scholarly journals Suppression of malignancy in hybrid cells: the mechanism

1985 ◽  
Vol 79 (1) ◽  
pp. 83-94 ◽  
Author(s):  
H. Harris
Keyword(s):  
Extracellular Matrix ◽  
Terminal Differentiation ◽  
Parent Cell ◽  
Malignant Cells ◽  
Hybrid Cells ◽  
Malignant Phenotype ◽  
Diploid Parent ◽  
Wide Range ◽  
Secondary Consequence

When malignant cells, defined by their ability to grow progressively in genetically compatible hosts, are fused with diploid fibroblasts of the same species, the resulting hybrid cells, so long as they retain certain specific chromosomes donated by the diploid parent cell, are non-malignant. When these particular chromosomes are eliminated from the hybrid, the malignant phenotype reappears, and the segregant cell is again able to grow progressively in vivo. In the present experiments the histological character of the lesions produced by the inoculation of crosses between malignant and non-malignant cells was examined. It was found, in a wide range of material, and without exception, that where one or other of the parent cells in the cross was of fibroblastic lineage, malignancy was suppressed when the hybrid cells produced a collagenous extracellular matrix in vivo; and it reappeared when genetic segregants were produced that had lost the ability to produce this matrix. These results are interpreted in terms of a general model in which it is proposed that the progressive multiplication of malignant cells in vivo is a secondary consequence of a genetically stable impairment of terminal differentiation.

The Analysis of Malignancy by Cell Fusion

1974 ◽  
Vol 16 (1) ◽  
pp. 189-198
Author(s):  
F. WIENER ◽  
G. KLEIN ◽  
H. HARRIS
Keyword(s):  
Cell Fusion ◽  
Tumour Cells ◽  
Complementation Analysis ◽  
Malignant Cells ◽  
Hybrid Cells ◽  
Malignant Phenotype ◽  
Recessive Character ◽  
Parental Chromosome ◽  
Wide Range

Previous studies with a variety of transplantable mouse tumours showed that in hybrids between malignant and non-malignant cells, malignancy behaved as a recessive character: the hybrid cells, so long as they retained something close to the complete parental chromosome sets, had little or no ability to grow progressively in vivo. In the experiments we now describe the heritable lesions determining the malignant phenotype were further explored by complementation analysis in which the various tumour cells were fused with each other. Forty-two clonal populations derived from twelve crosses between different kinds of tumour cells were examined. Only one cross generated hybrid cells with reduced tumorigenicity: in all other cases the hybrid cells formed were highly malignant. It thus appears that, in a wide range of different tumours, the lesions determining the malignant phenotype, although recessive, fail to complement each other.

scholarly journals A different approach to tumour suppression. The Alexandra Kefalides Memorial Lecture

1996 ◽  
Vol 109 (9) ◽  
pp. 2189-2197 ◽  
Author(s):  
H. Harris ◽  
J. Rawlins ◽  
J. Sharps
Keyword(s):  
Hybrid Cell ◽  
Terminal Differentiation ◽  
Therapeutic Benefit ◽  
Memorial Lecture ◽  
Parent Cell ◽  
Malignant Cells ◽  
Clinical Context ◽  
Tumour Suppression ◽  
Keratin 1

When tumour cells are fused with normal ones, malignancy is suppressed. It has been shown that this suppression is associated with the imposition on the hybrid cell of the terminal differentiation programme of the normal parent cell. We report here the consequences of imposing the synthesis of keratin 1 and keratin 10, markers of terminal differentiation in the epidermal keratinocyte, on malignant cells of keratinocyte and non-keratinocyte lineage. We find that there is extreme selection in vivo against cells making keratin 1: tumours arising from inocula of such cells are invariably produced by the selective overgrowth of cells in which keratin 1 synthesis has been drastically reduced, usually to trace levels. No such selection operates against keratin 10. It is possible that if substantial synthesis of keratin 1 could be induced in malignant cells in a clinical context, some therapeutic benefit might accrue.

