Tumor-cell infiltration is a major obstacle to successful therapy for brain tumors. Membrane-type matrix metalloproteinases (MT-MMPs), a metzincin subfamily of six proteases, are important mediators of infiltration. The cellular source of MT-MMPs and their role in glioma biology, however, remain controversial.
View Article and Find Full Text PDFBackground: The histological differentiation of individual types of vascular anomalies (VA), such as lymphatic malformations (LM), hemangioma (Hem), paraganglioma (PG), venous malformations (VeM), arteriovenous malformations (AVM), pyogenic granulomas (GP), and (not otherwise classified) vascular malformations (VM n.o.c.
View Article and Find Full Text PDFLichen planus (LP) is a common, chronic relapsing inflammatory disorder of the skin and mucous membranes which often poses a major therapeutic challenge due to its refractory course. Novel pathogenesis-based therapies are urgently needed. As several studies have shown that IL-17 may contribute to LP pathogenesis, we investigated whether therapeutic targeting of IL-17 T cells leads to clinical improvement of mucosal and cutaneous LP lesions.
View Article and Find Full Text PDFParaneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin.
View Article and Find Full Text PDFAutoantibodies against desmoglein (Dsg) 1 and Dsg3 primarily cause blister formation in the autoimmune disease pemphigus vulgaris (PV). Src was proposed to contribute to loss of keratinocyte cohesion. However, the role and underlying mechanisms are unclear and were studied here.
View Article and Find Full Text PDFBackground: We examined the expression of CD200, a ligand of immune tolerance, in transitional cell carcinoma of the human bladder (TCC).
Materials And Methods: CD200 was analyzed by immunohistochemistry (IHC) in 90 patients with suspected TCC lesions of the bladder. Expression of CD200 was exemplarily validated by quantitative reverse transcription polymerase chain reaction and western blot analysis.
In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity.
View Article and Find Full Text PDFPlakophilins (PKP1 to PKP3) are essential for the structure and function of desmosomal junctions as demonstrated by the severe skin defects observed as a result of loss-of-function mutations in mice and men. PKPs play additional roles in cell signaling processes, such as those controlling the cellular stress response and cell proliferation. A key post-translational process controlling PKP function is phosphorylation.
View Article and Find Full Text PDFThe plakophilin family (PKP1 to PKP3) is an essential component of the desmosomal adhesion complex with differentiation-dependent and partially overlapping expression and possible participation of the corresponding genes in malignant transformation. Here, we describe a new protein variant of the human PKP3 gene, namely PKP3b, which differs from the published PKP3a only at the amino-terminus by the splicing in of the newly identified exon 1b. Specific antibodies have demonstrated differential expression patterns of the two variants.
View Article and Find Full Text PDFThe zinc finger transcription factor Gli3 is an important mediator of Sonic hedgehog (Shh) signaling. During early embryonic development Gli3 participates in patterning and growth of the central nervous system, face, skeleton, limb, tooth and gut. Precise regulation of the temporal and spatial expression of Gli3 is crucial for the proper specification of these structures in mammals and other vertebrates.
View Article and Find Full Text PDFThe migratory ability of tumor cells requires cytoskeletal rearrangement processes. Epidermal growth factor receptor (EGFR)-signaling tightly correlates with tumor progression in head and neck squamous cell carcinomas (HNSCCs), and has previously been implicated in the regulation of cytokeratin (CK) expression. In this study, HNSCC cell lines were treated with EGF, and CK expression levels were monitored by Western blot analysis.
View Article and Find Full Text PDFInhibitors of protein deacetylases represent a novel therapeutic option for cancer diseases due to their effects on transcriptional regulation by interfering with histones acetylation and on several other cellular pathways. Recently, their ability to modulate several transcription factors and, interestingly, also co-factors, which actively participate in formation and modulation of transcription complexes was shown. We here investigate whether HMGA2 (High Mobility Group AT-2 hook), a nuclear non-histone transcriptional co-factor with known oncogenic properties, can be influenced by the novel pan-deacetylase inhibitor panobinostat (LBH589) in human hepatocellular carcinoma models.
View Article and Find Full Text PDFThree related proteins of the plakophilin family (PKP1_3) have been identified as junctional proteins that are essential for the formation and stabilization of desmosomal cell contacts. Failure of PKP expression can have fatal effects on desmosomal adhesion, leading to abnormal tissue and organ development. Thus, loss of functional PKP 1 in humans leads to ectodermal dysplasia/skin fragility (EDSF) syndrome, a genodermatosis with severe blistering of the epidermis as well as abnormal keratinocytes differentiation.
