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PubMed2004

Bidirectional gastric differentiation in cellular mucin phenotype (foveolar and pyloric) in serrated adenoma and hyperplastic polyp of the colorectum.

This study examined whether gastric pyloric gland-type mucin is expressed in serrated adenoma (SA) and in hyperplastic polyp (HP) of the colorectum, and whether cellular position-based gastric differentiation is observed in these lesions as previously hypothesized. Immunostaining was performed for MUC6 and alpha-linked GlcNAc residue (pyloric gland-type mucin markers), human gastric mucin (HGM; foveolar-type mucin marker) and Ki-67 (proliferating cell marker) for 31 SA, 22 HP, 21 traditional tubular adenoma (TA) and 20 hyperplastic nodule (HN). MUC6 showed varying expression in SA, 22/31 (71.0%); HP, 15/22 (68.2%); TA, 2/21 (9.5%); and HN, 0/20 (0%) with significantly higher frequencies in SA and HP compared to those in TA and HN. The alpha-linked GlcNAc residue was found only in SA (3/31, 9.7%) and in HP (2/22, 9.1%). In SA and HP, HGM was typically expressed in the entire crypt length, but some reduction in expression was shown in the basal crypt portion below the proliferative zone. MUC6 and alpha-linked GlcNAc residues were expressed in the basal crypt portion below or below and including proliferative zone. These data demonstrate that SA and HP show bidirectional gastric (foveolar and pyloric gland) differentiation with respect to mucin cellular phenotype and the potential for cellular position-based differentiation, which mimics the gastric antral mucosa.

Adenoma↗

PubMed1992

Cell surface oligosaccharide modulation during differentiation: VI. The effect of biomodulation on the senescent and neoplastic cell phenotype.

These investigations test the hypothesis developed previously, that there are biomolecules which control and integrate cellular differentiation. Our specific interest in cellular differentiation lies in the area of what we refer to as basal or primitive cellular differentiation mechanisms. These mechanisms are common to all cells, and are required for simple recognition and growth regulation. We have investigated two models, the IMR-90 human fetal lung fibroblast model as a representative of normal growth control, and the CG model, canine glioma cells, a transplantable growth transformed cell line. These two models represent normal, and aberrant cellular differentiation control. In previous studies we have shown that the arrangement of the cell surface oligosaccharide structure on these cell types are predictive of phenotypic transition. We have developed, and partially characterized a series of BIOMODULATORS (BM) which delay the onset of display of neoplastic cells. Three classes of BIOMODULATOR have been explored; (1) a large molecular weight natural product (25-35 kDa), PokeWeed Mitogen (PWM); (2) a small molecular weight natural product (500 Da) Cellular Activator and Differentiator (CAD) and a number of natural and synthetic analogs; and (3) an indolizidine alkaloid natural product, Swainsonine (Sw) which has a known cellular target (oligosaccharide biosynthesis). Preliminary data is presented which structurally links some of these BIOMODULATORS in terms of their effective stereochemistry. These BIOMODULATORS, when used before PDL 38, prevent the cell surface oligosaccharide display changes typical of morphological senescence and delay their onset to PDL 100 or more. These BIOMODULATORS also appear to have regulatory effects on the neoplastic cell models. This re-regulation results in increases in generation time and an increase in the ability of these cells to be recognized by cytotoxic lymphocytes. Proton NMR linewidth measurements of the fraction of 'bound' water associated with the cellular surface of treated and untreated cell populations showed induced physical changes in the cell surface related to the use of the BIOMODULATOR and correlated to the oligosaccharide display changes. These data were interpreted as indicating an increase in the organizational level of these cells. The data for normal and neoplastic cell populations are compared and contrasted in an effort to form the basis for an analytical approach to the control and integration of differentiation mechanisms.

Animals↗

PubMed2006

JWA, a novel signaling molecule, involved in the induction of differentiation of human myeloid leukemia cells.

