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PubMed1995

Expression of differentiation-related phenotypes and apoptosis are independently regulated during myeloid cell differentiation.

When human promyelocytic leukemia cell line HL-60 was treated with various differentiation-inducers, apoptosis always occurred after the full appearance of differentiation-related phenotypes. However, the two phenomena could be dissociated when HL-60 cells were treated with PDBu. When HL-60 cells were cultured with PDBu for more than 36 h, apoptosis was induced following differentiation. Apoptosis was not, however, observed when PDBu was removed within 24 h, even though induction of differentiation-related phenotypes, such as NBT-reducing ability and surface marker expression, was the same as that in the control. Northern blot analysis revealed that bcl-2 mRNA was rapidly down-regulated within 6 h of the treatment with PDBu. The amount of bcl-2 mRNA recovered to that of undifferentiated HL-60 cells when PDBu was washed out within 24 h. In contrast, the recovery of bcl-2 was incomplete when the cells were treated with PDBu for more than 36 h, suggesting that bcl-2 is also a critical regulator of the cell fate during myeloid differentiation. This hypothesis was confirmed by experiments using antisense oligonucleotides, i.e., blocking the recovery of bcl-2 mRNA by antisense oligonucleotides could result in the induction of apoptosis in HL-60 cells from which PDBu was removed within 24 h. Moreover, overexpression of BCL-2 in HL-60 cells could block apoptosis during differentiation without any significant effect on differentiation itself. These results strongly suggest that apoptosis is not a simple consequence of differentiation-induction, and that apoptosis and differentiation are regulated independently in myeloid cells.

Apoptosis↗
PubMed2003

Differential effect of HIV protease inhibitors on adipogenesis: intracellular ritonavir is not sufficient to inhibit differentiation.

OBJECTIVES: Lipodystrophy is a major side effect of HIV protease inhibitor (PI) antiretroviral therapy. It has been shown that protease inhibitors interfere in vitro with adipocyte differentiation. However, there is no evidence that PIs accumulate into preadipocytes and adipocytes and that intra-cellular accumulation is sufficient to alter differentiation. We assessed the effect of six different PIs on the differentiation of cells from four clonal lines. We also studied the capacity of ritonavir to accumulate both into drug-sensitive and drug-resistant cultured adipocytes. METHODS: Adipocyte differentiation of mouse 3T3-F442A, 3T3-L1 and Ob1771 cells as well as embryonic stem cells were investigated at pharmacological concentrations of indinavir, saquinavir, ritonavir, amprenavir, nelfinavir and lopinavir. We used a sensitive ELISA to determine intracellular concentration of ritonavir from 3T3-L1 and Ob1771 preadipocytes. RESULTS: Nelfinavir and lopinavir inhibited adipocyte differentiation whereas amprenavir was ineffective. Indinavir, saquinavir and ritonavir inhibited differentiation of 3T3-L1 and 3T3-F442A cells but did not alter differentiation of either Ob1771 or embryonic stem cells. We showed that ritonavir accumulated in preadipocytes and fully differentiated 3T3-L1 adipocytes as a function of its extracellular concentration. Although Ob1771 cells were resistant and 3T3-L1 cells were sensitive to ritonavir, the drug accumulated to similar levels in both cases. CONCLUSIONS: Protease inhibitors inhibit adipocyte differentiation depending on the cell model used. We showed for the first time that ritonavir accumulates into preadipocytes and adipocytes, suggesting a direct effect on intracellular targets. However, intracellular accumulation was clearly not sufficient as Ob1771 cells remained resistant to the inhibitory effect of ritonavir.

3T3 Cells↗
PubMed1989

Combined effects of differentiation-inducing factor and other cytokines on induction of differentiation of mouse myeloid leukemic cells.

