scholarly journals The Basement Membrane in a 3D Breast Acini Model Modulates Delivery and Anti-Proliferative Effects of Liposomal Anthracyclines

2020 ◽  
Vol 13 (9) ◽  
pp. 256
Author(s):  
Tabea Wiedenhoeft ◽  
Tobias Braun ◽  
Ronald Springer ◽  
Michael Teske ◽  
Erik Noetzel ◽  
...  
Keyword(s):  
Cell Culture ◽  
Basement Membrane ◽  
Cancer Progression ◽  
Basement Membranes ◽  
Target Cells ◽  
Proliferative Effect ◽  
Liposomal Formulations ◽  
Aclacinomycin A ◽  
Treatment Prognosis ◽  
Phospholipid Liposome

Breast cancer progression is marked by cancer cell invasion and infiltration, which can be closely linked to sites of tumor-connected basement membrane thinning, lesion, or infiltration. Bad treatment prognosis frequently accompanies lack of markers for targeted therapy, which brings traditional chemotherapy into play, despite its adverse effects like therapy-related toxicities. In the present work, we compared different liposomal formulations for the delivery of two anthracyclines, doxorubicin and aclacinomycin A, to a 2D cell culture and a 3D breast acini model. One formulation was the classical phospholipid liposome with a polyethylene glycol (PEG) layer serving as a stealth coating. The other formulation was fusogenic liposomes, a biocompatible, cationic, three-component system of liposomes able to fuse with the plasma membrane of target cells. For the lysosome entrapment-sensitive doxorubicin, membrane fusion enabled an increased anti-proliferative effect in 2D cell culture by circumventing the endocytic route. In the 3D breast acini model, this process was found to be limited to cells beneath a thinned or compromised basement membrane. In acini with compromised basement membrane, the encapsulation of doxorubicin in fusogenic liposomes increased the anti-proliferative effect of the drug in comparison to a formulation in PEGylated liposomes, while this effect was negligible in the presence of intact basement membranes.

scholarly journals Extracellular chloride signals collagen IV network assembly during basement membrane formation

2016 ◽  
Vol 213 (4) ◽  
pp. 479-494 ◽  
Author(s):  
Christopher F. Cummings ◽  
Vadim Pedchenko ◽  
Kyle L. Brown ◽  
Selene Colon ◽  
Mohamed Rafi ◽  
...  
Keyword(s):  
Cell Culture ◽  
Basement Membrane ◽  
Collagen Iv ◽  
Atomic Level ◽  
Basement Membranes ◽  
Tissue Architecture ◽  
Dynamic Interactions ◽  
Conformational Switch ◽  
And Function ◽  
Fundamental Mechanism

Basement membranes are defining features of the cellular microenvironment; however, little is known regarding their assembly outside cells. We report that extracellular Cl− ions signal the assembly of collagen IV networks outside cells by triggering a conformational switch within collagen IV noncollagenous 1 (NC1) domains. Depletion of Cl− in cell culture perturbed collagen IV networks, disrupted matrix architecture, and repositioned basement membrane proteins. Phylogenetic evidence indicates this conformational switch is a fundamental mechanism of collagen IV network assembly throughout Metazoa. Using recombinant triple helical protomers, we prove that NC1 domains direct both protomer and network assembly and show in Drosophila that NC1 architecture is critical for incorporation into basement membranes. These discoveries provide an atomic-level understanding of the dynamic interactions between extracellular Cl− and collagen IV assembly outside cells, a critical step in the assembly and organization of basement membranes that enable tissue architecture and function. Moreover, this provides a mechanistic framework for understanding the molecular pathobiology of NC1 domains.

Physical Properties of Isolated Perfused Renal Tubular Basement Membranes

1971 ◽  
Vol 29 ◽  
pp. 390-391
Author(s):  
Jared Grantham ◽  
Larry Welling
Keyword(s):  
Basement Membrane ◽  
Basement Membranes ◽  
Transport Mechanisms ◽  
Permeability Characteristics ◽  
Peritubular Capillaries ◽  
Strategic Location ◽  
Tubular Lumen ◽  
Glomerular Filtrate ◽  
Urine Formation ◽  
Renal Tubular

In the course of urine formation in mammalian kidneys over 90% of the glomerular filtrate moves from the tubular lumen into the peritubular capillaries by both active and passive transport mechanisms. In all of the morphologically distinct segments of the renal tubule, e.g. proximal tubule, loop of Henle and distal nephron, the tubular absorbate passes through a basement membrane which rests against the basilar surface of the epithelial cells. The basement membrane is in a strategic location to affect the geometry of the tubules and to influence the movement of tubular absorbate into the renal interstitium. In the present studies we have determined directly some of the mechanical and permeability characteristics of tubular basement membranes.

