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PubMed2004

Simulating growth dynamics and radiation response of avascular tumour spheroids-model validation in the case of an EMT6/Ro multicellular spheroid.

The goal of this paper is to provide both the basic scientist and the clinician with an advanced computational tool for performing in silico experiments aiming at supporting the process of biological optimisation of radiation therapy. Improved understanding and description of malignant tumour dynamics is an additional intermediate objective. To this end an advanced three-dimensional (3D) Monte-Carlo simulation model of both the avascular development of multicellular tumour spheroids and their response to radiation therapy is presented. The model is based upon a number of fundamental biological principles such as the transition between the cell cycle phases, the diffusion of oxygen and nutrients and the cell survival probabilities following irradiation. Efficient algorithms describing tumour expansion and shrinkage are proposed and applied. The output of the biosimulation model is introduced into the (3D) visualisation package AVS-Express, which performs the visualisation of both the external surface and the internal structure of the dynamically evolving tumour based on volume or surface rendering techniques. Both the numerical stability and the statistical behaviour of the simulation model have been studied and evaluated for the case of EMT6/Ro spheroids. Predicted histological structure and tumour growth rates have been shown to be in agreement with published experimental data. Furthermore, the underlying structure of the tumour spheroid as well as its response to irradiation satisfactorily agrees with laboratory experience.

Algorithms↗
PubMed2006

Multicellular rosette formation links planar cell polarity to tissue morphogenesis.

Elongation of the body axis is accompanied by the assembly of a polarized cytoarchitecture that provides the basis for directional cell behavior. We find that planar polarity in the Drosophila embryo is established through a sequential enrichment of actin-myosin cables and adherens junction proteins in complementary surface domains. F-actin accumulation at AP interfaces represents the first break in planar symmetry and occurs independently of proper junctional protein distribution at DV interfaces. Polarized cells engage in a novel program of locally coordinated behavior to generate multicellular rosette structures that form and resolve in a directional fashion. Actin-myosin structures align across multiple cells during rosette formation, and adherens junction proteins assemble in a stepwise fashion during rosette resolution. Patterning genes essential for axis elongation selectively affect the frequency and directionality of rosette formation. We propose that the generation of higher-order rosette structures links local cell interactions to global tissue reorganization during morphogenesis.

Actins↗
PubMed2003

The evolution of multicellularity and early animal genomes.

Several independent molecular datasets, including complete mtDNA sequence, indicate that Choanozoa are most closely related to multicellular animals. There is still confusion concerning basal animal phylogeny, although recent data indicate that Placozoa are not degenerate cnidarians and hence (along with sponges) occupy a pivotal position. The transition in evolution from diploblast to bilaterian animals is becoming better understood, with gene expression data arguing that cnidarians have forerunners of the anteroposterior and dorsoventral body axes, and even a putative homologue of mesoderm. The homeobox and kinase gene families have been further analysed in basal animals, although more data are required to enable detailed comparison with Bilateria.

Animals↗
PubMed2004

Contingent, non-neutral evolution in a multicellular parasite: natural selection and gene conversion in the Echinococcus granulosus antigen B gene family.

Recent studies have demonstrated that the Echinococcus granulosus antigen B (AgB) interferes with the intermediate hosts' immune response and is encoded by a multigene family. The number of members within the family is still uncertain, but there are several evidences of a large genetic variability. The E. granulosus AgB genomic sequences available in nucleotide databases can be grouped into four clades, corresponding to genes EgAgB1, EgAgB2, EgAgB3 and EgAgB4. In the present study, we use PCR amplifications followed by cloning and sequencing to evaluate the genetic variability for AgB isoforms. Two pairs of primers were independently used for PCR amplification. Both PCR reactions from each of three isolated protoscolex (larvae) were cloned in a plasmid vector and the plasmid inserts of 30 colonies from each cloning experiment were sequenced. Using phylogenetic tools, the 113 EgAgB clones are classified as follows: 25 are related to EgAgB1, 24 to EgAgB2, 9 to EgAgB3 and 39 to EgAgB4. The remaining 16 clones form a separate cluster, which we name EgAgB5, more closely related to EgAgB3 than to any of the other genes. Within each gene group, a number of variant sequences occur, which differ from one another by one or few nucleotides. One EgAgB3 clone has a premature stop codon (pseudogene) and an EgAgB2 clone lacks the region corresponding to the intron. The overall variation cannot be explained by differences among the asexual protoscoleces, or by experimental artifacts. Using Echinococcuss AgB genes from other species/strains as outgroups, neutrality is rejected for EgAgB2, and balancing selection is detected for EgAgB5, which also seems to be involved in gene conversion. We suggest that EgAgB1-EgAgB5 represent a family of contingency genes, that is, genes that are variably expressed, so that some but not others are expressed in each individual parasite. Contingency genes are common in parasitic protozoa and other microparasites, but the EgAgB family is the first set identified in a multicellular parasite.