Dysregulation of hematopoietic cellular differentiation contributes to leukemogenesis. Unfortunately, relatively little is known about how cell differentiation is regulated. JWA (AF070523) is a novel all-trans retinoic acid (ATRA) responsible gene that initially isolated from ATRA-treated primary human tracheal bronchial epithelial cells. For the notable performance achieved by ATRA in the differentiation induction therapy, we investigated the role of JWA in the induction of differentiation of human myeloid leukemia cells. Our results showed that JWA was not only regulated by ATRA but also by several other differentiation inducers such as phorbol-12-myristate-13-acetate (TPA), arabinoside (Ara-C), and hemin, involved in the mechanisms of differentiation along different lineages of myeloid leukemia cells arrested at different stages of development. Generally, JWA was up-regulated by these inducers in a time-dependent manner. Inhibition of JWA by RNA interference decreased the induced cellular differentiation. However, in NB4 cells treated with ATRA, dissimilar with others, the expression of JWA was down-regulated, and the induced cellular differentiation could be enhanced by silencing of JWA. Collectively, JWA works as a potential critical molecule, associated with multi-directional differentiation of human myeloid leukemia cells. In NB4 cells, JWA may function as a lineage-restricted gene during differentiation along the monocyte/macrophage-like or granulocytic pathway.

Blotting, Western↗

PubMed1993

Correlation of the expression of double-stranded RNA-dependent protein kinase (p68) with differentiation in head and neck squamous cell carcinoma.

p68 is an inducible protein kinase which is believed to be an important factor in the regulation of both viral and cellular protein synthesis. We have produced a monoclonal antibody (TJ4C4) which specifically detects p68, and which can be used to detect this antigen in formalin-fixed, paraffin-embedded tissues. Because p68 plays an important role in cellular protein synthesis, we hypothesized that it may correlate with normal and neoplastic cellular differentiation. One hundred and seventy-seven head and neck squamous cell carcinoma specimens, representing 82 patients, were studied. The relative amount, frequency, and distribution of p68 expression were determined by microscopic evaluation of ABC immunoperoxidase-stained specimens. A spectrum of immunoreactivity was detected in 156 of 177 tumors, as well as within the normal squamous epithelium. Normal, actively proliferating cells, such as the basal layer of squamous epithelium, expressed comparatively little p68. Increased p68 expression was noted to parallel the morphologic features of cellular differentiation. In neoplastic tissue, p68 expression also increased with the degree of cellular differentiation. These data demonstrate that the expression of p68 parallels the degree of cellular differentiation in squamous cell carcinoma of the head and neck region, as well as within normal squamous mucosa. Therefore, p68 may provide an objective biologic measure of cellular differentiation which does not depend on morphologic features.

Aged↗

PubMed2004

Cadherins: an integral role in inflammatory bowel disease and mucosal restitution.

The intestinal epithelium is characterized by rapid cellular turnover with continuous proliferation of multipotential stem cells within Lieberkuhn's crypts, cellular migration along the crypt-villus axis, cellular differentiation, polarization, apical apoptosis, and luminal shedding. These processes are critical for the development and maintenance of normal intestinal epithelial architecture and function and involve complex cell-cell and cell-substratum interactions, which are mediated by epithelial (E)-cadherin and the integrins, respectively. This review outlines the role of E-cadherin and its cytoplasmic binding proteins, the catenins, as well as the interplay with other mucosal adhesion and restitution molecules during physiological processes in the intestinal epithelium mediating embryogenesis, cellular differentiation, cellular migration, and mucosal repair, as well as what is known about the dysregulation of assembly of the E-cadherin-catenin adhesion complex in inflammatory bowel disease.

Animals↗

PubMed2005

Epigenetic modification as an enabling mechanism for leukemic transformation.