Recent Advances in the Function of the 67 kDa Laminin Receptor and its Targeting for Personalized Therapy in Cancer

2017 ◽  
Vol 23 (32) ◽  
pp. 4745-4757 ◽  
Author(s):  
Ada Pesapane ◽  
Pia Ragno ◽  
Carmine Selleri ◽  
Nunzia Montuori
Keyword(s):  
Cell Adhesion ◽  
Cancer Progression ◽  
Ribosome Biogenesis ◽  
Critical Role ◽  
Protein Translation ◽  
Basement Membranes ◽  
Laminin Receptor ◽  
Cell Surface Receptor ◽  
Future Application ◽  
Neoplastic Cells

The 67 kDa high affinity laminin receptor (67LR) is a non-integrin cell surface receptor for laminin, the major component of basement membranes. Interactions between 67LR and laminin play a major role in mediating cell adhesion, migration, proliferation and survival. 67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic precursor (37LRP), most probably by fatty acid acylation. Interestingly, 37LRP, also called p40 or OFA/iLR (oncofetal antigen/immature laminin receptor), is a multifunctional protein with a dual activity in the cytoplasm and in the nucleus. In the cytoplasm, 37LRP it is associated with the 40S subunit of ribosome, playing a critical role in protein translation and ribosome biogenesis while in the nucleus it is tightly associated with nuclear structures, and bound to components of the cytoskeleton, such as tubulin and actin. 67LR is mainly localized in the cell membrane, concentrated in lipid rafts. Acting as a receptor for laminin is not the only function of 67LR; indeed, it also acts as a receptor for viruses, bacteria and prions. 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. The primary function of 67LR in cancer is to promote tumor cell adhesion to basement membranes, the first step in the invasion-metastasis cascade. Thus, 67LR is overexpressed in neoplastic cells as compared to their normal counterparts and its overexpression is considered a molecular marker of metastatic aggressiveness in cancer of many tissues, including breast, lung, ovary, prostate, stomach, thyroid and also in leukemia and lymphoma. Thus, inhibiting 67LR binding to laminin could be a feasible approach to block cancer progression. Here, we review the current understanding of the structure and function of this molecule, highlighting its role in cancer invasion and metastasis and reviewing the various therapeutic options targeting this receptor that could have a promising future application.

scholarly journals SARS-CoV-2 infection and recurrence of anti-glomerular basement disease: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Alexander Winkler ◽  
Emanuel Zitt ◽  
Hannelore Sprenger-Mähr ◽  
Afschin Soleiman ◽  
Manfred Cejna ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Plasma Cells ◽  
Rapidly Progressive Glomerulonephritis ◽  
Kidney Injury ◽  
Pulmonary Involvement ◽  
Pulmonary Haemorrhage ◽  
Basement Membranes ◽  
High Avidity ◽  
History Of

Abstract Background Anti-glomerular basement membrane disease (GBM) disease is a rare autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary haemorrhage. Recently, an association between COVID-19 and anti-glomerular basement membrane (anti-GBM) disease has been proposed. We report on a patient with recurrence of anti-GBM disease after SARS-CoV-2 infection. Case presentation The 31-year-old woman had a past medical history of anti-GBM disease, first diagnosed 11 years ago, and a first relapse 5 years ago. She was admitted with severe dyspnoea, haemoptysis, pulmonary infiltrates and acute on chronic kidney injury. A SARS-CoV-2 PCR was positive with a high cycle threshold. Anti-GBM autoantibodies were undetectable. A kidney biopsy revealed necrotising crescentic glomerulonephritis with linear deposits of IgG, IgM and C3 along the glomerular basement membrane, confirming a recurrence of anti-GBM disease. She was treated with steroids, plasma exchange and two doses of rituximab. Pulmonary disease resolved, but the patient remained dialysis-dependent. We propose that pulmonary involvement of COVID-19 caused exposure of alveolar basement membranes leading to the production of high avidity autoantibodies by long-lived plasma cells, resulting in severe pulmonary renal syndrome. Conclusion Our case supports the assumption of a possible association between COVID-19 and anti-GBM disease.

scholarly journals A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadine Aschmoneit ◽  
Sophia Steinlein ◽  
Lennart Kühl ◽  
Oliver Seifert ◽  
Roland E. Kontermann
Keyword(s):  
T Cell ◽  
Binding Site ◽  
Cancer Cell ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
Egf Receptor ◽  
Bispecific Antibodies ◽  
Target Cells ◽  
Single Chain