Alleles↗
PubMed2006

The evolution of High Mobility Group Box (HMGB) chromatin proteins in multicellular animals.

Mammalian HMGB proteins are abundant chromatin components, and are characterized by the presence of 2 HMG-box domains and an acidic tail. HMG boxes are present in a large number of DNA-binding proteins, and HMGB chromatin proteins represent a small and specific subset of HMG-box proteins. The comparison of DNA sequences that code for HMG-box proteins suggests that the ancestral HMG box was coded by an intronless gene, which picked up one or more introns during its radiation. Canonical HMGB proteins are only present in multicellular animals, from sponges onwards, and appear to have arisen through the fusion of two different genes, each coding for one of the boxes. The organization of HMGB genes was very conserved during Metazoan evolution, with the only deviations appearing in Caenorhabditis and Dipteran (Drosophila and Anopheles) species.

Amino Acid Sequence↗
PubMed2004

Simulating the impact of a molecular 'decision-process' on cellular phenotype and multicellular patterns in brain tumors.

Experimental evidence indicates that human brain cancer cells proliferate or migrate, yet do not display both phenotypes at the same time. Here, we present a novel computational model simulating this cellular decision-process leading up to either phenotype based on a molecular interaction network of genes and proteins. The model's regulatory network consists of the epidermal growth factor receptor (EGFR), its ligand transforming growth factor-alpha (TGF alpha), the downstream enzyme phospholipaseC-gamma (PLC gamma) and a mitosis-associated response pathway. This network is activated by autocrine TGF alpha secretion, and the EGFR-dependent downstream signaling this step triggers, as well as modulated by an extrinsic nutritive glucose gradient. Employing a framework of mass action kinetics within a multiscale agent-based environment, we analyse both the emergent multicellular behavior of tumor growth and the single-cell molecular profiles that change over time and space. Our results show that one can indeed simulate the dichotomy between cell migration and proliferation based solely on an EGFR decision network. It turns out that these behavioral decisions on the single cell level impact the spatial dynamics of the entire cancerous system. Furthermore, the simulation results yield intriguing experimentally testable hypotheses also on the sub-cellular level such as spatial cytosolic polarization of PLC gamma towards an extrinsic chemotactic gradient. Implications of these results for future works, both on the modeling and experimental side are discussed.

Brain Neoplasms↗
PubMed2003

Bacterial biofilms: prokaryotic adventures in multicellularity.

The development of bacterial biofilms includes both the initial social behavior of undifferentiated cells, as well as cell death and differentiation in the mature biofilm, and displays several striking similarities with higher organisms. Recent advances in the field provide new insight into differentiation and cell death events in bacterial biofilm development and propose that biofilms have an unexpected level of multicellularity.

Bacteria↗
PubMed2005

Novel patterns of the gene expression regulation in the prestalk region along the antero-posterior axis during multicellular development of Dictyostelium.

Simultaneous hybridization with differentially labeled fluorescent probes for in situ hybridization analysis revealed several novel expression patterns of prestalk genes during multicellular development of Dictyostelium. Seven prestalk genes and one prespore gene (pspA) were analyzed in this study. The patterns identified here indicate that prestalk cells are more heterogeneous than previously thought. Heterogeneity was observed in peripheral prestalk tissues such as the pstAO domain of a slug and the prestalk region surrounding a stalk tube of a culminant. Heterogeneity was also observed in the core pstAB cells of the slug and immature stalk cells within the stalk tube. The upper- and lower-cups of a late culminant were also composed of several subdomains.