Cancer is now thought of as a fundamentally genetic disease, in that changes in the genome result in aberrant gene expression of oncogenes and tumor suppressor genes to promote oncogenesis. However, with our increasing knowledge of gene regulation, it is becoming obvious that changes in nucleotide sequence are not the sole mechanism for eliciting changes in transcription. An additional layer of regulation of gene expression, called epigenetics, is now being realized as increasingly important in oncogenesis. Epigenetics is defined as non-sequence based changes in chromatin that elicit changes in gene expression that are propagated through mitosis and/or meiosis. The alleles of the genes containing these epigenetic marks are termed epialleles. Epigenetics has been linked to cancer since 1983 by the work of Andy Feinberg and Bert Vogelstein, but has largely remained in the shadows. These changes in chromatin are now at the forefront of research in the field of oncogenesis, both as mechanisms of oncogenesis and as prognostic indicators of cancer risk. Leukemia, due to the defects in cellular differentiation associated with the disease, has important connections to epigenetic gene regulation. Cellular differentiation has been studied as a model system for epigenetic gene control in Drosophila. Homeobox genes in the antennapedia and bithorax gene clusters have long been known to be regulated by trithorax group and Polycomb group of genes, which regulate transcription through chromatin remodeling mechanisms. The ectopic expression of the mammalian homologs of the homeobox genes has been linked to leukemic transformation since 1988, and has continued to show extensive connections. These connections that leukemia has with cellular differentiation make this group of diseases amenable to exploring the mechanisms of epigenetic gene regulation as they pertain to oncogenesis. This review will examine leukemia, with an emphasis on myelogenous leukemia, as a defect in cellular differentiation and examine possibilities of epigenetic gene regulation of oncogenes and tumor suppressor genes.

Animals↗

PubMed2006

AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation.

Human T cell leukemia virus type 1 (HTLV-1) has previously been shown to infect antigen-presenting cells and their precursors in vivo. However, the role these important cell populations play in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis or adult T cell leukemia remains unresolved. To better understand how HTLV-1 infection of these important cell populations may potentially impact disease progression, the regulation of HTLV-1 viral gene expression in established monocytic cell lines was examined. U-937 promonocytic cells transiently transfected with a HTLV-1 long-terminal repeat (LTR) luciferase construct were treated with phorbol 12-myristate 13-acetate (PMA) to induce cellular differentiation. PMA-induced cellular differentiation resulted in activation of basal and Tax-mediated transactivation of the HTLV-1 LTR. In addition, electrophoretic mobility shift analyses demonstrated that PMA-induced cellular differentiation induced DNA-binding activity of cellular transcription factors to Tax-responsive element 1 (TRE-1) repeat II. Supershift analyses revealed that factors belonging to the activator protein 1 (AP-1) family of basic region/leucine zipper proteins (Fra-1, Fra-2, JunB, and JunD) were induced to bind to TRE-1 repeat II during cellular differentiation. Inhibition of AP-1 DNA-binding activity by overexpression of a dominant-negative c-Fos mutant (A-Fos) in transient expression analyses resulted in severely decreased levels of HTLV-1 LTR activation in PMA-induced U-937 cells. These results have suggested that following infection of peripheral blood monocytes, HTLV-1 viral gene expression may become up-regulated by AP-1 during differentiation into macrophages or dendritic cells.

Base Sequence↗

PubMed1983

Cellular enzymatic differentiation in brain vessels of normal and protein-deprived rats. Biochemical studies.

Brain capillary development was studied in normal and protein-deprived rats using the specific activity of alkaline phosphatase (EC 3.1.3.1) and gamma-glutamyl transpeptidase (EC 2.3.2.1) in whole brain homogenates and microvessels obtained by gradient centrifugation according to Orlowski et al. (1974). Pre- and postnatal protein deprivation was induced by a 50% reduction in the dietary protein content. The density of microvessel fragments changed during development. Most of the early developmental increase in the specific activity of both enzymes in whole brain homogenates of normal rats can probably be explained by a rapid formation of new capillary segments. The increase in specific activity of gamma-glutamyl transpeptidase in microvessels was interpreted as a sign of cellular differentiation. Protein deprivation resulted in reduced specific activity of both enzymes in whole brain homogenates of 30-day-old rats, probably as a result of the decreased length per volume of the cerebral capillary network at this age (Conradi et al. 1979a). Signs of impaired endothelial growth were also present in the protein-deprived rats since the distribution of microvessel fragments in the 30-day-old protein-deprived rats was similar to that in 3-week-old normal rats. The specific activity of alkaline phosphatase was decreased in the microvessel fractions of 30- and 96-day-old protein-deprived rats, apparently signifying an effect of the protein deprivation on the endothelial cells. These effects of protein deprivation on the brain capillary endothelial transport system may have negative consequences for growth and function in the brain.

