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At least 469 records · Page 26Linked to original sources
PubMed1997

Multicellular tumor spheroids grown from pancreatic carcinoma cell lines: use as an orthotopic xenograft in athymic nude mice.

Carcinoma of the pancreas is the fifth leading cause of cancer death, with the majority of patients presenting with unresectable disease. Research into new adjuvant therapies is hampered by the lack of suitable in vivo and in vitro models. We have examined the potential of seven pancreatic carcinoma cell lines to grow as multicellular tumor spheroids (MTS). Three of seven (43%) cell lines were scored positive for MTS formation, and the growth characteristics for spheroid models of the cell lines PANC1 and MIAPaCa2 are presented. Implantation of PANC1 MTS into the pancreas of athymic nude mice produces tumors with reproducible growth characteristics and histology.

Animals↗
PubMed1978

The multicellular spheroid as a model tumor allograft. II. Characterization of spheroid-infiltrating cytotoxic cells.

Alloimmune lymphoid cells infiltrating multicellular spheroids of EMT6 mammary sarcoma cells (a solid tumor allograft model) have been characterized according to their morphological and functional properties. Both lymphocytes and macrophages were found within spheroids at the time of peak tumor cell damage. Cytotoxic cells specific for allograft antigens were also present. Using a short-term 51-Cr release assay, the cells responsible for cytotoxicity were characterized as a nonadherent, nonphagocytic T cell population. Velocity sedimentation cell separation further demonstrated that these cytotoxic cells had the physical properties of small lymphocytes. Some evidence for selective spheroid infiltration by specifically alloimmune cells was also obtained. The possible relationship of this cellular infiltrate to graft damage is discussed.

Animals↗
PubMed2006

Continuum versus discrete model: a comparison for multicellular tumour spheroids.

We study multicellular tumour spheroids with a continuum model based on partial differential equations (PDEs). The model includes viable and necrotic cell densities, as well as oxygen and glucose concentrations. Viable cells consume nutrients and become necrotic below critical nutrient concentrations. Proliferation of viable cells is contact-inhibited if the total cellular density locally exceeds volume carrying capacity. The model is discussed under the assumption of spherical symmetry. Unknown model parameters are determined by simultaneously fitting the cell number to several experimental growth curves for different nutrient concentrations. The outcome of the PDE model is compared with an analogous off-lattice agent-based model for tumour growth. It turns out that the numerically more efficient PDE model suffices to explain the macroscopic growth data. As in the agent-based model, we find that the experimental growth curves are only reproduced when a necrotic core develops. However, evaluation of morphometric properties yields differences between the models and the experiment.

Animals↗
PubMed1981

Strategies for specifying form and pattern: adhesion-guided multicellular assembly.

We define a material pattern as a particular arrangement of material elements in space. We then make an effort to categorize the developmental strategies that underlie the emergence of multicellular patterns. These strategies are divided into three broad categories according to whether cell position influences or is influenced by cell fate. In that category of strategies in which cell fate influences cells to move to particular positions, we focus our attention upon morphogenetic and patterning phenomena that appear to be determined by adhesion-mediated interactions of cells with each other and with their surroundings. The differential adhesion hypothesis details how cellular adhesive properties can guide tissue movements and specify patterns of cell association. Motile, adhesive cells will naturally tend to group so as to maximize their adhesive interactions (minimize interfacial free energy). A homogeneous population of uniformly adhesive (isotropic) cells will tend toward spherical form. Cell surface adhesive anisotropies can determine other most-stable (equilibrium) configurations of the population, such as cell sheets, tubes and vesicles. Heterogeneous cell populations may preferentially either intermix or sort out, depending upon the balance of adhesive forces between like and unlike elements. The precise configuration adopted will depend upon the particular adhesive relationships that prevail. Both this end state and the approach toward it arise from the adhesive relationships among the interacting cells. Such morphogenetic phenomena as tissue spreading and the segregation of organ primordia are probably brought about in this way. We outline here some results of our recent experiments on the morphogenesis of the salamander pronephric duct. These illustrate the reality of emergent adhesion-generated tissue immiscibility as a cause of organ segregation and point toward a craniocaudally travelling adhesion gradient as the information that guides the migrating pronephric duct to the cloaca.

