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Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
Wang W, Lollis EM, Bordeleau F, Reinhart-King CA
(2019) FASEB J 33: 1199-1208
MeSH Terms: Adherens Junctions, Animals, Antigens, CD, Cadherins, Capillary Permeability, Chick Embryo, Endothelium, Vascular, Enzyme Activation, Extracellular Matrix, Female, Focal Adhesion Protein-Tyrosine Kinases, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Transgenic, Phosphorylation, Protein Transport, Tyrosine, src-Family Kinases
Show Abstract · Added April 10, 2019
Tumor vasculature is known to be more permeable than the vasculature found in healthy tissue, which in turn can lead to a more aggressive tumor phenotype and impair drug delivery into tumors. While the stiffening of the stroma surrounding solid tumors has been reported to increase vascular permeability, the mechanism of this process remains unclear. Here, we utilize an in vitro model of tumor stiffening, ex ovo culture, and a mouse model to investigate the molecular mechanism by which matrix stiffening alters endothelial barrier function. Our data indicate that the increased endothelial permeability caused by heightened matrix stiffness can be prevented by pharmaceutical inhibition of focal adhesion kinase (FAK) both in vitro and ex ovo. Matrix stiffness-mediated FAK activation determines Src localization to cell-cell junctions, which then induces increased vascular endothelial cadherin phosphorylation both in vitro and in vivo. Endothelial cells in stiff tumors have more activated Src and higher levels of phosphorylated vascular endothelial cadherin at adherens junctions compared to endothelial cells in more compliant tumors. Altogether, our data indicate that matrix stiffness regulates endothelial barrier integrity through FAK activity, providing one mechanism by which extracellular matrix stiffness regulates endothelial barrier function. Additionally, our work also provides further evidence that FAK is a promising potential target for cancer therapy because FAK plays a critical role in the regulation of endothelial barrier integrity.-Wang, W., Lollis, E. M., Bordeleau, F., Reinhart-King, C. A. Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
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19 MeSH Terms
Consider Changing the Horse for Your CAR-T?
Wilson MH
(2018) Mol Ther 26: 1873-1874
MeSH Terms: Animals, Antigens, CD19, Heterografts, Horses, Immunoglobulin G, Immunotherapy, Adoptive, T-Lymphocytes
Added December 13, 2018
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7 MeSH Terms
Insulin exits skeletal muscle capillaries by fluid-phase transport.
Williams IM, Valenzuela FA, Kahl SD, Ramkrishna D, Mezo AR, Young JD, Wells KS, Wasserman DH
(2018) J Clin Invest 128: 699-714
MeSH Terms: Animals, Antigens, CD, Biological Transport, Capillaries, Diabetes Mellitus, Glucose, Glucose Clamp Technique, Humans, Hyperinsulinism, Image Processing, Computer-Assisted, Insulin, Intravital Microscopy, Kinetics, Male, Mice, Mice, Inbred C57BL, Models, Theoretical, Muscle, Skeletal, Protein Binding, Receptor, Insulin, Rhodamines
Show Abstract · Added March 14, 2018
Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.
1 Communities
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21 MeSH Terms
Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension.
Suzuki T, Carrier EJ, Talati MH, Rathinasabapathy A, Chen X, Nishimura R, Tada Y, Tatsumi K, West J
(2018) Am J Physiol Lung Cell Mol Physiol 314: L118-L126
MeSH Terms: Animals, Antigens, CD, Cadherins, Cells, Cultured, Endothelium, Vascular, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Humans, Hypertension, Pulmonary, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pulmonary Artery
Show Abstract · Added March 26, 2019
Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sor/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.
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MeSH Terms
CD318 is a ligand for CD6.
Enyindah-Asonye G, Li Y, Ruth JH, Spassov DS, Hebron KE, Zijlstra A, Moasser MM, Wang B, Singer NG, Cui H, Ohara RA, Rasmussen SM, Fox DA, Lin F
(2017) Proc Natl Acad Sci U S A 114: E6912-E6921
MeSH Terms: A549 Cells, Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Antigens, Neoplasm, Arthritis, Rheumatoid, Cell Adhesion Molecules, Cell Line, Cell Line, Tumor, Encephalomyelitis, Autoimmune, Experimental, Humans, Ligands, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Proteins, Synovial Membrane, T-Lymphocytes
Show Abstract · Added March 22, 2018
It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.
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18 MeSH Terms
Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma.
Codreanu SG, Hoeksema MD, Slebos RJC, Zimmerman LJ, Rahman SMJ, Li M, Chen SC, Chen H, Eisenberg R, Liebler DC, Massion PP
(2017) J Proteome Res 16: 3266-3276
MeSH Terms: 5-Lipoxygenase-Activating Proteins, Adenocarcinoma, Adenocarcinoma of Lung, Adult, Aged, Antigens, CD, Arachidonate 5-Lipoxygenase, Biomarkers, Tumor, CD11 Antigens, Cell Adhesion Molecules, Diagnosis, Differential, Female, GPI-Linked Proteins, Gene Expression Regulation, Neoplastic, Glucose Transporter Type 3, Humans, Integrin alpha Chains, Lung Neoplasms, Male, Middle Aged, Neoplasm Proteins, Proteomics, Respiratory Mucosa, Solitary Pulmonary Nodule, Tandem Mass Spectrometry, Tissue Array Analysis, Transcriptome
Show Abstract · Added January 29, 2018
We hypothesized that distinct protein expression features of benign and malignant pulmonary nodules may reveal novel candidate biomarkers for the early detection of lung cancer. We performed proteome profiling by liquid chromatography-tandem mass spectrometry to characterize 34 resected benign lung nodules, 24 untreated lung adenocarcinomas (ADCs), and biopsies of bronchial epithelium. Group comparisons identified 65 proteins that differentiate nodules from ADCs and normal bronchial epithelium and 66 proteins that differentiate ADCs from nodules and normal bronchial epithelium. We developed a multiplexed parallel reaction monitoring (PRM) assay to quantify a subset of 43 of these candidate biomarkers in an independent cohort of 20 benign nodules, 21 ADCs, and 20 normal bronchial biopsies. PRM analyses confirmed significant nodule-specific abundance of 10 proteins including ALOX5, ALOX5AP, CCL19, CILP1, COL5A2, ITGB2, ITGAX, PTPRE, S100A12, and SLC2A3 and significant ADC-specific abundance of CEACAM6, CRABP2, LAD1, PLOD2, and TMEM110-MUSTN1. Immunohistochemistry analyses for seven selected proteins performed on an independent set of tissue microarrays confirmed nodule-specific expression of ALOX5, ALOX5AP, ITGAX, and SLC2A3 and cancer-specific expression of CEACAM6. These studies illustrate the value of global and targeted proteomics in a systematic process to identify and qualify candidate biomarkers for noninvasive molecular diagnosis of lung cancer.