Age Factors↗

PubMed2004

Inhibition of lens fiber cell morphogenesis by expression of a mutant SV40 large T antigen that binds CREB-binding protein/p300 but not pRb.

Simian virus (SV) 40 large T antigen can both induce tumors and inhibit cellular differentiation. It is not clear whether these cellular changes are synonymous, sequential, or distinct responses to the protein. T antigen is known to bind to p53, to the retinoblastoma (Rb) family of tumor suppressor proteins, and to other cellular proteins such as p300 family members. To test whether SV40 large T antigen inhibits cellular differentiation in vivo in the absence of cell cycle induction, we generated transgenic mice that express in the lens a mutant version of the early region of SV40. This mutant, which we term E107KDelta, has a deletion that eliminates synthesis of small t antigen and a point mutation (E107K) that results in loss of the ability to bind to Rb family members. At embryonic day 15.5 (E15.5), the transgenic lenses show dramatic defects in lens fiber cell differentiation. The fiber cells become post-mitotic, but do not elongate properly. The cells show a dramatic reduction in expression of their beta- and gamma-crystallins. Because CBP and p300 are co-activators for crystallin gene expression, we assayed for interactions between E107KDelta and CBP/p300. Our studies demonstrate that cellular differentiation can be inhibited by SV40 large T antigen in the absence of pRb inactivation, and that interaction of large T antigen with CBP/p300 may be enhanced by a mutation that eliminates the binding to pRb.

Animals↗

PubMed1992

Retinoids: uses and abuses.

There is no doubt that modern retinoids are a two-edged sword. While they appear to normalize many abnormal biologic processes, i.e. modulate cellular differentiation and cellular proliferation, at the same time they can severely "abnormalize" other processes, i.e. embryonic organogenesis. Pharmaceutical ingenuity in separating their toxicity from their efficacy will determine their ultimate value to the therapist.

Cell Differentiation↗

PubMed2006

Malignant peripheral nerve sheath tumors (MPNST)--clinicopathological study and treatment outcome of twenty-four cases.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is biologically an aggressive tumor for which the treatment of choice is the surgery. We reviewed the clinical profile, diagnostic methods, treatment patterns, and outcome of twenty-four MPNST patients in this study. PATIENTS AND METHODS: A retrospective analysis of 24 MPNST patients, treated from 1994 to 2002, in the department of Surgical Oncology at All India Institute of Medical Sciences, New Delhi, was done. A combination of gross, histopathological and immunohistochemical findings, and proliferation markers (MIB1) were considered for diagnosis and grade of the MPNST. Survival analysis was done by the Kaplan-Meier method and differences were evaluated with the log-rank test. Multivariate analysis was carried out by using Cox's proportional hazards model by using SPSS (Version 9, Chicago, Illinois) software. RESULTS: MPNST constituted 12% of all soft tissue sarcomas, where 21% (5/24) of patients had associated Von Recklinghausen's disease (VRHD). A higher incidence of male preponderance and multifocal MPNST were noted in the present series. At a mean follow-up of 38 months, 13 (54 %) patients had relapse of disease and 5-year over all and disease free survival were 58% and 35% respectively. In univariate analysis, sex (p = 0.05), tumor depth (p < 0.03), and cellular differentiation (p < 0.002) were shown to be adverse prognostic factors for disease free survival and sex (p = 0.04), cellular differentiation (p < 0.0004), and tumor grade (p = 0.05) for overall survival. However, in multivariate analysis, cellular differentiation (p < 0.005) and tumor grade (p < 0.01) emerged as independent prognostic factors for both disease free and overall survival, respectively. Postoperative radiotherapy (RT) has shown a definite role in both disease free and overall survival in this study. CONCLUSION: MPNSTs constituted a significant proportion (12%) of soft tissue sarcoma in our medical center. Heterogeneous differentiation and multifocality of the tumor were few distinct features of MPNST. Sex and cellular differentiation were noticed as the new adverse prognostic factors and adjuvant radiotherapy has been proved to be a significant treatment tool in the current series.