The extracellular matrix of hybrids between melanoma cells and normal fibroblasts

1988 ◽  
Vol 91 (2) ◽  
pp. 281-286
Author(s):  
M.C. Copeman ◽  
H. Harris
Keyword(s):  
Extracellular Matrix ◽  
Protease Activity ◽  
Malignant Tumour ◽  
Melanoma Cells ◽  
Chromosome Loss ◽  
Type I ◽  
Chromosome 4 ◽  
Hybrid Cells

It has been shown that when malignant tumour cells are fused with normal fibroblasts the suppression of malignancy in the hybrids is linked to their ability to produce a collagenous extracellular matrix in vivo. When, as a consequence of chromosome loss, segregants arise that reacquire malignancy, these do not produce any detectable matrix. In this paper we examine the main components of the extracellular matrix produced in vitro by hybrids between malignant mouse melanoma cells and normal mouse fibroblasts. Hybrids in which malignancy is suppressed synthesize about ten times as much type 1 procollagen as the malignant segregants derived from them; they also retain more fibronectin in the cell layer and release less protease activity into the medium. Malignant segregants more closely resemble the parental melanoma cells in producing fibronectin and mainly types IV and V procollagen. When hybrid cells in which malignancy is initially suppressed are grown continuously in vitro, the production of type I procollagen declines, and the production of type V procollagen and the release of protease activity into the medium increase. These changes, which are associated with the loss from the hybrid cells of both copies of the chromosome 4 derived from the parental fibroblast, predict the reacquisition of malignancy when the cells are inoculated into mice. It is possible that one gene or set of genes located on chromosome 4 determines both the execution of the fibroblast differentiation programme and the suppression of malignancy.

scholarly journals Thrombospondin-4, an extracellular matrix protein expressed in the developing and adult nervous system promotes neurite outgrowth.

1995 ◽  
Vol 131 (4) ◽  
pp. 1083-1094 ◽  
Author(s):  
S Arber ◽  
P Caroni
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Nervous System ◽  
Neuromuscular Junction ◽  
Neurite Outgrowth ◽  
Adult Skeletal Muscle ◽  
Wide Range ◽  
Thrombospondin 4

Extracellular matrix (ECM) molecules are involved in multiple aspects of cell-to-cell signaling during development and in the adult. In nervous system development, specific recognition processes, e.g., during axonal pathfinding and synaptogenesis involve modulation and signaling by ECM components. Much less is known about their presence and possible roles in the adult nervous system. We now report that thrombospondin-4 (TSP-4), a recently discovered member of the TSP gene family is expressed by neurons, promotes neurite outgrowth, and accumulates at the neuromuscular junction and at certain synapse-rich structures in the adult. To search for muscle genes that may be involved in neuromuscular signaling, we isolated cDNAs induced in adult skeletal muscle by denervation. One of these cDNAs coded for the rat homologue of TSP-4. In skeletal muscle, it was expressed by muscle interstitial cells. The transcript was further detected in heart and in the developing and adult nervous system, where it was expressed by a wide range of neurons. An antiserum to the unique carboxyl-terminal end of the protein allowed to specifically detect TSP-4 in transfected cells in vitro and on cryostat sections in situ. TSP-4 associated with ECM structures in vitro and in vivo. In the adult, it accumulated at the neuromuscular junction and at synapse-rich structures in the cerebellum and retina. To analyze possible activities of TSP-4 towards neurons, we carried out coculture experiments with stably transfected COS cells and motor, sensory, or retina neurons. These experiments revealed that TSP-4 was a preferred substrate for these neurons, and promoted neurite outgrowth. The results establish TSP-4 as a neuronal ECM protein associated with certain synapse-rich structures in the adult. Its activity towards embryonic neurons in vitro and its distribution in vivo suggest that it may be involved in local signaling in the developing and adult nervous system.

scholarly journals Visualizing the metazoan proliferation-terminal differentiation decision in vivo