Ambystoma↗
PubMed2001

Motions caused by the growth of Bacillus subtilis macrofibres in fluid medium result in new forms of movement of the multicellular structures over solid surfaces.

Bacillus subtilis macrofibres, highly ordered multicellular structures, undergo twisting and writhing motions when they grow in fluid medium as a result of forces generated by the elongation of individual cells. Macrofibres are denser than the fluid medium in which they are cultured, consequently they settle to the bottom of the growth chamber and grow in contact with it. The ramifications of growth on plastic and glass surfaces were examined. Macrofibres were observed to rotate about a vertical axis near the centre of their length in a chiral-specific direction. Right-handed fibres rotated clockwise on plastic surfaces at approximately 4 degrees min(-1), left-handed structures of lower twist rotate anti-clockwise at about half that rate. Very large ball structures produced late in macrofibre formation perched on many small protruding fibres but rotated only when driven by large fibres attached to their periphery. Closer examination showed that fibres made contact with surfaces at only a few points along their length (between 1 and 6 on glass). The regions in contact with the surface changed periodically as a result of rotation of the fibre shaft caused by growth. Every time the weight of a fibre transferred from one contact point to another, each section of the fibre took a small step approximately proportional to its distance from the fibre mid-point. The net result was a rolling of each section over the surface so that the fibre rotation about a vertical axis was produced. Macrofibres also took large steps when part of the structure rose off the floor, swept through an arc in the fluid and then returned to the floor at a new location. The rate of movement during a large step, measured as the change of angle between the moving and stationary portions of the fibre, was 5 degrees s(-1). These observations reveal that the forces derived from helical growth that lead to macrofibre formation also cause characteristic macrofibre motion that differs from classical motility.

Bacillus subtilis↗
PubMed1994

A genetic link between light response and multicellular development in the bacterium Myxococcus xanthus.

The Gram-negative bacterium Myxococcus xanthus responds to blue light by producing carotenoid pigments (Car+ phenotype). Genes for carotenoid synthesis lie at two unlinked chromosomal sites, the carC and the carBA operon, but are integrated in a single "light regulon" by the action of common trans-acting regulatory elements. Three known regulatory genes are grouped together at the (light-inducible) carQRS operon. By screening the Car phenotype of a large collection of transposon-induced mutants, we have identified a new car locus that has been named carD (carD1 for the mutant allele). The carD gene product plays a critical role in the light regulon, as it is required for activation of the carQRS and carC promoters by blue light. The carD1 mutant is impaired in the (starvation-induced) developmental process that allows M. xanthus cells both to form multicellular fruiting bodies and to sporulate. Our results indicate that the carD gene product is also required for the expression of a particular set of development-specific genes that are normally activated through the action of intercellular signals.

Carotenoids↗
PubMed2006

Evidence for variation in abundance of antisense transcripts between multicellular animals but no relationship between antisense transcriptionand organismic complexity.

Given that humans have about the same number of genes as mice and not so many more than worm, what makes us more complex? Antisense transcripts are implicated in many aspects of gene regulation. Is there a functional connection between antisense transcription and organismic complexity, that is, is antisense regulation especially prevalent in humans? We used the same robust protocol to identify antisense transcripts in humans and five other metazoan genomes (mouse, rat, chicken, fruit fly, and nematode), and found that the estimated proportions of genes involved in antisense transcription are highly sensitive to the number of transcripts included in the analysis. By controlling for transcript abundance, we find that the probability that any given transcript is putatively involved in sense-antisense regulation is no higher in humans than in other vertebrates but appears unusually high in flies and especially low in nematodes. Similarly, there is no evidence that the proportion of sense-antisense transcripts is especially higher in humans than other vertebrates in a given subset of transcript sequences such as mRNAs, coding sequences, conserved, or nonconserved transcripts. Although antisense transcription might be enriched in mammalian brains compared with nonbrain tissues, it is no more enriched in human brain than in mouse brain. Overall, therefore, while we see striking variation between multicellular animals in the abundance of antisense transcripts, there is no evidence for a link between antisense transcription and organismic complexity. More particularly, we see no evidence that humans are in any way unusual among the vertebrates in this regard. Instead, our results suggest that antisense transcription might be prevalent in almost all metazoan genomes, nematodes being an unexplained exception.