Mouse myeloid leukemic M1 cells are induced to differentiate into macrophage-like cells by differentiation-inducing factors (D-factors) and granulocyte colony-stimulating factor. We examined the effects of recombinant human tumor necrosis factor (rTNF), lymphotoxin (rLT) and interleukin 1 (rIL-1) on the induction of differentiation of M1 cells, compared with the effects of D-factor purified from the conditioned medium of mouse Ehrlich ascites tumor cells and recombinant human granulocyte colony-stimulating factor (rG-CSF). rIL-1 induced phagocytic activity, a typical marker of cell differentiation, in at most 30% of M1 cells at concentrations ranging from 10(-10) M to 10(-7) M. The differentiation-inducing activity of rIL-1 was similar to that of rG-CSF and less than that of D-factor. rTNF induced phagocytic activity in 14% of M1 cells only at a high concentration (10(-7) M). rLT did not induce differentiation of the cells even at 10(-7) M. rTNF stimulated induction of differentiation of M1 cells by D-factor, rG-CSF or rIL-1 by two or three fold. The combination of any two of the cytokines D-factor, rG-CSF and rIL-1 induced differentiation of M1 cells more efficiently than any of these cytokines alone. Moreover, the combination of three cytokines rG-CSF, rIL-1 and rTNF, all of which are known to be produced by macrophages, was more effective than the combination of any two of these cytokines in induction of differentiation of M1 cells.

Animals↗
PubMed1981

Epithelial-directed mesenchyme differentiation in vitro model of murine odontoblast differentiation mediated by quail epithelia.

To assess the requirement for specific or possibly non-specific epithelial instructions for mesenchymal cell differentiation, we designed studies to evaluate and compare homotypic with heterotypic tissue recombinations across vertebrate species. These studies further tested the hypothesis that determined dental papilla mesenchyme requires epithelial-derived instructions to differentiate into functional odontoblast cells using a serumless, chemically-defined medium. Theiler stage 25 C57BL/6 or Swiss Webster cap stage mandibular first molar tooth organs or trypsin-dissociated, homotypic epithelial-mesenchymal tissue recombinants resulted in the differentiation of odontoblasts within 3 days. Epithelial differentiation into functional ameloblasts was observed within 7 days. Trypsin-dissociated and isolated mesenchyme did not differentiate into odontoblasts under these experimental conditions. Heterotypic recombinants between quail Hamburger-Hamilton stages 22-26 mandibular epithelium and Theiler stage 25 dental papilla mesenchyme routinely resulted in odontoblast differentiation within 3 days in vitro. Odontoblast differentiation and the production of dentine extracellular matrix continued throughout the 10 days in organ culture. Ultrastructural observations of the interface between quail and mouse tissues indicated the reconstitution of the basal lamina as well as the maintenance of an intact basal lamina during 10 days in vitro. Quail epithelial cells did not differentiate into ameloblasts and no enamel extracellular matrix was observed. These results show that quail mandibular epithelium can provide the required developmental instructions for odontoblast differentiation in the absence of serum or other exogenous humoral factors in a chemically-defined medium. They also suggest the importance of reciprocal epithelial-mesenchymal interactions during epidermal organogenesis.

Ameloblasts↗
PubMed2006

Effect of leukemia inhibitory factor on embryonic stem cell differentiation: implications for supporting neuronal differentiation.

AIM: Leukemia inhibitory factor (LIF), a pleiotropic cytokine, has been used extensively in the maintenance of mouse embryonic stem cell pluripotency. In this current work, we examined the effect of the LIF signaling pathway in embryonic stem (ES) cell differentiation to a neural fate. METHODS: In the presence of LIF (1000 U/mL), the production of neuronal cells derived from embryoid bodies (EB) was tested under various culture conditions. Inhibition of the LIF pathway was examined with specific inhibitors. The effects of cell apoptosis and proliferation on neural differentiation were examined. ES cell differentiation into three-germ layers was compared. RESULTS: Under various culture conditions, neuronal differentiation was increased in the presence of LIF. Blocking the LIF-activated STAT3 signaling pathway with specific inhibitors abolished the neuronal differentiation of ES cells, whereas inhibition of the LIF-activated MEK signaling pathway impaired the differentiation of ES cells toward a glial fate. LIF suppressed cell apoptosis and promoted cell proliferation during ES cell differentiation. LIF inhibited the differentiation of ES cells to both mesoderm and extraembryonic endoderm fates, but enhanced the determination of neural progenitors. CONCLUSION: These results suggest that LIF plays a positive role during the differentiation of ES cells into neuronal cells.