Animals↗
PubMed2006

Modeling of oxygen transport across tumor multicellular layers.

PURPOSE: Tumor oxygen level plays a major role in the response of tumors to different treatments. The purpose of this study was to develop a method of determining oxygen transport properties in a recently developed 3D model of tumor parenchyma, the multicellular layer (MCL). METHODS: OCM-1 human choroidal melanoma cells were grown as 3D MCLs on collagen-coated culture plate inserts. A recessed-cathode oxygen microelectrode was used to measure oxygen tension (PO(2)) profiles across 8 different MCL from the free surface to the insert membrane. The profiles were fitted to four different one-dimensional diffusion models: 1-, 2-, and 3-region models with uniform oxygen consumption (q) in each region and a modified 3-region model with a central region where q=0 and PO(2)=0. RESULTS: Depending upon the presence of a central region of anoxia, the PO(2) profiles were fitted best by either the two-region model or the modified 3-region model. Consumption of tumor cells near the insert membrane was higher than that of cells close to the free surface (33.1+/-13.6 x 10(-4) vs. 11.8+/-6.7 x 10(-4) mm Hg/mum(2), respectively). CONCLUSIONS: The model is useful for determining oxygenation and consumption in MCL, especially for cell lines that cannot be grown as spheroids. In the future, this model will permit the study of parameters important in tumor oxygenation in vitro.

Biological Transport, Active↗
PubMed2004

A new form of bacterial movement, dragging of multicellular aggregate structures over solid surfaces, is powered by macrofiber supercoiling.

Growing Bacillus subtilis macrofibers use twist and supercoiling to: power their own self-assembly, join fibers together into multiclonal aggregates, move themselves over solid surfaces, and to drag other structures (cargo) over solid surfaces. The dragging of multiclonal aggregates attached to the ends of growing macrofibers is analyzed here. The linkage between fibers and cargo arose naturally in macrofiber cultures. Dragging was triggered when growing macrofibers became linked to cargo at both of their ends. Such macrofibers supercoiled, reduced their length, and dragged the cargo toward one another. In parallel experiments immobile wire was used in place of cargo at one end of macrofibers that were linked to cargo at the other. The cargo was dragged toward the wire when these fibers supercoiled. To estimate the force required for dragging we determined the dimensions of the cargo, the buoyant density of macrofibers in the growth medium where dragging occurred, the rate and distance over which the aggregate structures were dragged, and the viscosity of the growth medium. Friction resulting from contact with the solid surface over which the structures were dragged was estimated using the measured parameters. The results indicate that the supercoiling tension required to overcome limiting friction must have been approximately 10 nN, while that needed to overcome fluid drag was of the order of 1 nN. These values suggest that only a small fraction of the total power available from macrofiber supercoiling was needed to drive this new form of multicellular bacterial movement.

Bacillus subtilis↗
PubMed1988

Partial purification of a protein growth inhibitor from multicellular spheroids.

We report the partial purification of growth inhibitors extracted from human and mouse multicellular tumor spheroids with extensive necrosis. Sephadex G-100 column chromatography of spheroid extracts separated inhibitory fractions which eluted just after the void volume of the column. Identical chromatography of monolayer cell extracts showed no inhibitory activity. High-performance liquid chromatography of spheroid extracts separated single active peaks at apparent molecular weights of 80-89 kD. These extracts were extremely heat labile, and activity was destroyed by moderate trypsin treatment. The isolation of similar growth inhibitors from spheroids of two cell lines suggests that inhibition is important in tumor cell growth control in a three-dimensional situation.

Adenocarcinoma↗
PubMed1975

Axon voltage-clamp simulations. A multicellular preparation.