2019 ◽  
Author(s):  
Rebecca C. Adikes ◽  
Abraham Q. Kohrman ◽  
Michael A. Q. Martinez ◽  
Nicholas J. Palmisano ◽  
Jayson J. Smith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Cell Lineage ◽  
Terminal Differentiation ◽  
Cyclin Dependent Kinase ◽  
C Elegans ◽  
Differentiated Cells ◽  
Imaging Tool ◽  
Wide Range

SummaryCell proliferation and terminal differentiation are intimately coordinated during metazoan development. Here, we adapt a cyclin-dependent kinase (CDK) sensor to uncouple these cell cycle-associated events live in C. elegans and zebrafish. The CDK sensor consists of a fluorescently tagged CDK substrate that steadily translocates from the nucleus to the cytoplasm in response to increasing CDK activity and consequent sensor phosphorylation. We show that the CDK sensor can distinguish cycling cells in G1 from terminally differentiated cells in G0, revealing a commitment point and a cryptic stochasticity in an otherwise invariant C. elegans cell lineage. We also derive a predictive model of future proliferation behavior in C. elegans and zebrafish based on a snapshot of CDK activity in newly born cells. Thus, we introduce a live-cell imaging tool to facilitate in vivo studies of cell cycle control in a wide-range of developmental contexts.

The Analysis of Malignancy by Cell Fusion

1971 ◽  
Vol 8 (3) ◽  
pp. 659-672
Author(s):  
G. KLEIN ◽  
U. BREGULA ◽  
F. WIENER ◽  
H. HARRIS
Keyword(s):  
Cell Line ◽  
Tumour Cell ◽  
Malignant Cell ◽  
Hybrid Cells ◽  
Metabolic Defects ◽  
L Cell ◽  
Wide Range ◽  
Derivatives Of ◽  
Selection Of

A wide range of different kinds of malignant cell were fused with certain derivatives of the L cell line and the ability of the resulting hybrid cells to grow progressively in vivo was examined. In all cases the highly malignant character of the tumour cells was suppressed by fusion with the L cell derivatives, whether or not these had metabolic defects that facilitated selection of the hybrid cells. So long as the hybrid cells retained the complete chromosome complements of the two parent cells, their ability to grow progressively in vivo was very limited, for tumours composed of such unreduced hybrids were not found. However, when they lost certain specific, but as yet unidentified, chromosomes, the hybrid cells regained the ability to grow progressively in vivo and gave rise to a tumour. These findings thus indicated that the L cell derivatives contributed something to the hybrid that suppressed the malignancy of the tumour cell, and that this contribution was lost when certain specific chromosomes were eliminated.

scholarly journals Fucoidan Inhibits the Proliferation of Leiomyoma Cells and Decreases Extracellular Matrix-Associated Protein Expression

2018 ◽  
Vol 49 (5) ◽  
pp. 1970-1986 ◽  
Author(s):  
Hsin-Yuan Chen ◽  
Tsui-Chin Huang ◽  
Li-Chun Lin ◽  
Tzong-Ming Shieh ◽  
Chi-Hao Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Protein Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cell Activity ◽  
Side Population Cell ◽  
Uterine Tumors ◽  
Wide Range

Background/Aims: Uterine leiomyomas (ULs) are benign uterine tumors, and the most notable pathophysiologic feature of ULs is excessive accumulation of extracellular matrix (ECM). Fucoidan is a polysaccharide extracted from brown seaweeds that has a wide range of pharmacological properties, including anti-fibrotic effects. We aimed to study the effect of fucoidan on the growth of ULs activated by transforming growth factor beta (TGFβ). Methods: We used ELT-3 (Eker rat leiomyoma tumor-derived cells) and HUtSMC (human uterine smooth muscle cells) as in vitro models. Cell viability was determined by the MTT assay. Cell colony formation was stained using crystal violet. The side population, cell cycle and apoptosis were analyzed using flow cytometry. Protein expression was assayed by western blot analysis. We also conducted in vivo experiments to confirm the inhibitory effects of fucoidan in nude mouse xenograft models. Tumor tissues were assayed by immunohistochemistry analysis. Results: In our study, fucoidan caused a 50% growth inhibition using a dose of 0.5 mg/ml and decreased the stem cell activity after 48 h. In addition, fucoidan induced sub-G1 cell cycle arrest and apoptosis. Fucoidan down-regulated fibronectin, vimentin, α-SMA and the COL1A1 protein levels in TGFβ3-induced ELT-3 cells. In the cellular mechanism, fucoidan abrogated TGFβ3-induced levels of p-Smad2 and p-ERK1/2, as well as β-catenin translocation into the nucleus. Furthermore, fucoidan suppressed xenograft tumor growth in vivo. Conclusion: Fucoidan displays anti-proliferation and anti-fibrotic effects and exerts protective effects against ULs development.

