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Seminars in Cancer Biology May 2020A great hallmark of breast cancer is the absence or presence of estrogen receptors ERα and ERβ, with a dominant role in cell proliferation, differentiation and cancer... (Review)
Review
A great hallmark of breast cancer is the absence or presence of estrogen receptors ERα and ERβ, with a dominant role in cell proliferation, differentiation and cancer progression. Both receptors are related with Epithelial-to-Mesenchymal Transition (EMT) since there is a relation between ERs and extracellular matrix (ECM) macromolecules expression, and therefore, cell-cell and cell-ECM interactions. The endocrine resistance of ERα endows epithelial cells with increased aggressiveness and induces cell proliferation, resulting into a mesenchymal phenotype and an EMT status. ERα signaling may affect the transcriptional factors which govern EMT. Knockdown or silencing of ERα and ERβ in MCF-7 and MDA-MB-231 breast cancer cells respectively, provoked pivotal changes in phenotype, cellular functions, mRNA and protein levels of EMT markers, and consequently the EMT status. Mesenchymal cells owe their migratory and invasive properties to invadopodia, while in epithelial cells, lamellipodia and filopodia are mostly observed. Invadopodia, are actin-rich protrusions of plasma membrane, promoting proteolytic degradation of ECM and tumor invasion. Cortactin and MMP-14 govern the formation and principal functions of invadopodia. In vitro experiments proved that lumican inhibits cortactin and MMP-14 expression, alters the formation of lamellipodia and transforms mesenchymal cells into epithelial-like. Conclusively, lumican may inhibit or even reverse the several metastatic features that EMT endows in breast cancer cells. Therefore, a lumican-based anti-cancer therapy which will pharmacologically target and inhibit EMT might be interesting to be developed.
Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Epithelial-Mesenchymal Transition; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Lumican; Molecular Targeted Therapy; Podosomes; Signal Transduction
PubMed: 31401293
DOI: 10.1016/j.semcancer.2019.08.003 -
Critical Reviews in Oncology/hematology Mar 2021Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as... (Review)
Review
Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.
Topics: Cell Line, Tumor; Extracellular Matrix; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Podosomes
PubMed: 33482351
DOI: 10.1016/j.critrevonc.2021.103236 -
Journal of Cellular and Molecular... Mar 2020In the ageing skeleton, the balance of bone reconstruction could commonly be broken by the increasing of bone resorption and decreasing of bone formation. Consequently,... (Review)
Review
In the ageing skeleton, the balance of bone reconstruction could commonly be broken by the increasing of bone resorption and decreasing of bone formation. Consequently, the bone resorption gradually occupies a dominant status. During this imbalance process, osteoclast is unique cell linage act the bone resorptive biological activity, which is a highly differentiated ultimate cell derived from monocyte/macrophage. The erosive function of osteoclasts is that they have to adhere the bone matrix and migrate along it, in which adhesive cytoskeleton recombination of osteoclast is essential. In that, the podosome is a membrane binding microdomain organelle, based on dynamic actin, which forms a cytoskeleton superstructure connected with the plasma membrane. Otherwise, as the main adhesive protein, integrin regulates the formation of podosome and cytoskeleton, which collaborates with the various molecules including: c-Cbl, p130 , c-Src and Pyk2, through several signalling cascades cross talking, including: M-CSF and RANKL. In our current study, we discuss the role of integrin and associated molecules in osteoclastogenesis cytoskeletal, especially podosomes, regulation and relevant signalling cascades cross talking.
Topics: Animals; Bone Resorption; Cytoskeleton; Humans; Integrins; Macrophage Colony-Stimulating Factor; Mice; Osteoclasts; Osteogenesis; Phosphatidylinositol 3-Kinases; Podosomes; RANK Ligand; Signal Transduction; Syk Kinase
PubMed: 32045092
DOI: 10.1111/jcmm.15052 -
Journal of Virology Apr 2021Macrophages are one of the major targets of (HIV-1) and play crucial roles in viral dissemination and persistence during AIDS progression. Here, we reveal the dynamic...