In this paper we extend the simulation of the voltage clamp of a single nerve fiber to a bundle of axons. These simulations included not only the description of the voltage clamp circuit and a single unidimensional cable to represent the preparation in the "node" region of a double sucrose gap used previously but also a series resistance and a shunt pathway. The output of the voltage control amplifier is applied across the membrane plus the series resistance, producing a voltage drop across the series resistance due to the current generated by the membrane in response to a depolarizing voltage step. Since the membrane current has an inward and an outward phase, voltage drops of opposite sign are produced across the series resistance. During the transient current and at all points along an axon, the potential deviation produced by the series resistance is opposite to the deviation produced by the longitudinal gradient. Only at a command potential equal to the sodium equilibrium potential, the membrane potential transiently matches the command potential. For the attempted voltage clamp of an axon, values of series resistance larger than 50 omega-cm2 allowed propagated action potentials in the membrane. In spite of the presence of propagated action potentials at the calbe membrane, the recorded current does not show "notches" and it has a phase of inward current and a phase of outward current. It is concluded that, in a multicellular preparation with series resistance, the recording of a square voltage pulse does not indicate voltage control of the transmembrane potential. The presence of a shunt pathway produces inaccurate values of current density. Neither series or shunt resistance produce "notches" in the current records.

Action Potentials↗
PubMed1981

A theoretical study on the sucrose gap technique as applied to multicellular muscle preparations. I. Saline-sucrose interdiffusion.

Voltage-clamp analysis of membrane currents in multicellular muscle preparations by means of the sucrose gap method is complicated by diffusion of saline and sucrose in the interstitial fluid spaces. This paper is the first part of a theoretical study made to analyze electrical events related to this diffusion process. Concentration profiles of ions and sucrose (both axial and radial) were computed by solving diffusion equations with boundary conditions appropriate for the different types of preparations and experimental arrangements used. In addition to steady-state solutions, analytical expressions were derived that describe the time-course with which concentration profiles become established after a stepwise change of the solute concentration in one of the compartments of the sucrose gap apparatus. The model accounts for the presence of an endothelial surface layer, or endocardium, which acts as an external diffusion barrier and is important in determining concentration gradients of solutes within heart cell preparations. Results of numerical computations dealing with several cases of experimental interest are presented.

Diffusion↗
PubMed1981

A theoretical study on the sucrose gap technique as applied to multicellular muscle preparations. II. Methodical errors in the determination of outward currents.

This paper presents a mathematical model for analyzing systematic errors associated with the membrane conductance of multicellular muscle preparations as determined in a sucrose gap apparatus. The errors arise because of the interdiffusion of sucrose and saline in the interstitial fluid spaces, which results (a) in spatial variations of equilibrium potentials, membrane conductance, and solution conductivity, and (b) in the existence of a liquid junction potential. The model was applied to simulate the measurement of outward currents predominantly carried by potassium ions; time variations were not considered. Output current/voltage (I/V) curves were computed and compared with the membrane I/V relationship used in the computation. The output curves look very much like experimental results but are distorted considerably from the membrane I/V relationship: (a) under favorable conditions (negligible shunt current), the membrane current is overestimated over the entire range of membrane potential, (b) regions with negative slope conductance of I/V relations with "anomalous rectifier" properties are found to be less pronounced or even absent, and (c) resting potentials may be either increased or reduced. The origin of these errors is related to currents emerging from the sucrose compartment (local circuit as well as externally applied currents). Their dependence on several experimental parameters is discussed.

Electrophysiology↗
PubMed1983

A theoretical study on the sucrose gap technique as applied to multicellular muscle preparations. III. Methodical errors in the determination of inward currents.

The analysis of errors associated with saline-sucrose interdiffusion in sucrose gap experiments on multicellular muscle preparations described in two previous papers (Lammel, E., 1981, Biophys. J., 36:533-553, 555-573) is extended to the determination of current-voltage relations that contain an activated inward current component. The membrane current-voltage (i(t)-V(m)) relation used in the computations was N-shaped and consisted of two components, an outward (background) current (i(bg)) with properties of anomalous (inward-going) membrane rectification, and an inward current (i(s)) resembling the slow inward current of cardiac muscle. Reconstruction of current-voltage relations, which simulate those determined experimentally, indicates that in the potential range in which the total membrane current (i(t)) is outward, i(t) is measured too high, whereas it is measured too low in the range of net inward current. Reversal potentials of the inward and outward components are both shifted to more negative values, that of the inward current being more affected. Simulation of the experimental approach to evaluate i(s) as the difference between i(t) and i(bg) shows that errors that produce values too high for i(bg) are partly compensated by errors that lead to values of the net inward component that are too low. The basic features of the distorting effects analyzed are independent of different assumptions made on the selectivity of the slow inward current channels. They are related to currents emerging from the sucrose compartment (local circuit as well as externally applied currents).