Animals↗
PubMed2005

Multicellular tumor spheroid in an off-lattice Voronoi-Delaunay cell model.

We study multicellular tumor spheroids by introducing a new three-dimensional agent-based Voronoi-Delaunay hybrid model. In this model, the cell shape varies from spherical in thin solution to convex polyhedral in dense tissues. The next neighbors of the cells are provided by a weighted Delaunay triangulation with on average linear computational complexity. The cellular interactions include direct elastic forces and cell-cell as well as cell-matrix adhesion. The spatiotemporal distribution of two nutrients--oxygen and glucose--is described by reaction-diffusion equations. Viable cells consume the nutrients, which are converted into biomass by increasing the cell size during the G1 phase. We test hypotheses on the functional dependence of the uptake rates and use computer simulations to find suitable mechanisms for the induction of necrosis. This is done by comparing the outcome with experimental growth curves, where the best fit leads to an unexpected ratio of oxygen and glucose uptake rates. The model relies on physical quantities and can easily be generalized towards tissues involving different cell types. In addition, it provides many features that can be directly compared with the experiment.

Animals↗
PubMed2006

Selective advantage for multicellular replicative strategies: a two-cell example.

This paper develops a quasispecies model where cells can adopt a two-cell survival strategy. Within this strategy, pairs of cells join together, at which point one of the cells sacrifices its own replicative ability for the sake of the other cell. We develop a simplified model for the evolutionary dynamics of this process, allowing us to solve for the steady state using standard approaches from quasispecies theory. We find that our model exhibits two distinct regimes of behavior: At low concentrations of limiting resource, the two-cell strategy outcompetes the single-cell survival strategy, while at high concentrations of limiting resource, the single-cell survival strategy dominates. The single-cell survival strategy becomes disadvantageous at low concentrations of limiting resource because the energetic costs of maintaining reproductive and metabolic pathways approach, and may even exceed, the rate of energy production, leaving little excess energy for the purposes of replicating a new cell. However, if the rate of energy production exceeds the energetic costs of maintaining metabolic pathways, then the excess energy, if shared among several cells, can pay for the reproductive costs of a single cell, leaving energy to replicate a new cell. Associated with the two solution regimes of our model is a localization to delocalization transition over the portion of the genome coding for the multicell strategy, analogous to the error catastrophe in standard quasispecies models. The existence of such a transition indicates that multicellularity can emerge because natural selection does not act on specific cells, but rather on replicative strategies. Within this framework, individual cells become the means by which replicative strategies are propagated. Such a framework is therefore consistent with the concept that natural selection does not act on individuals, but rather on populations.

Animals↗
PubMed2005

Bridging the Gap between mesoscopic and macroscopic models: the case of multicellular tumor spheroids.

Multicellular tumor spheroids are valuable experimental tools in cancer research. By introducing an intermediate model, we have been able to successfully relate mesoscopic and macroscopic descriptions of spheroid growth. Since these descriptions stem from completely different roots (cell dynamics, and energy conservation and scaling arguments, respectively), their consistency validates both approaches and allows us to establish a direct correspondence between parameters characterizing processes occurring at different scales. Our approach may find applications as an example of bridging the gap between models at different scale levels in other contexts.

Cell Growth Processes↗
PubMed2005

Strong-coupling dynamics of a multicellular chemotactic system.

Chemical signaling is one of the ubiquitous mechanisms by which intercellular communication takes place at the microscopic level, particularly via chemotaxis. Such multicellular systems are popularly studied using continuum, mean-field equations. In this Letter we study a stochastic model of chemotactic signaling. The Langevin formalism of the model makes it amenable to calculation via nonperturbative analysis, which enables a quantification of the effect of fluctuations on both the weak and the strongly coupled biological dynamics. In particular, we show that the (i) self-localization due to autochemotaxis is impossible. (ii) When aggregation occurs, the aggregate performs a random walk with a renormalized diffusion coefficient D(R) proportiuonal to epsilon-2N-3. (iii) The stochastic model exhibits sharp transitions in cell motile behavior for negative chemotaxis, behavior that has no parallel in the mean-field Keller-Segel equations.