Macrophages are one of the major targets of (HIV-1) and play crucial roles in viral dissemination and persistence during AIDS progression. Here, we reveal the dynamic podosome-mediated entry of HIV-1 into macrophages. Inhibition of podosomes prevented HIV-1 entry into macrophages, while stimulation of podosome formation promoted viral entry. Single-virus tracking revealed the temporal and spatial mechanism of the dynamic podosome-mediated viral entry process. The core and ring structures of podosomes played complex roles in viral entry. The HIV coreceptor, CCR5, was recruited to form specific clusters at the podosome ring, where it participated in viral entry. The podosome facilitated HIV-1 entry with a rotation mode triggered by dynamic actin. Our discovery of this novel HIV-1 entry route into macrophages, mediated by podosomes critical for cell migration and tissue infiltration, provides a new view of HIV infection and pathogenesis, which may assist in the development of new antiviral strategies.Macrophages are motile leukocytes and play critical roles in HIV-1 infection and AIDS progression. Podosomes, as small dynamic adhesion microdomains driven by the dynamic actin cytoskeleton, are mainly involved in cell migration of macrophages. Herein, we found that HIV-1 uses dynamic podosomes to facilitate its entry into macrophages. Single-virus imaging coupled with drug assays revealed the mechanism underlying the podosome-mediated route of HIV-1 entry into macrophages, including the dynamic relationship between the viral particles and the podosome core and ring structures, the CCR5 coreceptor. The dynamic podosome-mediated entry of HIV-1 into macrophages will be very significant for HIV-1 pathogenesis, especially for viral dissemination via macrophage migration and tissue infiltration. Thus, we report a novel HIV-1 entry route into macrophages mediated by podosomes, which extends our understanding of HIV infection and pathogenesis.
PubMed: 33627394
DOI: 10.1128/JVI.02480-20 -
Neuroscience Nov 2020Alzheimer's disease (AD) is a neurodegenerative disease mainly associated with aging, oxidative stress and genetic mutations. There are two pathological proteins... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disease mainly associated with aging, oxidative stress and genetic mutations. There are two pathological proteins involved in AD; Amyloid-β peptide and microtubule-associated protein Tau (MAPT). The β- and γ-secretase enzyme cleaves the Amyloid precursor protein, which results in the formation of extracellular plaques in brain. While, Tau undergoes hyperphosphorylation and other post-translational modifications (PTMs), which eventually generates Tau oligomers, and intracellular neurofibrillary tangles (NFTs) in neurons. Moreover, the brain-resident glia and infiltrated macrophages elevate the level of CNS inflammation, which trigger the oxidative damage of neuronal circuits by reactive oxygen species (ROS) and Nitric oxide (NO). Microglia is the primary immune cell in the CNS, which is continuously surveilling the neuronal synapses and pathogen invasion. Microglia in the resting state is called 'Ramified', which possess long surveilling extensions with a small cell body. But, upon activation, microglia retracts the cellular extensions and transform into round migratory cells, called as 'Amoeboid' state. Activated microglia undergoes actin remodeling by forming lamellipodia and filopodia, which directs the migratory axis while podosomes formed are involved in extracellular matrix degradation for invasion. Protein-aggregates in malfunctioning synapses and in CNS milieu can be detected by microglia, which results in its activation and migration. Subsequently, the phagocytosis of synapses leads to the inflammatory burst and memory loss. The extracellular nucleotides released from damaged neurons and the cytokine-chemokine gradients allow the neighboring microglia and macrophages to migrate-infiltrate at the site of neuronal-damage. The ionotropic (P2XR) and metabotropic (P2YR) purinergic receptor recognize extracellular ATP/ADP, which propagates through the intracellular calcium signaling, chemotaxis, phagocytosis and inflammation. The P2Y receptors give 'find me' or 'eat me' signals to microglia to either migrate or phagocytose cellular debris. Further, the actin cytoskeleton helps microglia to mediate directed chemotaxis and neuronal repair during neurodegeneration. Hence, we aim to emphasize the connection between purinergic signaling and actin-driven mechanical movements of microglia for migration and inflammation in AD.
Topics: Actins; Alzheimer Disease; Chemotaxis; GTP-Binding Proteins; Humans; Microglia; Neurodegenerative Diseases; Receptors, Purinergic
PubMed: 32941933
DOI: 10.1016/j.neuroscience.2020.09.024 -
BioEssays : News and Reviews in... Nov 2020Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin... (Review)
Review
Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin-containing focal adhesions and cadherin-containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin-containing hemidesmosomes oppose force transduction and traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin-enriched microdomains. This review discusses mechanotransduction by multiple integrin- and cadherin-based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Cytoskeleton; Humans; Integrins; Mechanotransduction, Cellular
PubMed: 32830356
DOI: 10.1002/bies.202000119 -
Experimental & Molecular Medicine Mar 2022Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate...
Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD.