Journal Article↗

PubMed2005

Cyclin D involvement demarcates a late transition in C. elegans embryogenesis.

During development, progression through the cell cycle must be coordinately regulated with cellular differentiation. Despite significant progress in identifying genes required independently for each of these processes, the molecules which facilitate this cross talk have for the most part been elusive. Using the six macrophage-like coelomocytes of the nematode Caenorhabditis elegans as a model system to gain insight into the mesodermal differentiation pathway, we have isolated a set of mutants that alter coelomocyte numbers. One of these mutations, cc600, apparently results from a partial loss-of-function in the C. elegans cyclin D gene, cyd-1. The mutant has coelomocyte-specific defects without changes in other lineages. The mutants show that cell growth, terminal differentiation and cellular function proceed in the absence of cyd-1 activity and cell division. The results suggest that certain mesodermal lineages may be uniquely affected by changes in cyd-1 activity.

Animals↗

PubMed1988

Control of myogenic differentiation by cellular oncogenes.

The establishment of a differentiated phenotype in skeletal muscle cells requires withdrawal from the cell cycle and termination of DNA synthesis. Myogenesis can be inhibited by serum components, purified mitogens, and transforming growth factors, but the intracellular signaling pathways utilized by these molecules are unknown. Recent studies have confirmed a role for proteins encoded by cellular proto-oncogenes in transduction of growth factor effects that lead to cell proliferation. To test the contrasting hypothesis that cellular oncogenes might also regulate tissue-specific gene expression in developing muscle cells, myoblasts have been modified by incorporation of the cognate viral oncogenes, the corresponding normal or oncogenic cellular homologs, and chimeric oncogenes, whose expression can be induced reversibly. Regulation of the endogenous cellular oncogenes also has been examined in detail. Down-regulation of c-myc is not obligatory for myogenesis; rather, inhibitory effects of myc on muscle differentiation are contingent on sustained proliferation. In contrast, activated src and ras genes block myocyte differentiation directly, through a mechanism that is independent of DNA synthesis and is rapidly reversible, resembling the effects of inhibitory growth factors. The coordinate regulation of diverse tissue-specific gene products including muscle creatine kinase, nicotinic acetylcholine receptors, sarcomeric proteins, and voltage-gated ion channels, raises the hypothesis that inhibitors such as transforming growth factor-beta and ras proteins might exert their effects through a transacting transcriptional signal shared by multiple muscle-specific genes.

Animals↗

PubMed1991

Differentiation dependent matrix formation (fibronectin and laminin) in an experimental murine rhabdomyosarcoma model.

Cellular differentiation processes along with formation of extracellular matrix proteins were investigated in methylcholanthrene-induced murine rhabdomyosarcomata. We used primary tumours, allotransplants in nude mice, and the respective tumour recurrences generated by repeated incomplete surgical tumour removal. The expression of the differentiation markers desmin and myoglobin as well as the presence of fibronectin and laminin was ascertained by immunohistochemical methods. The question arises, whether or not correlations between the grade of cellular differentiation (desmin, myoglobin) and extracellular matrix formation (fibronectin, laminin) exist in tumours with striated muscle cell differentiation. The constant relations between cellular differentiation and matrix formation in original tumours also applied to allotransplants and tumour recurrences in which partially modulations of differentiation in comparison with original tumours could be recognized.