Animals↗
PubMed1986

Transcriptional and posttranscriptional control of c-myc during myogenesis: its mRNA remains inducible in differentiated cells and does not suppress the differentiated phenotype.

It is widely accepted that the cellular oncogene c-myc plays an important role in the control of cell proliferation and that its expression diminishes in differentiated cells. We examined whether there is a correlation between c-myc expression and cell proliferation or differentiation by using a subclone of a rat skeletal muscle cell line L6E9. Myoblasts irreversibly withdraw from the cell cycle, fuse to form multinucleated myotubes, and express muscle-specific genes (terminal differentiation). Muscle-specific genes can also be expressed in the absence of fusion (biochemical differentiation). Such mononucleated but biochemically differentiated cells can be stimulated to reenter the cell cycle. c-myc was induced by insulin, insulin-like growth factor, or serum factors in G0-arrested cells, whereas induction by protein synthesis inhibitors or superinduction by protein synthesis inhibitors in combination with serum factors occurred in all physiological states tested. We found that c-myc expression was reduced in biochemically and terminally differentiated cells as well as in quiescent undifferentiated cells but that it remained inducible by growth factors in all three physiological states. Results of nuclear runoff transcription assays suggested that the induction of c-myc mRNA by growth factors and its deinduction in these physiological states were regulated mainly at the transcriptional level. In contrast, induction and superinduction of c-myc mRNA by protein synthesis inhibitors alone and in combination with growth factors, respectively, were regulated posttranscriptionally mainly by stabilization of c-myc mRNA. Moreover, c-myc and muscle-specific genes could be simultaneously transcribed in both biochemically and terminally differentiated cells. These results indicate that irreversible repression of c-myc is not required for terminal myogenic differentiation and that its expression is insufficient by itself to suppress the differentiated phenotype.

Animals↗
PubMed2005

Differential expression of IGF system components in proliferating vs. differentiating growth plate chondrocytes: the functional role of IGFBP-5.

The growth plate is an important target tissue for insulin-like growth factors (IGFs), but little is known about the regulation of the IGF system during the developmental sequence of chondrocytes. We therefore examined the expression profile of IGF system components in proliferating vs. differentiating growth plate chondrocytes by use of two cell culture models of the growth cartilage. In rat growth plate chondrocytes in primary culture, IGF-I expression increased twofold during the process of differentiation. IGF-binding protein-3 (IGFBP-3) expression showed a biphasic pattern of with a twofold increase at the onset of differentiation and a downregulation in late differentiating chondrocytes to 25% of baseline levels; the expression patterns of IGFBP-2, -4 and -6 were not dependent on the developmental stage. In IGF- and IGFBP-3-deficient RCJ3.1C5.18 (RCJ) mesenchymal chondrogenic cells, IGFBP-2 and -6 synthesis declined by 50% during differentiation. IGFBP-5 expression was markedly upregulated during the process of differentiation in both cell culture models. Although IGFBP-5 overexpression did not have an IGF-independent effect on RCJ cell differentiation, it promoted IGF-I-enhanced differentiation of these cells. A potential mechanism for this effect is the specific increase of Akt phosphorylation in IGFBP-5-overexpressing cells in the presence of IGF-I, indicating an increased activity of the phosphatidylinositol (PI) 3-kinase pathway. These data suggest that the developmental stage of the chondrocyte is an important determinant of IGF and IGFBP expression and imply a functional role for IGFBP-5 for upregulating IGF action during chondrocyte differentiation in vivo.

Animals↗
PubMed1988

Differential mechanism for differentiation into immunoglobulin-secreting cells in human resting B lymphocyte subsets isolated on the basis of cell density.