Animals↗
PubMed2003

Measuring the mechanical stress induced by an expanding multicellular tumor system: a case study.

Rapid volumetric growth and extensive invasion into brain parenchyma are hallmarks of malignant neuroepithelial tumors in vivo. Little is known, however, about the mechanical impact of the growing brain tumor on its microenvironment. To better understand the environmental mechanical response, we used multiparticle tracking methods to probe the environment of a dynamically expanding, multicellular brain tumor spheroid that grew for 6 days in a three-dimensional Matrigel-based in vitro assay containing 1.0-microm latex beads. These beads act as reference markers for the gel, allowing us to image the spatial displacement of the tumor environment using high-resolution time-lapse video microscopy. The results show that the volumetrically expanding tumor spheroid pushes the gel outward and that this tumor-generated pressure propagates to a distance greater than the initial radius of the tumor spheroid. Intriguingly, beads near the tips of invasive cells are displaced inward, toward the advancing invasive cells. Furthermore, this localized cell traction correlates with a marked increase in total invasion area over the observation period. This case study presents evidence that an expanding microscopic tumor system exerts both significant mechanical pressure and significant traction on its microenvironment.

Brain↗
PubMed1990

Parasite diversity and the evolution of diploidy, multicellularity and anisogamy.

It may be reasonably assumed that a diversity of parasite genotypes in any one cell or organism is more harmful than a population of uniform genotypes. If this is accepted the following consequences follow: (i) Parasite mixing, due to cytoplasm mixing, at the time of zygote formation is a new and additional cost of sex. The rapid divisions typical of zygotic cleavage may be viewed as an adaptation to minimize the degree of mixing of parasites in each daughter cell. The faster the divisions the less chance parasite populations have to grow and mix. Mitosis is the fastest form of cell division. Prolongation of the diploid phase follows as a consequence of mitosis in a diploid zygote. This view is unusual in that it demands no advantage per se to the possession of two chromosome sets. (ii) The cells of the blastula formed from rapid zygotic divisions are different as regards their symbiotic inclusions. If the right to gametogenesis is restricted, then every replicator symbiont and nuclear genome alike and hence every cell of the developing embryo, will have an incentive to compete. Selection between the clonal blastula cells would result in the cells of low parasite diversity forming the gametes. Thus, germ line restriction is in the interests of the nuclear genome. Controlling the right to gametogenesis is only possible if the blastula remains intact. Hence, multicellularity might have evolved so as to enable the limitation of the right to gametogenesis and hence reduce the parasite diversity of gametes. Inter-cell competition during embryogenesis is central to Buss's seminal notion of the evolution of developmental complexity within the metazoa. The above theory provides the missing motive force behind such competition. (iii) For a given zygote size, the fittest zygotes are those produced by the gametes most disparate in size because these have a lower diversity of parasites. This may be the advantage of anisogamy. The novelty of this new view of anisogamy is that it puts a premium on sperm being very small, in order to exclude parasites from sperm cytoplasm. The hypothesis is briefly tested by examining if there are alternative means of parasite limitation in organisms with large gametes.

Animals↗
PubMed1984

Repair of fractionated radiation in plateau phase cultures of human tumor cells and human multicellular tumor spheroids.

We have measured potentially lethal damage repair (PLDR) after fractionated radiation, delivered at 24-h intervals in density-inhibited plateau phase cultures of four human tumor cell lines derived from tumors of differing radiocurability (two melanoma and two breast). The repair of potentially lethal damage conferred significant radioresistance on the human melanoma cells but not on the breast carcinoma cells. We examined the effects of fractionated radiation on human tumor cells adapted to become multicellular tumor spheroids (MTS). MTS derived from a human neuroblastoma were "cured" by a total fractionated radiation dose about 50% of that required for MTS derived from a human melanoma.

Breast Neoplasms↗