extravasation   42

Vimentin intermediate filament and plectin provide a scaffold for invadopodia, facilitating cancer cell invasion and extravasation for metastasis - ScienceDirect
vimentin kd reduces invadopodia - also show 'anchoring' of invadopodia (F actin dots) to vimentin filaments. Argue that plectin is involved in the anchoring.

To investigate the molecular mechanisms of cancer metastasis, we have isolated a high-metastatic bladder cancer cell subpopulation from a low-metastatic cell line by using an in vivo selection system. Cells in the subpopulation showed a high ability to form invadopodia, the filamentous actin (F-actin)-based membrane protrusions that play an essential role in cancer cell invasion. Analysis of the gene expression profile revealed that the expression of an intermediate filament (IF) protein, vimentin and a cytoskeletal linker protein, plectin was up-regulated in the high-metastatic subpopulation compared with the low metastatic cell line. Here we report a novel role of vimentin IF and plectin in metastasis. In invasive bladder cancer cells, the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of extracellular matrix degradation, transendothelial migration and metastasis. In addition, the vimentin assembly into the filaments was required for invadopodia formation. Our results suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular process for cancer cell invasion and extravasation for metastasis.
vimentin  plectin  invadopodia  invasion  extravasation 
5 weeks ago by Segalllab
Melanoma-Derived Soluble DC-HIL/GPNMB Promotes Metastasis by Excluding T-Lymphocytes from the Pre-Metastatic Niches - ScienceDirect
Interesting that these are high heparansulphate sites - so perhaps DC-HIL is marking high HS containing ES cells, which enable more effective extravasation and inhibition of T cells (for some reason....). Another paper in cancer research says GPNMB I think also goes up with tumor cell stemness/dormancy.

"In summary, melanoma exploits the DC-HIL pathway to increase the success rate of metastasis by secreting sDC-HIL, which binds to the DHL+ EC vascular niches. This binding awakens the angiogenic potential and excludes T cells from the niches while enhancing the migration of BMPs and tumor cells. Therefore, sDC-HIL is an endothelial gatekeeper for selectively blocking the access of T cells to the vascular niches. In this context, blocking sDC-HIL function may be a promising approach for preventing metastasis of melanoma because we showed that infusion of anti-DC-HIL mAb markedly regressed metastases. This possibility is not restricted to melanoma because we showed that some of patients with metastatic forms of other malignancies also produce very high levels of sDC-HIL in the blood (unpublished data).
extravasation  lung_colonization  endothelium  heparan_sulfate  immune_suppression 
10 weeks ago by Segalllab
Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells - ScienceDirect
They find that ctcs arrest at sites where blood flow is lower. Also see cases where endothelial cells crawl over the tumor cells to result in extravsaation. Also see structures that might be tnts?

"Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. These results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth."
extravasation  brain_metastasis  TNTs 
december 2018 by Segalllab
Macrophages Promote Circulating Tumor Cell–Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients | Cancer Research
Interesting evaluation of how irradiated tissue can attract macrophages and thentumor cells - possible relationship to extravasation?

Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8+ T cells. Macrophages (CD11b+F480+) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC.

Significance: This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed.
Macrophages  extravasation  radiation 
october 2018 by Segalllab
Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration - ScienceDirect
For extravasation - CD97 can activate platelets to release LPA and other factors that can enhance it- did not work with breast cancer though (?!?)

"During hematogenous dissemination, platelets interact with tumor cells leading to platelet activation and release of soluble mediators that alter the phenotype of the tumor cells and surrounding host cells (Labelle and Hynes, 2012). Although physiologically important events distal to tumor cell-platelet interactions such as TEM and invasiveness have been described (Labelle and Hynes, 2012, Schumacher et al., 2013), the proximal events, which initiate platelet activation, are incompletely characterized. We identify a role for the adhesion GPCR CD97 in activating platelets. Of particular interest is the additional activity of tumor CD97 as a motility receptor for LPA released from platelets. One result of CD97 binding to platelets would be to concentrate platelet-derived LPA in proximity to CD97-LPAR heterodimers to induce RHO signaling, producing an invasive phenotype. Simultaneously, platelet activation leads to granule release and consequent dissociation of the endothelial barrier, thereby coupling the timing of tumor cell motility to endothelial barrier disruption (Figure 5D). Consistent with TEM assays, we observed CD97-dependence for tumor cell induced in vivo vascular permeability and platelet-enhanced metastasis in preclinical models.
extravasation  TEM  CD97  LPA 
august 2018 by Segalllab
IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells | PNAS
In summary, we present new evidence that IL-1β triggers CNS autoimmunity by acting on several fronts. In addition to its demonstrated role in the expansion of encephalitogenic GM-CSF–producing TH17 cells, we now report that pioneer CCR2+ monocytes must express IL-1β to be able to cross the blood–CNS barrier and initiate neuroinflammation in EAE. Furthermore, we show that IL-1β is a critical regulatory cytokine for GM-CSF production by CNS ECs, which in turn induces the differentiation of monocytes into APCs within the perivascular space of CNS blood vessels.
IL1B  transendothelial_migration  iTEM  eTEM  extravasation  CCR2  Macrophages 
june 2018 by Segalllab
Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes
APBA3 is important for 60% of macrophage ATP in glycolysis and KO reduces chemotaxis and VEGFA secretion - seems to be important for macrophage enhancement of extravasation?