We have investigated differential mechanism for differentiation of human peripheral blood resting B cells to Ig-secreting cells. Purified resting B cells were further fractionated into subsets by discontinuous density gradients of Percoll, and proliferation and differentiation responses to Staphylococcus aureus Cowan I (SAC) and/or T cell-derived soluble factors were studied. High density resting B cells were stimulated to proliferate vigorously in response to SAC, but were poorly differentiated by SAC in presence of T cell factors. In contrast, low density resting B cells failed to proliferate in response to SAC and/or T cell factors; these cells could, however, be induced by stimulation with SAC plus T cell factors to become cells actively secreting Ig. These results indicate that there may exist heterogeneity in the human resting B cells: one subset of resting B cells (B cells with low density) can differentiate directly into Ig-secreting cells without the need for proliferation, and another subset (B cells with high density) can proliferate actively without subsequent differentiation into Ig-secreting cells. To address whether these resting B cell subsets belong to the same lineage, only high density B cells recovered from circulating resting B cells were first stimulated for 7 d with SAC, refractionated on Percoll gradients, and differentiation response of the refractionated B cells to SAC and T cell factors was examined. B cells shifting toward low density fraction were located in the resting status and could differentiate in response to SAC plus T cell factors. These results indicate that some of B cells with high density belong to the same cell lineage as those with low density and they must first proliferate before differentiation.

Antibody-Producing Cells↗
PubMed2004

Fos modulates myeloid cell survival and differentiation and partially abrogates the c-Myc block in terminal myeloid differentiation.

Previously, we have shown that Fos/Jun transcription factor complexes function as positive modulators of myeloid differentiation. Fos, which is stably induced during normal myeloid differentiation, is not induced upon differentiation of M1 myeloblastic leukemia cells. Establishing M1 cells that express a beta-estradiol-conditional FosER chimera, we show that in the absence of the differentiation inducer interleukin-6 (IL-6), Fos expression in M1 myeloblasts promoted apoptotic cell death, entailing cytochrome c release and caspase-9 activation. In contrast, in the presence of IL-6, Fos-mediated apoptosis was abrogated, and Fos promoted terminal differentiation, increasing the sensitivity of M1 cells to be induced for differentiation by IL-6. Fos-mediated apoptosis was accelerated by deregulated c-Myc. Furthermore, restoring Fos expression in M1 partially abrogated the block imparted by deregulated c-Myc on the myeloid differentiation program, increased the sensitivity of the cells to be induced for differentiation, and curtailed their leukemic phenotype. These data provide evidence that Fos/Jun transcription factor complexes play a role in modulating both myeloid cell survival and differentiation and suggest that genetic lesions that alter Fos expression may cooperate with deregulated c-Myc in leukemogenesis.

Animals↗
PubMed2003

G-CSF signaling can differentiate promyelocytes expressing a defective retinoic acid receptor: evidence for divergent pathways regulating neutrophil differentiation.

Several lines of investigation suggest that granulocyte colony-stimulating factor (G-CSF) augments all-trans retinoic acid (ATRA)-induced neutrophil differentiation in acute promyelocytic leukemia (APL). We sought to characterize the relationship between G-CSF- and ATRA-mediated neutrophil differentiation. We established a G-CSF receptor-transduced promyelocytic cell line, EPRO-Gr, derived from the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent EPRO cell line harboring a dominant-negative retinoic acid receptor alpha (RARalpha). In EPRO-Gr, neutrophil differentiation occurs either in GM-CSF upon addition of ATRA or upon induction with G-CSF alone. Transient transfection of EPRO-Gr cells with a RARE-containing reporter plasmid demonstrates increased activity in the presence of ATRA, but not G-CSF, while STAT3 phosphorylation occurs only in response to G-CSF. This suggests that ATRA-mediated differentiation of EPRO-Gr cells occurs via a RARE-dependent, STAT3-independent pathway, while G-CSF-mediated differentiation occurs via a RARE-independent, STAT3-dependent pathway. ATRA and G-CSF thus regulate differentiation by divergent pathways. We characterized these pathways in the APL cell line, NB4. ATRA induction of NB4 cells resulted in morphologic differentiation and up-regulation of C/EBPepsilon and G-CSFR, but not in STAT3 phosphorylation. The addition of G-CSF with ATRA during NB4 induction resulted in STAT3 phosphorylation but did not enhance differentiation. These results may elucidate how G-CSF and ATRA affect the differentiation of primary and ATRA-resistant APL cells.