View Article and Find Full Text PDFBackground: The zinc-finger transcription factor GLI3 is an important mediator of Sonic hedgehog signaling and crucial for patterning of many aspects of the vertebrate body plan. In vertebrates, the mechanism of SHH signal transduction and its action on target genes by means of activating or repressing forms of GLI3 have been studied most extensively during limb development and the specification of the central nervous system. From these studies it has emerged, that Gli3 expression must be subject to a tight spatiotemporal regulation.
View Article and Find Full Text PDFThe lymph node sinus are channel structures of unquestionable importance in immunology and pathology, specifically in the filtering of the lymph, the transport and processing of antigens, the adhesion and migration of immune cells, and the spread of metastatic cancer cells. Our knowledge of the cell and molecular biology of the sinus-forming cells is still limited, and the origin and biological nature of these cells have long been a matter of debate. Here, we review the relevant literature and present our own experimental results, in particular concerning molecular markers of intercellular junctions and cell differentiation.
View Article and Find Full Text PDFBackground: The transforming growth factors (TGF)-beta, TGF-beta1, TGF-beta2 and TGF-beta 3, and their receptors [T beta RI, T beta RII, T beta R III (betaglycan)] elicit pleiotropic functions in the prostate. Although expression of the ligands and receptors have been investigated, the splice variants have never been analyzed. We therefore have analyzed all ligands, the receptors and the splice variants T beta RIB, T beta RIIB and TGF-beta 2B in human prostatic cells.
View Article and Find Full Text PDFDesmosomes are cell adhesion structures (junctions) that are particularly abundant in cells derived from the ectodermal lineages. These junctions are required to maintain the integrity of organs subjected to mechanical stress, in particular the skin and the heart. This conclusion is partially based on tissue fragility phenotypes observed in mice with null mutations in certain desmosomal genes.
View Article and Find Full Text PDFPlakophilins (PKPs) are a set of 3 constitutive armadillo repeat proteins of the desmosomal plaque, termed PKP 1, PKP 2, and PKP 3, which have been shown to be functionally relevant for desmosomal adhesion. We have performed a systematic immunohistochemical study of the 3 PKPs in oral and pharyngeal squamous cell carcinomas (SqCCs; n = 40); colorectal, pancreatic, and prostate adenocarcinomas (n = 31), and hepatocellular carcinomas (HCCs; n = 8). In SqCCs, PKP 1 and PKP 3 revealed common desmosome-type immunostaining, their expression level being inversely correlated with the degree of malignancy.
View Article and Find Full Text PDFThe linkage of the different types of cytoskeletal proteins to cell adhesion structures at the cytoplasmic membrane and the connection of these contact sites to corresponding sites of adjacent cells is a prerequisite for integrity and stability of cells and tissues. The structurally most prominent types of such cell-cell adhesion complexes are the desmosomes (maculae adhaerentes), which are found in all epithelia and certain non-epithelial tissues. As an element of the cytoskeleton, intermediate filaments are connected to the adhesive desmosomal transmembrane proteins by the cytoplasmic desmosomal plaque proteins.
View Article and Find Full Text PDFDesmoglein 2 (Dsg2) is a Ca(2+)-dependent adhesion molecule of desmosomes and is synthesized in all desmosome-bearing tissues from their earliest appearance onward. To examine the function of Dsg2, its gene was inactivated by homologous recombination in embryonal stem (ES) cells for the generation of knockout mice. DSG2 -/- mice and a considerable number of DSG2 +/- mice died at or shortly after implantation.
View Article and Find Full Text PDFCurrent classification systems in proliferative mammary gland pathology are based on a two-cell system, recognizing only glandular and myoepithelial lines of differentiation. A third cell type has recently been characterized in normal breast tissue by double-immunofluorescence analysis to express cytokeratin 5 (Ck5) only. These cells were shown to represent progenitor or adult stem cells that give rise to the glandular and myoepithelial cell lineage.
View Article and Find Full Text PDFRecently, a number of interleukin-10 (IL-10) homologues, among them IL-24 formerly known as melanocyte differentiation factor-7 (mda-7), has been described. Since IL-10 is released by macrophages and plays an important role in the resolution of inflammatory processes, we hypothesized that IL-24 might also be expressed in cells of the monocyte/macrophage lineage. We analyzed IL-24 expression on the mRNA and protein level in stimulated rat and human macrophages.
View Article and Find Full Text PDFBreast biology and pathology are currently shaped by the two-cell concept that recognizes only glandular and myoepithelial cells. In the present study, we have visualized a previously unidentified cell population within the epithelial compartment of the breast, which displays the phenotypic characteristics of a committed stem cell. Immunofluorescence double labeling with digital image processing and Western blotting were applied to normal breast tissue as well as to noninvasive and invasive breast cancers using antibodies to basal cytokeratin 5 (Ck5), glandular cytokeratins 8/18 (Ck8/18/19), and smooth muscle alpha-actin (SMA) as markers for myoepithelial cells (SMA).
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