Studies on the surface properties of hybrid cells. III. A membrane glycoprotein found on the surface of a wide range of malignant cells

1981 ◽  
Vol 48 (1) ◽  
pp. 147-170
Author(s):  
M.A. Atkinson ◽  
M.E. Bramwell
Keyword(s):  
Sialic Acid ◽  
Molecular Mass ◽  
Surface Properties ◽  
Apparent Molecular Mass ◽  
Membrane Glycoprotein ◽  
Malignant Cells ◽  
Hybrid Cells ◽  
Wide Range

We report here the presence of a glycoprotein of apparent molecular mass 90000 daltons on the surface of membranes of malignant cells, which is absent or very much reduced on the surface of non-malignant cells. This glycoprotein is rich in sialic acid and appears to be sensitive to the concentration of cAMP under certain conditions. Analysis of the labelled sugars present in the glycoproteins of cells metabolically labelled with [14C]glucosamine suggests that all the enzymes necessary for the conversion of the tracer precursor into the sugars normally found to be labelled are present in both the malignant and the non-malignant cells.

Studies on the surface properties of hybrid cells. II. Sialyl-transferase activity on the surface of malignant and non-malignant cells

1980 ◽  
Vol 46 (1) ◽  
pp. 203-220
Author(s):  
M.A. Atkinson ◽  
M.E. Bramwell
Keyword(s):  
Surface Properties ◽  
Surface Activity ◽  
Cell Lines ◽  
Plasma Membranes ◽  
Malignant Cell ◽  
Transferase Activity ◽  
Malignant Cells ◽  
Hybrid Cells ◽  
Wide Range ◽  
The Difference

A measurable surface activity of sialyl-transferase is demonstrated by a number of different methods to exist on the plasma membranes of both malignant and non-malignant cells. The amount of enzyme present on the surface of malignant cells is found to be higher than that on the non-malignant ones in a wide range of malignant and non-malignant cell lines. It is proposed that the difference in apparent activity results in part from the presence of incomplete glycoproteins in the surface membranes of the malignant cells and in part from an increased rate of membrane synthesis in these cells.

Studies on the surface properties of hybrid cells. I. Sialyl-transferase activity in homogenates of malignant and non-malignant cells

1980 ◽  
Vol 46 (1) ◽  
pp. 187-201
Author(s):  
M.A. Atkinson ◽  
M.E. Bramwell
Keyword(s):  
Tissue Culture ◽  
Sialic Acid ◽  
Elevated Level ◽  
Malignant Cell ◽  
Cell Populations ◽  
Transferase Activity ◽  
Malignant Cells ◽  
Hybrid Cells ◽  
Cell Homogenate ◽  
Wide Range

We report here a method for the assay of the sialyl-transferase activity in crude homogenates of a wide range of cell lines growing in tissue culture. Our results indicate that particulate preparations from both malignant and non-malignant cells show a Km of 0.25 mM towards CMP-sialic acid in the presence of an excess of glycoprotein acceptor. There appear to be increased amounts of the enzyme associated with the preparations from malignant sources which are reflected in an increase in the apparent Vmax of these. The elevated level of sialyl-transferase activity seen in the malignant cell populations is, paradoxically, associated with a decrease in the amount of bound sialic acid associated with both the whole cell homogenate preparations and the surface of these cells.

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