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At least 667 records · Page 37Linked to original sources
PubMed1983

The relative resistance of non-cycling cells in 9L multicellular spheroids to spirohydantoin mustard.

Surviving fractions of 9L spheroid cells treated with 1.5, 3.0 and 6.0 micrograms/ml of spirohydantoin mustard (SHM) decreased when assayed 6 hr after treatment but increased thereafter. Flow cytometric analysis showed that exponentially growing 9L monolayer cells treated with SHM accumulated at the G2/M border within 24 hr. Cells dissociated from spheroids treated with 3 and 6.0 micrograms/ml of SHM accumulated at the G2/M border during the first 24 hr after treatment and remained there for the next 12 hr. However, 50% of the cells remained at the 2C DNA peak. Spheroid cells with 2C DNA content 24 hr after treatment were assumed to be non-cycling cells at the time of treatment, and cells that accumulated at the G2/M peak appeared to be cycling cells at the time of treatment; approximately 50% of cells in untreated 9L spheroids are in the noncycling pool. G1 and/or early S phase 9L cells in exponential growth elutriated immediately after treatment with SHM had significantly lower (P greater than 0.001) plating efficiencies than 9L cells in S and G2/M phases. When spheroids were dissociated, elutriated and plated for colony-forming efficiency 24 hr after treatment with 3 micrograms/ml of SHM, fractions enriched in 2C DNA content had significantly higher (P greater than 0.001) plating efficiencies than elutriated cells enriched in 4C DNA. These results indicate that SHM is less effective against non-cycling 9L spheroid cells with 2C DNA content than against cycling 9L spheroids cells.

Animals↗
PubMed1985

Influence of the oxygen pressure in the culture medium on the oxygenation of different types of multicellular spheroids.

Six different types of spheroids of both human and rodent origin were cultured, using the liquid-overlay technique. Oxygen gradients were measured with micro-electrodes, when the spheroids were attached to thin cover-glasses. The gradients were measured from the upper surface towards the center of the spheroids. Stable and reproducible gradients were obtained. Large variations were seen in the steepness of the gradients, depending both on the type and on the size of the spheroids. An interesting phenomenon was discovered. When some types of spheroids were cultured in a medium with a low oxygen pressure (medium equilibrated with gas containing 4-5% O2), the gradients continuously changed and became flatter. Detailed studies showed that most of the changes occurred within 2 days after the transfer to the low oxygen pressure. After 2 days, no further dramatic changes took place. This phenomenon was seen in two types of human glioma (U-118 MG and U-178 MG) and two types of embryonic, hamster lung-cell (V-79-379A and CHEL) spheroids. In the cases of human-osteosarcoma (U-393 OS) and human thyroid-cancer (HTh7) spheroids, no such changes could be seen. The low oxygen tension in the culture medium was chosen to mimic the environmental conditions in solid tumors.

Animals↗
PubMed1988

Effects of changes in oxygen tension, pH, and glucose concentration on the response to CCNU of EMT6 mouse tumor monolayer cells and multicellular spheroids.

We have studied the effect of individually changing medium glucose content, pH and oxygen tension upon the response to CCNU (1-(2-chloroethyl)3-cyclohexyl-1-nitrosourea) of EMT6/Ca/VJAC cells grown as early plateau phase monolayer cultures or small (200 microns diameter) spheroids. The effect of changing all three factors together has also been studied in the spheroid model. All the changes in medium conditions (except for 4 hr hypoxia) were maintained for 24 hr prior to drug exposure. Plating efficiency (PE) of monolayer cells was decreased by reduced medium pH (below 6.5) or oxygen tension while no change in PE was brought about by reduced medium glucose content. In small spheroids reduction in PE caused by low pH was similar to that seen in monolayer, there was again no effect of reduced glucose, and the effect of hypoxia was clearly less than in monolayer. Combination treatment of spheroids (pH 6.5, 120 mg/l glucose and hypoxia) reduced the PE of spheroid cells to 50% of control. Reducing medium glucose content from 920 to 0 mg/l, or oxygen tension from 20% to near zero (for either 4 or 24 hr) reduced the sensitivity of monolayer cells to CCNU. A similar pattern was seen for reducing medium pH from 7.2 to 6.1 during the 24 hr pre-incubation period and 1 hr drug exposure period. A reverse trend was, however, seen if medium pH during the drug exposure period was maintained at 7.2 following reduced pH pre-incubation. Reduced sensitivity to CCNU was seen for cells within small spheroids pre-incubated in medium at low pH (for both schedules) or under hypoxia (for either 4 or 24 hr) whereas reduced medium glucose content appeared to have no such effect. Cells in small spheroids after 24 hr combination treatment were also less sensitive to CCNU than cells from control spheroids.