Animals↗

PubMed1994

Use of texture parameters in the classification of soft tissue tumors.

Soft tissue tumors are a challenging group of tumors that presents wide morphologic variety. For pathologists, the degree of cellular differentiation, the cellular and nuclear polymorphism and the mitotic rate are major criteria for diagnosis. In image analysis, the architectural organization of such tumors shows local variations that can be understood as texture variations. This study introduced a method of measuring the architectural organization of soft tissue tumors from texture analysis of tissue sections at low magnification. We studied 40 cases of soft tissue tumors classified by pathologists into three groups according to their histologic patterns. Twelve texture parameters were calculated on subimages of 128 x 128 pixels. Our results show that tissue architecture evaluated by texture analysis provides good discrimination of myxoid, spindle cell and round cell tumors.

Cell Differentiation↗

PubMedDate not supplied

Guidelines for prophylactic radical lymph node dissection in cases of carcinoma of the external ear.

All cases of squamous-cell carcinoma of the external ear that were treated at the ENT Clinic, University Hospital, Lund, Sweden, between 1970 and 1977 were analyzed retrospectively to determine parameters for predicting the development of metastases. These cases included 62 males and 3 females, with a mean age of 77 years. The frequency of metastases for these patients was 16.4%. The carcinomas were graded according to four parameters: depth of growth, mode of invasion, cellular differentiation, and cellular plasmolymphocytic response. We concluded that depth of growth and mode of invasion were the most useful of these parameters and that prophylactic lymph node dissection should be performed in cases of tumors larger than 4 cm in diameter, of tumors infiltrating the cartilage, and of smaller tumors with maximum scores for depth of growth and mode of invasion.

Aged↗

PubMed2000

bFGF induces differentiation and death of olfactory neuroblastoma cells.

Olfactory neuroblastoma (ONB) is a highly vascularized and malignant tumor arising in olfactory neuronal precursors from the paranasal sinuses. Previously, we showed that treatment of JFEN cells with transforming growth factor (TGF)-alpha caused them to differentiate and respond to chemical odorants, whereas basic fibroblast growth factor (bFGF) treated cells differentiated and died. In the present study we show that established ONB tumors treated with bFGF upregulate the bFGF receptor (FGFR1) prior to differentiation. This cellular differentiation was evidenced by bFGF-induced expression of the human runt homologue AML1 (PEBP2 alpha B, CBFA-2) that is highly expressed in developing olfactory neuroepithelium and TrkA, a preferred nerve growth factor receptor. Since TrkA is expressed in supporting cells, but not in mature olfactory neurons, we hypothesize that the expression of AML1 and TrkA in bFGF-treated JFEN cells induced supporting cell differentiation. Collectively, these results have implications for the treatment of patients afflicted with ONB.

Animals↗

PubMed2025

3D STED Imaging of Isolated Arabidopsis thaliana Nuclei.

Microscopy imaging of chromatin offers valuable insights into its spatial organization in the nucleus, a novel epigenetic dimension influencing the genome's functions. Particularly, visualization at the nanoscale in single cells is uniquely complementary to molecular profiling methods averaging chromatin configuration and composition over thousands of cells. How are chromatin and chromosomal domains distributed in relation to gene expression? How variable are these configurations? How do chromatin domains evolve in structure, composition, and distribution during cellular differentiation or cellular responses to environmental stimuli? Super-resolution microscopy techniques, like stimulated emission depletion (STED), are key in answering such questions. However, such imaging techniques are not often used in the field of plant cell biology compared to mammalian counterparts, which has greatly advanced our understanding of the 3D principles in genome organization. In an effort to bridge this gap, we provide a clear guide for isolating, embedding, immunostaining, and STED imaging intact leaf nuclei from Arabidopsis thaliana in 3D.

Arabidopsis↗