Cell Communication↗
PubMed2000

The mid-pericarp cell layer in soybean pod walls is a multicellular compartment enriched in specific lipoxygenase isoforms.

Specific lipoxygenase isoforms immunolocalize to the cytosol of a single cell layer in the soybean (Glycine max L.) pod wall. The cells of this layer, termed the mid-pericarp layer (MPL), are larger than adjacent cells and are highly branched. The entire MPL appears to form an elaborate interdigitated network within the pod wall. A particularly striking feature of the MPL is the presence of extensive regions of very thin, approximately 30 nm, cell wall, which connect the cells of the MPL. It was demonstrated that after mechanical wounding of the pod wall, 40-kD fluorescein-dextran was able to move throughout the MPL. In addition, when pod walls are cut, an exudate flows from the MPL that is highly enriched in lipoxygenase isoforms (approximately 40% of the total protein). The MPL of soybean pod walls may represent a novel multicellular compartment involved in defense of leguminous plants.

Electrophoresis, Polyacrylamide Gel↗
PubMed1998

The sex-inducing pheromone and wounding trigger the same set of genes in the multicellular green alga Volvox.

The sex-inducing pheromone of the multicellular green alga Volvox carteri is a glycoprotein that triggers development of males and females at a concentration <10(-16) M. By differential screening of a cDNA library, two novel genes were identified that are transcribed under the control of this pheromone. Unexpectedly, one gene product was characterized as a lysozyme/chitinase, and the other gene product was shown to encode a polypeptide with a striking modular composition. This polypeptide has a cysteine protease domain separated by an extensin-like module from three repeats of a chitin binding domain. In higher plants, similar protein families are known to play an important role in defense against fungi. Indeed, we found that the same set of genes triggered by the sexual pheromone was also inducible in V. carteri by wounding.

Amino Acid Sequence↗
PubMed1981

Cell kinetic characteristics in different parts of multicellular spheroids of human origin.

The growth fraction, the cell cycle time, and the duration of the individual cell cycle phases were determined as a function of distance from the surface of multicellular spheroids of the human cell line NHIK 3025. The techniques employed were percentage of labelled mitoses and labelling index measurements after autoradiography and flow cytometric measurements of DNA histograms. To separate cell populations from the different parts of the spheroid, fractionated trypsinization was employed. The results were compared with corresponding values in NHIK 3025 cell populations grown as monolayer cultures. While practically all cells in exponentially growing monolayer populations are proliferating, the growth fraction was between 0.6 and 0.7 in the outer parts of the spheroid. The inner region was mainly occupied by a necrotic mass. The proliferating fraction of the recognizable cells in the inner region was slightly below 0.5. The mean cell cycle time of NHIK 3025 cells in monolayer culture is 18 hr. The mean cell cycle time of proliferating cells in the periphery of the spheroid was 30 hr, compared to 41 hr in the inner region (150 micrometer from the spheroid surface). All phases of the cell cycle were prolonged compared to populations of exponentially growing monolayer cells. Within each part of the spheroid the distribution of cell cycle times was considerably broadened compared with monolayer populations.

Cell Line↗
PubMed1982

A model for the growth of multicellular spheroids.

Based on biological observations and the basic physical properties of tri-dimensional structures, a mathematical expression is derived to relate the growth rate of multicellular spheroids to some easily measurable parameters. This model involves properties both of the individual cells and of the spheroid structure, such as the cell doubling time in monolayer, the rate of cell shedding from the spheroid and the depth of the external rim of cycling cells. The derived growth equation predicts a linear expansion of the spheroid diameter with time. The calculated growth rate for a number of spheroid cell types is in good agreement with experimental data. The model provides a simple and practical view of growth control in spheroids, and is further adapted to include parameters presumably responsible for the growth saturation in large spheroids.

Animals↗
PubMed1986

Growth characteristics of human melanoma multicellular spheroids in liquid-overlay culture: comparisons with the parent tumour xenografts.