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27 MeSH Terms
ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
Rellinger EJ, Padmanabhan C, Qiao J, Appert A, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH
(2017) Biochem Biophys Res Commun 491: 463-468
MeSH Terms: Antigens, CD, Antineoplastic Agents, Apoptosis, Cadherins, Caspase 3, Cell Cycle, Cell Line, Tumor, Drug Synergism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Humans, Isoxazoles, Mesenchymal Stem Cells, Niacinamide, Poly(ADP-ribose) Polymerases, Sarcoma, Ewing, Signal Transduction, Small Molecule Libraries, TNF-Related Apoptosis-Inducing Ligand, Vimentin
Show Abstract · Added March 14, 2018
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Single cell analysis of human tissues and solid tumors with mass cytometry.
Leelatian N, Doxie DB, Greenplate AR, Mobley BC, Lehman JM, Sinnaeve J, Kauffmann RM, Werkhaven JA, Mistry AM, Weaver KD, Thompson RC, Massion PP, Hooks MA, Kelley MC, Chambless LB, Ihrie RA, Irish JM
(2017) Cytometry B Clin Cytom 92: 68-78
MeSH Terms: Antigens, CD, Flow Cytometry, HLA-DR Antigens, Humans, Jurkat Cells, Leukocyte Common Antigens, Neoplasms, Single-Cell Analysis
Show Abstract · Added September 7, 2016
BACKGROUND - Mass cytometry measures 36 or more markers per cell and is an appealing platform for comprehensive phenotyping of cells in human tissue and tumor biopsies. While tissue disaggregation and fluorescence cytometry protocols were pioneered decades ago, it is not known whether established protocols will be effective for mass cytometry and maintain cancer and stromal cell diversity.
METHODS - Tissue preparation techniques were systematically compared for gliomas and melanomas, patient derived xenografts of small cell lung cancer, and tonsil tissue as a control. Enzymes assessed included DNase, HyQTase, TrypLE, collagenase (Col) II, Col IV, Col V, and Col XI. Fluorescence and mass cytometry were used to track cell subset abundance following different enzyme combinations and treatment times.
RESULTS - Mechanical disaggregation paired with enzymatic dissociation by Col II, Col IV, Col V, or Col XI plus DNase for 1 h produced the highest yield of viable cells per gram of tissue. Longer dissociation times led to increasing cell death and disproportionate loss of cell subsets. Key markers for establishing cell identity included CD45, CD3, CD4, CD8, CD19, CD64, HLA-DR, CD11c, CD56, CD44, GFAP, S100B, SOX2, nestin, vimentin, cytokeratin, and CD31. Mass and fluorescence cytometry identified comparable frequencies of cancer cell subsets, leukocytes, and endothelial cells in glioma (R = 0.97), and tonsil (R = 0.98).
CONCLUSIONS - This investigation establishes standard procedures for preparing viable single cell suspensions that preserve the cellular diversity of human tissue microenvironments. © 2016 International Clinical Cytometry Society.
© 2016 International Clinical Cytometry Society.
3 Communities
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8 MeSH Terms
Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice.
Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K
(2016) Sci Rep 6: 28473
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adiponectin, Animals, Antigen Presentation, Antigens, CD1d, B7-1 Antigen, Diet, High-Fat, Disease Models, Animal, Disease Progression, Galactosylceramides, Insulin Resistance, Interferon-gamma, Lymphocyte Activation, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Obesity
Show Abstract · Added July 30, 2016
It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.
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21 MeSH Terms
Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34(+) cells of juvenile myelomonocytic leukemia.
Nakazawa Y, Matsuda K, Kurata T, Sueki A, Tanaka M, Sakashita K, Imai C, Wilson MH, Koike K
(2016) J Hematol Oncol 9: 27
MeSH Terms: Antigens, CD34, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Coculture Techniques, Flow Cytometry, Humans, Immunotherapy, Adoptive, K562 Cells, Leukemia, Myelomonocytic, Juvenile, Ligands, Mutation, Receptors, Antigen, T-Cell, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Recombinant Fusion Proteins, Stem Cell Factor, T-Lymphocytes, Thrombopoietin
Show Abstract · Added September 11, 2017
BACKGROUND - Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML.
METHODS - We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34(+) cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34(+) cells.
RESULTS - GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34(+) cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34(+) cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34(+) cell proliferation, particularly CD34(+)CD38(-) cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34(+) cell colony growth.
CONCLUSIONS - Ligand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML.
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18 MeSH Terms