AbstractHER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. In this study, we developed bispecific antibodies for T-cell retargeting to HER3-expressing tumor cells, utilizing either a single-chain diabody format (scDb) with one binding site for HER3 and one for CD3 on T-cells or a trivalent bispecific scDb-scFv fusion protein exhibiting an additional binding site for HER3. The scDb-scFv showed increased binding to HER3-expressing cancer cell lines compared to the scDb and consequently more effective T-cell activation and T-cell proliferation. Furthermore, the bivalent binding mode of the scDb-scFv for HER3 translated into more potent T-cell mediated cancer cell killing, and allowed to discriminate between moderate and low HER3-expressing target cells. Thus, our study demonstrated the applicability of HER3 for T-cell retargeting with bispecific antibodies, even at moderate expression levels, and the increased potency of an avidity-mediated specificity gain, potentially resulting in a wider safety window of bispecific T-cell engaging antibodies targeting HER3.

scholarly journals Die Kaliumhydrogenphosphat-induzierte Nephropathie des Hundes. I. Pathogenese der Tubulusatrophiee [Potassium Hydrogen Phosphate Induced Nephropathy in the Dog. I. Pathogenesis of Tubular Atrophy—author's trans.]

1980 ◽  
Vol 17 (6) ◽  
pp. 699-719 ◽  
Author(s):  
P. Schneider ◽  
G. Pappritz ◽  
R. Müller-Peddinghaus ◽  
M. Bauer ◽  
H. Lehmann ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Epithelial Cells ◽  
Basement Membrane ◽  
Basement Membranes ◽  
Tubular Epithelial Cells ◽  
Beagle Dogs ◽  
Lysosomal Degradation ◽  
Tubular Basement Membrane ◽  
Tubular Atrophy ◽  
Study Results

A nephropathy with severe tubular atrophy was observed in Beagle dogs after oral administration of K2HPO4 for 14 or 38 weeks. We describe the complete lysosomal degradation of atrophying tubular epithelial cells. During two experiments of 14 and 38 weeks duration, respectively, a total of 15 Beagle dogs received 0.8 g K2HPO4/kg body weight daily with their food. All dogs were examined clinically at regular intervals. Renal biopsies were taken in the fourth week from beagles of the 14-week study. Results were compared with those of control dogs. At the end of the experiments the animals were killed and necropsies done. Different stains and histochemical reactions were applied to paraffin sections of the kidneys. Acid phosphatase and β-glucuronidase were found on cryostat sections. Kidneys fixed by perfusion of five Beagles from the 38-week study and three Beagles of the 14-week study, and from five control dogs, were examined electron microscopically. Ultrahistochemically, acid phosphatase was demonstrated. Clinically, the dogs in both experiments vomited, were cachectic, and had elevated creatinine and blood urea nitrogen. Morphologically, qualitatively identical changes were seen, but the renal damage was most marked at 38 weeks. There were disseminated tubular atrophy (usually of the proximal tubules), focal scar tissue and nephrocalcinosis. The following pathogenesis was established for the lesions of the proximal tubule: Tubular atrophy begins with loss of differentiation of epithelial cells. Enzyme histochemistry, ultrahistochemistry and electron microscopy show an increase in autophagic vacuoles and autophagolysosomes. The lysosomal bodies showing fusion enclose large parts of the cytoplasm as the process continues. Complete lysosomal degradation of epithelial cells and extrusion of large lysosomes into the tubular lumen follow. After complete enzymatic digestion of the intratubular detritus, the residue is empty, convoluted and collapsed tubular basement membrane. Atrophic tubular epithelial cells have many organelle-free zones at their base, which contain fine filamentous material resembling that of the basement membrane. The degradation processes described here may explain why clinically the urinary sediment contains few cylinders and epithelial cells and why proteinuria decreases significantly toward the end of the experiment. So far, it is not clear whether the tubular basement membrane is synthesized by the tubular cells, by fibroblasts or by both cell types. The presence of basement membrane-like material in tubular epithelial cells and in parietal epithelial cells of the glomerulus favors the view that epithelial cells produce the basement membranes and that increased production of basement membrane-like material is a sign of loss of differentiation.

scholarly journals A Cell Culture Substrate with Biologically Relevant Size-Scale Topography and Compliance of the Basement Membrane