The growth characteristics of multicellular spheroids, derived from human melanoma xenografts and cultivated in liquid-overlay culture, were studied and compared with those of the parent tumours. Six of the seven melanomas investigated formed spheroids, which grew exponentially up to a volume of 1-2 X 10(7) microns 3 (a diameter of 270-340 microns) before the growth rate tapered off. The morphology of the spheroids varied considerably among the melanomas; some spheroids grew as densely packed, spherical structures of cells whereas others were loosely packed and showed an irregular shape. Central necrosis developed when the spheroids attained a diameter of 150-200 microns. The histological and cytological appearance of the spheroids was remarkably similar to that of the parent xenograft in five of the six cases. The sixth melanoma contained two subpopulations with distinctly different DNA content, one of which was predominant in the spheroids, the other in the tumours. This gave rise to clear histological and cytological differences. The volume-doubling time of the spheroids during the exponential growth phase ranged from 1.7 +/- 0.2 to 2.7 +/- 0.4 days and the fraction of cells in S from 13 +/- 1 to 28 +/- 2%. The volume-doubling time decreased with increasing fraction of cells in S, indicating that the differences in growth rate were due mainly to differences in the growth fraction or to differences in the duration of G1. The spheroid volume-doubling times did not correlate with those of the parent xenografts (Td = 4.2-22.5 days at V = 200 mm3), possibly because the cell loss factors of the xenografts were large and varied among the melanomas. The fractions of cells in G1/G0, S and G2 + M in the spheroids and the xenografts did not correlate either, but were found to be within the same narrow ranges in the spheroids and the xenografts--i.e. 50-80% (G1/G0), 10-30% (S) and 10-20% (G2 + M).

Animals↗
PubMed1994

Evaluation of the growth rate of MCF-7 breast cancer multicellular spheroids using three mathematical models.

Growth data on 60 multicellular spheroids of MCF-7 human breast cancer cells were fitted, on an individual basis, by the Gompertz, Bertalanffy and logistic equations. MCF-7 spheroids, initiated and grown in medium containing oestrogens, exhibited a growth rate that decreased continuously as spheroid size increased. Plots of spheroid volume v. time generated sigmoid curves that showed an early portion with an approximately exponential volume increase; a middle region or retardation phase characterized by a continuously decreasing growth rate; and, finally, a late segment or plateau phase approaching zero growth rate, that permitted an estimate of the maximum spheroid size (Vmax). Growth curves generated by MCF-7 spheroids under different experimental conditions (hormones, drugs and radiation exposures) can be compared after normalization. Linearized forms of the fitted Gompertz curves provided a convenient way to express differences in growth rate.

Breast Neoplasms↗
PubMed1995

Long-term culture of organotypic multicellular glioma spheroids: a good culture model for studying gliomas.

Gliomas, as well as other solid tumours, contain tumour stroma composed of connective tissue, macrophages, capillaries and other non-cellular constituents. Therefore, a homogeneous culture of tumour cells alone, as is often used as a culture model for gliomas, is not ideal to study all aspects of gliomas. In the present study we describe an alternative culture model, i.e. organotypic multicellular spheroids (OMS), that histologically closely resembles the tumour in vivo. Glioma explants, obtained at surgery from five patients, were cultured on agarose to form OMS, which were cultured for up to 16 weeks. At regular intervals, OMS were fixed and histological and immunocytochemical analyses were carried out. The histology as well as the immunocytochemical characteristics of the OMS proved to be almost unchanged after a culture period of 16 weeks. In contrast to monolayer cultures, glial fibrillary acidic protein (GFAP) expression in the OMS is preserved after 16 weeks of culture. However, in OMS from three out of five patients, small GFAP-negative cells appeared in the outer cell layers between 1 and 2 weeks of culture. Furthermore, after about 6 weeks of culture, the capillaries disappeared from the OMS. After prolonged culture, tumour cell heterogeneity, the cellular composition, and the histology of the OMS still closely resembled the tumour in vivo. It is suggested that OMS provide a good long-term culture model for the study of gliomas.

Adult↗