"Thus, APBA3 seems to be necessary for intravascular monocytes/macrophages to form the metastatic niche in the lungs. However, it remains unclear whether APBA3-mediated metastatic niche formation is induced by IMs in the blood or those migrating to the lung tissues from the blood. Recently, both intravascular and extravascular monocytes/macrophages have been reported to associate with extravasation of tumor cells in the lungs (14, 51). Thus, APBA3-mediated metastatic niche formation might also be regulated by both intravascular and extravascular monocytes/macrophages."
Macrophage  premetastatic_niche  inflammatory  chemotaxis  CCL2  Metastasis  extravasation 
september 2017 by Segalllab
Flow Dynamics and HSPC Homing in Bone Marrow Microvessels: Cell Reports
Intravital imaging using 2 photon microscopy of bone marrow in calvaria, including following HSPC extravasation.
bone_marrow  Intravital  multiphoton  extravasation  HSPC 
june 2017 by Segalllab
Venular Basement Membranes Ubiquitously Express Matrix Protein Low-Expression Regions - The American Journal of Pathology
interesting observations of regions of vein basement membranes which have less ECm and might be the sites where neutrophils extravasate.
extravasation  neutrophils  basement_membrane  vasculature 
april 2017 by Segalllab
FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis
NOTE - RETRACTED - MAJOR FALSIFICATION OF RESULTS!!!!!very interesting - FMN2 is involved in generating those perinuclear focal adhesions as part of a system for maintaining the nucleus, especially in 3 d when squeezing through small holes - loss of FMN2 leads to damaged nuclei when they try to squeeze through. Shown to be important in melanoma for intravasation/extravasation.
nuclear_stability  intravasation  extravasation  invasion  formins  focal_adhesions 
january 2017 by Segalllab
Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis : Nature : Nature Research
another way to extravasate - kill the endothelial cell! perhaps APP secretion and binding by DR6 on endothelial cells mediates this
extravasation  necroptosis  endothelial  cells 
september 2016 by Segalllab
Neutrophils Suppress Intraluminal NK Cell–Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells
Focusing mainly on 4T1 but also do a 231/huvec extravasation in vitro assay (eTEM). Increased neutrophils stimulate extravasation through inhibition of NK cells and stimulation of endothelial cells via IL1B (also MMP9/VEGF are involved). Makes me wonder about revisiting IL1B in the iTEM assay....
neutrophils  extravasation  metastasis  4t1  231_cells  HUVEC  eTEM  il1b  nk_cells  VEGFA  mmp9 
august 2016 by Segalllab
F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling : Nature Communications : Nature Publishing Group
evaluation of neutrophil eTEM and extravasation using HUVECs in vitro. Find that endothelial cells RhoA is important for minimizing leakage during the diapedesis though not for diapedesis itself.
eTEM  extravasation  neutrophils  RhoA  HUVEC 
may 2016 by Segalllab
TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response
Although this is extravasation of neutrophils, possibly still relevant for intravasation. Basic idea that localized calcium influxes from TRPC6 could be important. "The LBRC consists of many interconnected 50-nm tubulovesicular membrane structures located beneath the plasma membrane at endothelial borders. During TEM, LBRC membrane traffics to surround the transmigrating leukocyte in a process known as targeted recycling ....Leukocyte–endothelial PECAM interactions lead to TRPC6 activation, which then mediates LBRC trafficking to surround the leukocyte and promote subsequent migration across the endothelium. TRPC6-selective pharmacological inhibitors, especially if targeted to the endothelium, could be used as an effective antiinflammatory therapy. Future studies will focus on mechanisms governing PECAM signaling to TRPC6, how TRPC6-mediated ↑[Ca2+]i regulates trafficking of the LBRC, and its potential role in cytoskeletal/junctional reorganization during TEM...."
extravasation  neutrophils  trpc6  calcium 
december 2015 by Segalllab
Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis : Nature Communications : Nature Publishing Group
in melanoma, sparc secretion can bind and activate vcam1 on endothelial cells to increase permeability and extravasation. No analysis of intravasation effects. Not upregulated in Bacs by NRG1/cxcl1.
melanoma  sparc  extravasation  vcam1 
august 2015 by Segalllab

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