Anaerobiosis↗
PubMed1989

Quantitation of hypoxia in multicellular spheroids by video image analysis.

Polyclonal antibodies to a series of radiation chemically produced 2-nitroimidazole-protein adducts have been used in the indirect immunofluorescent detection of hypoxic cells in EMT6/Ed spheroids. The spheroids were incubated with the radioactive 2-nitrioimidazoles under atmospheres of air, several intermediate oxygen concentrations, and nitrogen. The fluorescence intensity of the marker across radii of spheroids labeled at various oxygen tensions, as measured by video image analysis, paralleled the autoradiographic grain density. Thus, we conclude that the immunohistochemical approach provides a quantitative measure of the distribution of 2-nitroimidazole adducts in spheroids. The advantages of speed, technical simplicity, economy, and independence from the requirement of radiolabeled precursor render the fluorescent marker of potential use in the clinical detection of cellular hypoxia and tissue ischemia.

Autoradiography↗
PubMed1992

Radiosensitivity, repair capacity, and stem cell fraction in human soft tissue tumors: an in vitro study using multicellular spheroids and the colony assay.

Radiation doses necessary to control 50% of spheroids (SCD50) were determined for five human soft tissue tumor lines after single dose and fractionated irradiation. Spheroids with 1000-1500 cells were used throughout. A similar number of cells per spheroid resulted in different sized spheroids for the respective cell lines. The parameters alpha, beta, and the number of regenerating cellular units per spheroid (SRU) were estimated from the spheroid control data using a direct fit according to the linear quadratic model assuming Poisson statistics. The number of spheroid regenerating cellular units was also determined from the growth delay at doses required for 10% spheroid control. In addition, alpha, beta, and the fraction of clonogenic cells of the five cell lines were obtained from a soft agar colony forming assay. The most precise parameter for radiation sensitivity was the SCD50, with a coefficient of variation smaller than 5%. SCD50 values ranged from 5.9 to 11.0 Gy for the five soft tissue tumor lines. Two of the five cell lines showed significantly higher alpha values and lower calculated survival fractions after 2 Gy (SF2) in the soft agar clonogenic assay than in the spheroid control assay. This points to a resistance-enhancing effect in the spheroid system. Whereas the fractions of SRU from the number of cells per spheroid, estimated from the spheroid control and growth delay assays, agreed well, no significant correlation existed between the fraction of SRU and the fraction of clonogenic cells in the soft agar colony forming assay. The alpha/beta ratios as a descriptive measure of the fractionation sensitivity of the tumor cell spheroids in the spheroid control assay corresponded well with those derived from the dose-cell survival data using a soft agar colony forming assay. Two of the five cell lines showed high fractionation sensitivities with alpha/beta values smaller than 5 Gy while those of the remaining three ranged from 7.8 to 10.8 Gy. Spheroids are structurally more similar to in vivo tumors than monolayer cultures. From the observed lack of correlation in the radiosensitivity parameters alpha and SF2 as well as in the fraction of SRU or clonogenic cells obtained from the spheroid control assay or the colony forming assay, one would expect even greater differences between results from colony forming assays and the radiosensitivity of in vivo tumors, at least for human soft tissue sarcomas.

Cell Aggregation↗
PubMed1996

Effects of sex- and glucocorticoid steroids on breast cancer cells grown as either multicellular tumor spheroids or monolayers.

