiology of macrophages and suggest that IF could play a key role in shaping the immune environment.

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.
kamm  interstitial_fluid_flow  macrophage_polarization  M2_macrophages  Src  STAT3 
january 2019 by Segalllab
Mechanisms and impact of altered tumour mechanics | Nature Cell Biology
Good summary with references to fluid pressure changes as well.

The physical characteristics of tumours are intricately linked to the tumour phenotype and difficulties during treatment. Many factors contribute to the increased stiffness of tumours; from increased matrix deposition, matrix remodelling by forces from cancer cells and stromal fibroblasts, matrix crosslinking, increased cellularity, and the build-up of both solid and interstitial pressure. Increased stiffness then feeds back to increase tumour invasiveness and reduce therapy efficacy. Increased understanding of this interplay is offering new therapeutic avenues.
interstitial_fluid_flow  interstitial_pressure  mechanobiology  tumor_stiffness  stiffness 
december 2018 by Segalllab
E-cadherin–integrin crosstalk in cancer invasion and metastasis | Journal of Cell Science
Per the title - possible relevance for IFF induced invasion?

"E-cadherin is a single-pass transmembrane protein that mediates homophilic cell–cell interactions. Tumour progression is often associated with the loss of E-cadherin function and the transition to a more motile and invasive phenotype. This requires the coordinated regulation of both E-cadherin-mediated cell–cell adhesions and integrin-mediated adhesions that contact the surrounding extracellular matrix (ECM). Regulation of both types of adhesion is dynamic as cells respond to external cues from the tumour microenvironment that regulate polarity, directional migration and invasion. Here, we review the mechanisms by which tumour cells control the cross-regulation between dynamic E-cadherin-mediated cell–cell adhesions and integrin-mediated cell–matrix contacts, which govern the invasive and metastatic potential of tumours. In particular, we will discuss the role of the adhesion-linked kinases Src, focal adhesion kinase (FAK) and integrin-linked kinase (ILK), and the Rho family of GTPases.
Ecadherin  Integrins  invasion  cell_cell_adhesion  interstitial_fluid_flow 
september 2018 by Segalllab
Mechanotransduction in tumor progression: The dark side of the force | JCB
Also cover interstitial flow.

" Recently, the importance of the anomalous mechanical properties of tumor tissues, which activate tumorigenic biochemical pathways, has become apparent. This mechanical induction in tumors appears to consist of the destabilization of adult tissue homeostasis as a result of the reactivation of embryonic developmental mechanosensitive pathways in response to pathological mechanical strains. These strains occur in many forms, for example, hypervascularization in late tumors leads to high static hydrodynamic pressure that can promote malignant progression through hypoxia or anomalous interstitial liquid and blood flow. The high stiffness of tumors directly induces the mechanical activation of biochemical pathways enhancing the cell cycle, epithelial–mesenchymal transition, and cell motility. Furthermore, increases in solid-stress pressure associated with cell hyperproliferation activate tumorigenic pathways in the healthy epithelial cells compressed by the neighboring tumor. The underlying molecular mechanisms of the translation of a mechanical signal into a tumor inducing biochemical signal are based on mechanically induced protein conformational changes that activate classical tumorigenic signaling pathways. Understanding these mechanisms will be important for the development of innovative treatments to target such mechanical anomalies in cancer.
mechanical_properties  interstitial_pressure  interstitial_fluid_flow 
september 2018 by Segalllab
Investigating Low-Velocity Fluid Flow in Tumors with Convection-MRI | Cancer Research
MRI measurements of interstitial fluid flow - assume extracellular volume of 12% - could vary in necrotic vs healthy regions?
interstitial_fluid_flow  interstitial_tumor_pressure  mri 
april 2018 by Segalllab

related tags

adherens_junctions  cell_cell_adhesion  ecadherin  fibril  fibroblasts  fibronectin  hgf  integrins  interstitial_pressure  interstitial_tumor_pressure  invasion  itgb1  kamm  m2_macrophages  macrophage_polarization  mechanical_properties  mechanobiology  microfluidics  mri  shear_stress  src  stat3  stiffness  strain_induced_motility  stress  stretch_activation  tumor_stiffness  vegfr3 

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