Animals↗
PubMed1996

Differential effects and glucocorticoid potentiation of bone morphogenetic protein action during rat osteoblast differentiation in vitro.

Bone morphogenetic proteins (BMPs) induce cartilage and bone differentiation in vivo and promote osteoblast differentiation from calvarial and marrow stromal cell preparations. Functional differences between BMP-2, -4, and -6 are not well understood. Recent investigations find that these three closely related osteoinductive proteins may exert different effects in primary rat calvarial cell cultures, suggesting the possibility of unique functions in vivo. In this study, we use a fetal rat secondary calvarial cell culture system to examine the differential effects of BMP-2, -4, and -6 on early osteoblast differentiation. These cells do not spontaneously differentiate into osteoblasts, as do cells in primary calvarial cultures, but rather require exposure to a differentiation initiator such as glucocorticoid or BMP. We determined that BMP-6 is a 2- to 2.5-fold more potent inducer of osteoblast differentiation than BMP-2 or -4. BMP-6 induced the formation of more and larger bone nodules as well as increased osteocalcin secretion. The effects of all three of these BMPs were potentiated up to 10-fold by cotreatment or pretreatment with the glucocorticoid triamcinolone (Trm). The Trm effects were synergistic with those of BMP-2 or -4, suggesting that this glucocorticoid may increase the cell responsiveness to these BMPs. Finally, BMP-6 did not require either cotreatment or pretreatment with Trm to achieve greater amounts of osteoblast differentiation than seen with BMP-2 or BMP-4 treatment, suggesting that BMP-6 may act at an earlier stage of cell differentiation.

Animals↗
PubMed1979

Stem cell growth and differentiation in Hydra attenuata. II. Regulation of nerve and nematocyte differentiation in multiclone aggregates.

The differentiation of nerve cells and nematocytes from interstitial stem cells in Hydra has been investigated under conditions of changing stem cell density. Interstitial stem cells were cultured in a feeder layer system consisting of aggregates of nitrogen mustard-inactivated tissue. The aggregates were seeded with varying numbers of stem cells from 10 to 400 per aggregate; between 4 and 7 days later the rates of nerve and nematocyte differentiation were measured. Nerve differentiation was scored by labelling the stem cell population with [3H]-thymidine and counting nests of 4 proliferating nematoblasts. In both cases the numbers of differentiating cells were normalized to the size of the stem cell population. The results indicate that the rate of nematocyte differentiation increases as the concentration of stem cells increases in aggregates; under the same conditions the rate of nerve differentiation remains essentially constant. To calculate the numbers of stem cells entering each pathway per generation, a computer was programmed to simulate the growth and differentiation of interstitial stem cells. Standard curves were prepared from the simulations relating the rates of nerve and nematocyte differentiation to the fraction of stem cells committed to each pathway per generation. The rates of nerve and nematocyte commitment were then estimated from the experimentally observed rates of differentiation using the standard curves. The results indicate that nerve commitment remains constant at about 0.13 stem cells per generation over a wide range of stem cell concentration. Nematocyte commitment, by comparison, increases from 0.15 to 0.21 stem cells per generation as stem cell concentration increases in aggregates. The fact that the ratio of nerve to nematocyte commitment changes under our conditions suggests that stem cell commitment is not a stochastic process but subject to control by environmental stimuli.

Animals↗
PubMed2006

The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation.

Myoblasts respond to growth factor deprivation either by diffentiation into multinucleated myotubes or by undergoing apoptosis. The induction of apoptosis and differentiation in myogenic lineage may use overlapping cellular mechanisms. Here we demonstrate that the expression of the small heat shock protein alphaB-crystallin as well as MyoD and myogenin is induced during myogenic differentiation in C2C12 cells, and these inductions occur at an early stage in the differentiation in vitro. To investigate the effect of alphaB-crystallin on myogenic differentiation and apoptosis, C2C12 cells were infected with adenovirus vector bearing full-length alphaB-crystallin cDNA. Overexpression of alphaB-crystallin in C2C12 cells suppressed differentiation-induced apoptosis and activation of caspase 3, and also decreased the expression of MyoD and myogenin during myogenic differentiation of C2C12 cells induced by the differentiation medium. Our findings suggest that stress such as growth factor deprivation plays an important role in triggering apoptosis associated with myogenic differentiation and alphaB-crystallin suppressed the differentiation, apoptosis and caspase 3 activity.