The effects of estradiol, medroxyprogesterone acetate (MPA) dexamethasone, dihydrotestosterone and the antihormones 4-OH tamoxifen and RU 38486 were studied in two established breast carcinoma cell lines, the estrogen-sensitive ZR-75-1 and the estrogen-independent BT 20 cells applying two different in vitro systems, spheroid and monolayer cell culture in steroid deprived medium. Growth of ZR-75-1 spheroids was dramatically stimulated by the addition of estradiol, an effect which was neutralized by the simultaneous addition of 4-OH tamoxifen. The antiestrogen alone as well as dihydrotestosterone and MPA reduced ZR-75-1 spheroid growth significantly. While growth of BT 20 spheroids was only transiently inhibited by tamoxifen and dihydrotestosterone, a persistent increase in BT 20 spheroid growth was observed under MPA treatment in a concentration of 1 microM. This effect, although statistically significant, was very moderate. With the exception of this finding, growth effects of the different test compounds were similar in both in vitro systems, tumor spheroids and monolayer cell cultures.

Breast Neoplasms↗
PubMed2004

DdAlix, an Alix/AIP1 homolog in Dictyostelium discoideum, is required for multicellular development under low Ca2+ conditions.

Apoptosis-linked gene 2 (ALG-2) interacting protein X (Alix), also called AIP1, is a widely conserved protein in eukaryotes. Alix and its homologs are involved in various phenomena such as apoptosis, regulation of cell adhesion, protein sorting, adaptation to stress conditions, and budding of human immunodeficiency virus (HIV). To investigate the role of Alix in development, we identified an Alix homolog in the cellular slime mold Dictyostelium discoideum and disrupted the gene by homologous recombination. The growth of DdAlix deletion mutant (alx-) cells was significantly impaired in the presence of 5 mM Li+. On an agar plate, alx- cells underwent normal development and formed fruiting bodies indistinguishable from those formed by wild-type cells. However, alx- cells could not form fruiting bodies in the presence of 5 mM Li+. Similar results were obtained when cells were developed in the presence of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), which is an antagonist of intracellular Ca2+ store. Furthermore, when the extracellular free Ca2+ was reduced to 10 nM, the ability of alx- cells, but not that of wild-type cells, to form fruiting bodies was impaired. The results indicate that DdAlix is essential for development under low Ca2+ conditions and suggest that DdAlix is involved in Ca2+ signaling during development.

Animals↗
PubMed2006

Development of a three-dimensional multiscale agent-based tumor model: simulating gene-protein interaction profiles, cell phenotypes and multicellular patterns in brain cancer.

Experimental evidence suggests that epidermal growth factor receptor (EGFR)-mediated activation of the signaling protein phospholipase Cgamma plays a critical role in a cancer cell's phenotypic decision to either proliferate or to migrate at a given point in time. Here, we present a novel three-dimensional multiscale agent-based model to simulate this cellular decision process in the context of a virtual brain tumor. Each tumor cell is equipped with an EGFR gene-protein interaction network module that also connects to a simplified cell cycle description. The simulation results show that over time proliferative and migratory cell populations not only oscillate but also directly impact the spatio-temporal expansion patterns of the entire cancer system. The percentage change in the concentration of the sub-cellular interaction network's molecular components fluctuates, and, for the 'proliferation-to-migration' switch we find that the phenotype triggering molecular profile to some degree varies as the tumor system grows and the microenvironment changes. We discuss potential implications of these findings for experimental and clinical cancer research.

Apoptosis↗
PubMed2003

Multicellular development and gliding motility in Myxococcus xanthus.

A great deal of progress has been made in the studies of fruiting body development and social gliding in Myxocococcus xanthus in the past few years. This includes identification of the bone fide C-signal and a receptor for type IV pili, and development of a model for the mechanism of adventurous gliding motility. It is anticipated that the next few years will see even more progress as the complete genome sequence is available and genomic and proteomic tools are applied to the study of M. xanthus social behaviors.

Movement↗
PubMed2004

Guenther Gerisch and Dictyostelium, the microbial model for ameboid motility and multicellular morphogenesis.

Beginning in 1960 and continuing to this day, Guenther Gerisch's work on the social ameba Dictyostelium discoideum has helped to make it the model organism of choice for studies of cellular activities that depend upon the actomyosin cytoskeleton. Gerisch has brought insight and quantitative rigor to cell biology by developing novel assays and by applying advanced genetic, biochemical and microscopic techniques to topics as varied as cell-cell adhesion, chemotaxis, motility, endocytosis and cytokinesis.

Amoeba↗