Langmuir ◽  
2014 ◽  
Vol 30 (8) ◽  
pp. 2101-2108 ◽  
Author(s):  
Shaun P. Garland ◽  
Clayton T. McKee ◽  
Yow-Ren Chang ◽  
Vijay Krishna Raghunathan ◽  
Paul Russell ◽  
...  
Keyword(s):  
Cell Culture ◽  
Basement Membrane ◽  
Biologically Relevant ◽  
Size Scale ◽  
Culture Substrate ◽  
A Cell ◽  
Cell Culture Substrate

scholarly journals Wnt5a Signaling in Normal and Cancer Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Yan Zhou ◽  
Thomas J. Kipps ◽  
Suping Zhang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Target Cells ◽  
Dependent Manner ◽  
Self Renewal ◽  
Surface Receptors ◽  
Canonical Wnt

Wnt5a is involved in activating several noncanonical Wnt signaling pathways, which can inhibit or activate canonical Wnt/β-catenin signaling pathway in a receptor context-dependent manner. Wnt5a signaling is critical for regulating normal developmental processes, including stem cell self-renewal, proliferation, differentiation, migration, adhesion, and polarity. Moreover, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a signaling in regulating normal and cancer stem cell self-renewal, cancer cell proliferation, migration, and invasion. In this article, we review recent findings regarding the molecular mechanisms and roles of Wnt5a signaling in stem cells in embryogenesis and in the normal or neoplastic breast or ovary, highlighting that Wnt5a may have different effects on target cells depending on the surface receptors expressed by the target cell.

scholarly journals Extracellular Vesicle Transmission of Chemoresistance to Ovarian Cancer Cells Is Associated with Hypoxia-Induced Expression of Glycolytic Pathway Proteins, and Prediction of Epithelial Ovarian Cancer Disease Recurrence

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3388
Author(s):  
Mona Alharbi ◽  
Andrew Lai ◽  
Shayna Sharma ◽  
Priyakshi Kalita-de Croft ◽  
Nihar Godbole ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Multiple Reaction Monitoring ◽  
Metabolic Reprogramming ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Target Cells ◽  
Glycolysis Pathway

Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells’ heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1–6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly (p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort (n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management.

Endothelial k-RasV12 Expression Induces Capillary Deficiency Attributable to Marked Tube Network Expansion Coupled to Reduced Pericytes and Basement Membranes

2021 ◽  
Author(s):  
Zheying Sun ◽  
Scott S. Kemp ◽  
Prisca K. Lin ◽  
Kalia N. Aguera ◽  
George E. Davis
Keyword(s):  
Protein Kinase ◽  
Basement Membrane ◽  
Arteriovenous Malformations ◽  
Network Formation ◽  
Tube Formation ◽  
Small Gtpase ◽  
Basement Membranes ◽  
Formation Mechanisms ◽  
Lumen Formation ◽  
The Impact

Objective: We sought to determine how endothelial cell (EC) expression of the activating k-Ras mutation, k-RasV12, affects their ability to form lumens and tubes and interact with pericytes during capillary assembly Approach and Results: Using defined bioassays where human ECs undergo observable tubulogenesis, sprouting behavior, pericyte recruitment to EC-lined tubes, and pericyte-induced EC basement membrane deposition, we assessed the impact of EC k-RasV12 expression on these critical processes that are necessary for proper capillary network formation. This mutation, which is frequently seen in human ECs within brain arteriovenous malformations, was found to markedly accentuate EC lumen formation mechanisms, with strongly accelerated intracellular vacuole formation, vacuole fusion, and lumen expansion and with reduced sprouting behavior, leading to excessively widened tube networks compared with control ECs. These abnormal tubes demonstrate strong reductions in pericyte recruitment and pericyte-induced EC basement membranes compared with controls, with deficiencies in fibronectin, collagen type IV, and perlecan deposition. Analyses of signaling during tube formation from these k-RasV12 ECs reveals strong enhancement of Src, Pak2 (P21 [RAC1 (Rac family small GTPase 1)] activated kinase 2), b-Raf (v-raf murine sarcoma viral oncogene homolog B1), Erk (extracellular signal–related kinase), and Akt activation and increased expression of PKCε (protein kinase C epsilon), MT1-MMP (membrane-type 1 matrix metalloproteinase), acetylated tubulin and CDCP1 (CUB domain-containing protein 1; most are known EC lumen regulators). Pharmacological blockade of MT1-MMP, Src, Pak, Raf, Mek (mitogen-activated protein kinase) kinases, Cdc42 (cell division cycle 42)/Rac1, and Notch markedly interferes with lumen and tube formation from these ECs. Conclusions: Overall, this novel work demonstrates that EC expression of k-RasV12 disrupts capillary assembly due to markedly excessive lumen formation coupled with strongly reduced pericyte recruitment and basement membrane deposition, which are critical pathogenic features predisposing the vasculature to develop arteriovenous malformations.

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