Animals↗
PubMed2006

Selection of neural differentiation-specific genes by comparing profiles of random differentiation.

Differentiation of embryonic stem cells (ESCs) into neurons requires a high level of transcriptional regulation. To further understand the transcriptional regulation of neural differentiation of ESCs, we used oligonucleotide microarray to examine the gene expressions of the guided differentiation (GD) model for dopaminergic (DA) neurons from mouse ESCs. We also determined the gene expression profiles of the random differentiation (RD) model of mouse ESCs into embryoid bodies. From K-means clustering analysis using the expression patterns of the two models, most of the genes (1,282 of 1,884 genes [68.0%]) overlapped in their expression patterns. Six hundred twenty-two differentially expressed genes (DEGs) from the GD model by random variance F-test were classified by their critical molecular functions in neurogenesis and DNA replication (Gene Ontology analysis). However, 400 genes among GD-DEGs (64.3%) showed a high correlation with RD in Spearman's correlation analysis (Spearman's coefficient p(s) >or= .6). The genes showing marginal correlation (-.4 < p(s) < .6) were present in the early stages of differentiation of both GD and RD, which were non-specific to brain development. Finally, we distinguished 66 GD-specific genes based on p(s) <or= -.4, the molecular functions of which were related mainly to vesicle formation, neurogenesis, and transcription factors. From among these GD-specific genes, we confirmed the expression of Serpini1 and Rab33a in P19 differentiation models and adult brains. From these results, we identified the specific genes required for neural differentiation by comparing gene expressions of GD with RD; these would potentially be the highly specific candidate genes necessary for differentiation of DA neurons.

Animals↗
PubMed1992

Gene expression during 3T3-L1 adipocyte differentiation. Characterization of initial responses to the inducing agents and changes during commitment to differentiation.

The mouse 3T3-L1 fibroblastic cell line rapidly differentiates to an adipocyte phenotype when post-confluent cells are treated for 48 h in fetal calf serum-containing medium supplemented with 1 microM dexamethasone (D), 0.5 mM methylisobutylxanthine (M) and 10 micrograms/ml insulin (I). D and I act synergistically to commit the cells to differentiate 24-48 h after initiating treatment, and this is blocked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. In order to identify cellular proteins involved in the differentiation process we analyzed differentiating 3T3-L1 cells using two-dimensional electrophoresis on large format gels. We observed changes in over 300 proteins during differentiation (over 100 within 5 h of initiating differentiation) and many of these are also changed at the level of mRNA (by analysis of in vitro translation products). About 75% of the initial changes were maximally induced by treatment with a combination of M and I, while no more than 10 proteins and their corresponding mRNAs were maximally induced by D within 3.5 h. Another 10 proteins were synergistically regulated by the combination of all three agents (DMI) within 3.5 h. Additional species were induced at later times. Five of these were synergistically induced by treatments that lead to differentiation, were first expressed at elevated levels during commitment and remained elevated in fully differentiated adipocytes. One or more of these proteins could well have a functional role in the commitment to and/or expression of the adipocyte differentiation program.

3T3 Cells↗
PubMed1990

Differential effects of c-myb and c-fes antisense oligodeoxynucleotides on granulocytic differentiation of human myeloid leukemia HL60 cells.

To gain some insight into the role of c-myb and c-fes in myeloid differentiation, the authors have analyzed the ability of HL60 cells to differentiate in response to several different inducers after inhibition of c-myb and c-fes function. This function has been inhibited almost completely by using deoxynucleotides complementary to two 18-nucleotide sequences of c-myb and c-fes encoding mRNA. After 5 days in culture, in several separate experiments with different oligomer preparations, more than 90% growth inhibition was observed in c-myb antisense-treated HL60 cells. At this time, independent of the differentiation inducer used, c-myb antisense-treated HL60 cells differentiate only along the monocytic pathway, whereas in sense oligomer-treated cultures, retinoic acid and dimethyl sulfoxide induced granulocytic differentiation. No perturbation of the HL60 cell growth was observed after 5 days of treatment with antisense c-fes oligomer. However, induction to granulocytic differentiation by retinoic acid and dimethyl sulfoxide resulted in progressive cell death, whereas monocytic differentiation by other differentiation inducers was only marginally affected. These results suggest that granulocytic, unlike monocytic, differentiation requires c-myb-conditioned proliferation and the activity of the protein encoded by c-fes.