Topics: Animals; Cell Adhesion; Cresols; Cytoskeletal Proteins; Humans; Indican; Mice; Monocytes; Podosomes; Protein Serine-Threonine Kinases; THP-1 Cells
PubMed: 35246616
DOI: 10.1038/s12276-022-00738-8 -
SLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis.Bone Feb 2023SLC4A2 belongs to the Na-independent solute carrier family 4 (SLC4) of anion exchangers, which regulate electroneutral exchange of Cl for HCO and mediate intra- and... (Review)
Review
SLC4A2 belongs to the Na-independent solute carrier family 4 (SLC4) of anion exchangers, which regulate electroneutral exchange of Cl for HCO and mediate intra- and extra-cellular pH, chloride concentration and cell volume. Slc4a2 also participates in gastric acid secretion, spermatogenesis and osteoclastogenesis. During osteoclast differentiation, Slc4a2 is exclusively expressed at the contra-lacunar membrane and is up-regulated with osteoclast maturation. Bi-allelic Slc4a2 loss-of-function mutations have been known to cause osteopetrosis in mice and cattle, but not in human. Recently, we have identified bi-allelic pathogenic variants in SLC4A2 in a patient affected by osteopetrosis with severe renal insufficiency, suggesting SLC4A2 deficiency causes a new type of autosomal recessive osteopetrosis (osteopetrosis, Ikegawa type). In this article, we review the advances in exploring the multiple functions of SLC4A2 with emphasis on its roles in osteoclast. Our review would contribute to understanding of the phenotypic spectrum and the pathomechanism of SLC4A2-associated osteopetrosis.
Topics: Animals; Cattle; Humans; Male; Mice; Chloride-Bicarbonate Antiporters; Mutation; Osteoclasts; Osteogenesis; Osteopetrosis
PubMed: 36343920
DOI: 10.1016/j.bone.2022.116603 -
BioEssays : News and Reviews in... Aug 2023During immune responses against invading pathogenic bacteria, the cytoskeleton network enables macrophages to implement multiple essential functions. To protect the host... (Review)
Review
During immune responses against invading pathogenic bacteria, the cytoskeleton network enables macrophages to implement multiple essential functions. To protect the host from infection, macrophages initially polarize to adopt different phenotypes in response to distinct signals from the microenvironment. The extracellular stimulus regulates the rearrangement of the cytoskeleton, thereby altering the morphology and migratory properties of macrophages. Subsequently, macrophages degrade the extracellular matrix (ECM) and migrate toward the sites of infection to directly contact invading pathogens, during which the involvement of cytoskeleton-based structures such as podosomes and lamellipodia is indispensable. Ultimately, macrophages execute the function of phagocytosis to engulf and eliminate the invading pathogens. Phagocytosis is a complex process that requires the cooperation of cytoskeleton-enriched super-structures, such as filopodia, lamellipodia, and phagocytic cup. This review presents an overview of cytoskeletal regulations in macrophage polarization, ECM degradation, migration, and phagocytosis, highlighting the pivotal role of the cytoskeleton in host defense against infection.
Topics: Macrophages; Cytoskeleton; Phagocytosis; Cell Membrane; Microtubules
PubMed: 37254735
DOI: 10.1002/bies.202200225 -
Communications Biology Mar 2020Integrin receptors orchestrate cell adhesion and cytoskeletal reorganization. The endocytic mechanism of integrin-β3 receptor at the podosome remains unclear. Using...
Integrin receptors orchestrate cell adhesion and cytoskeletal reorganization. The endocytic mechanism of integrin-β3 receptor at the podosome remains unclear. Using viscous RGD-membrane as the model system, here we show that the formation of podosome-like adhesion promotes Dab2/clathrin-mediated endocytosis of integrin-β3. Integrin-β3 and RGD ligand are endocytosed from the podosome and sorted into the endosomal compartment. Inhibitions of podosome formation and knockdowns of Dab2 and clathrin reduce RGD endocytosis. F-actin assembly at the podosome core exhibits protrusive contact towards the substrate and results in plasma membrane invaginations at the podosome ring. BIN1 specifically associates with the region of invaginated membrane and recruits DNM2. During the podosome formation, BIN1 and DNM2 synchronously enrich at the podosome ring and trigger clathrin dissociation and RGD endocytosis. Knockdowns of BIN1 and DNM2 suppress RGD endocytosis. Thus, plasma membrane invagination caused by F-actin polymerization promotes BIN1-dependent DNM2 recruitment and facilitate integrin-β3 endocytosis at the podosome.
Topics: Actins; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Cell Adhesion; Cell Membrane; Cells, Cultured; Clathrin; Dynamin II; Endocytosis; Fibroblasts; Gene Knockdown Techniques; Humans; Integrin beta3; Ligands; Membranes, Artificial; Mice; Nerve Tissue Proteins; Oligopeptides; Podosomes; Polymerization; Rats; Transfection; Tumor Suppressor Proteins
PubMed: 32170110
DOI: 10.1038/s42003-020-0843-2