Cell Cycle↗
PubMed1990

Neuroendocrine differentiation in poorly differentiated lung carcinomas: a light microscopic and immunohistologic study.

Frozen, unfixed tissue sections from 56 poorly differentiated, non-small cell primary lung tumors were examined by the immunoperoxidase technique with a panel of monoclonal antibodies to neuroendocrine (chromogranin A (CGA), synaptophysin (SYN), S-100) and intermediate filament (cytokeratin, vimentin, neurofilament) antigens. Although light microscopic features of neuroendocrine (NE) differentiation were not present, staining for CGA and/or SYN was identified in 5/17 (29%) large cell carcinomas (LCC) and 4/19 (21%) poorly differentiated adenocarcinomas (PDA). Diffuse, strong SYN staining was present in two LCC and one PDA. Heterogeneous intermediate filament expression (vimentin and/or neurofilament) was frequent (LCC, 10/17 (59%); PDA, 10/19 (53%)) and accompanied NE markers in 8/9 (89%) cases. Poorly differentiated squamous carcinomas were more homogeneous, with focal SYN in only 1/20 (5%) and focal presence of intermediate filaments other than cytokeratin in only 2/20 (10%). We conclude: (a) immunohistologic evidence of NE differentiation is present in a significant proportion of pulmonary large cell and poorly differentiated adenocarcinomas and rare in poorly differentiated squamous carcinomas; (b) NE differentiation is generally accompanied by heterogeneous intermediate filament expression; (c) divergent NE differentiation is not necessarily reflected by light microscopic features.

Adenocarcinoma↗
PubMed1989

Human myelogenous leukemia cell line HL-60 cells resistant to differentiation induction by retinoic acid. Decreased content of glycosphingolipids and granulocytic differentiation by neolacto series gangliosides.

We have recently reported that neolacto series gangliosides (NeuAc-nLc) are increased during granulocytic differentiation of human myelogenous leukemia cell line HL-60 cells induced by retinoic acid and that HL-60 cells are differentiated into mature granulocytes when the cells are cultivated with NeuAc-nLc (Nojiri, H., Kitagawa, S., Nakamura, M., Kirito, K., Enomoto, Y., and Saito, M. (1988) J. Biol. Chem. 263, 7443-7446). In contrast to these wild-type-HL-60 cells, HL-60 cells resistant to differentiation induction by retinoic acid showed a markedly decreased content of gangliosides, especially NeuAc-nLc, and did not show any increase in the content of gangliosides when cultivated with retinoic acid. Neutral glycosphingolipids, the precursors of gangliosides, were not accumulated in these resistant cells. When retinoic acid-resistant HL-60 cells were cultivated in the presence of NeuAc-nLc, the cells were found to be differentiated into mature granulocytes on morphological and functional criteria. The differentiation of cells was dependent on the concentration of gangliosides and was accompanied by inhibition of cell growth. Wild-type HL-60 cells differentiated by NeuAc-nLc showed the changes in ganglioside composition, which were similar to those in wild-type HL-60 cells differentiated by retinoic acid; among the gangliosides changed, 2----3 sialylparagloboside and 2----3 sialylnorhexaosylceramide were increased. These findings suggest (a) that the synthesis of particular NeuAc-nLe molecules is an important step for retinoic acid-induced granulocytic differentiation and this step could be bypassed or replaced by exogenous NeuAc-nLc, and (b) that the defective synthesis of particular NeuAc-nLc molecules is responsible for the failure of differentiation induction in retinoic acid-resistant HL-60 cells by retinoic acid.

Cell Differentiation↗