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PubMed2005

Generation of dose-volume histograms using Monte Carlo simulations on a multicellular model in radionuclide therapy.

An accurate calculation of the absorbed dose at the cellular level can lead to the optimization of the administered activity and the best clinical response in radionuclide therapy. This paper describes the implementation of dose-volume histograms (DVHs) for dosimetry at the cellular level in radionuclide therapy. The FOTELP code, based on Monte Carlo simulations of photon and electron transport, was used on a three-dimensional multicellular tumor model, which includes tumor morphometry and cell-labeling parameters. Differential and cumulated DVHs were generated for different radionuclides (Cu-67, I-131, Sm-153, Y-90, and Re-188) and labeled cell densities (10, 20, 40, 80, and 100%). DVHs were generated as a percentage of tumor cells in the function of a relative absorbed dose, defined as a cell-absorbed dose divided by an average tumor-absorbed dose. DVHs for high-energy beta emitters, such as Re-188 and Y- 90, were very close to the average tumor-absorbed dose. For low-energy beta emitters, such as Cu-67 and I-131, spectra showed that many cells absorbed a much lower dose than the average tumor-absorbed dose. Nonhomogeneity of the radionuclide distribution in tumor, presented by labeled cell density, had a greater influence on DVHs for low-energy beta emitters. Radionuclide therapy plans can be optimized using DVHs.

Dose-Response Relationship, Radiation↗
PubMed2005

The application of dose-rate volume histograms and survival fractions to multicellular dosimetry.

The distribution of therapeutic radiopharmaceuticals in volumes smaller than those that can be fully resolved by the imaging system, such as by PET and SPECT scanners, is usually assumed to be homogeneous. The aim of this study was to investigate the implications of such an assumption at a scale that can be defined as multicellular for heterogeneous activity localizations of (32)P, (90)Y, and (131)I. Dose-rate distributions from heterogeneous radioactivity uptakes have been calculated in cubic volumes of 1, 3, and 4 mm using the in-house software package DOVE. These have been studied by the use of dose-rate volume histograms, and the influence of the heterogeneous dose distribution on the treatment outcome has been analyzed by the calculation of Integral Survival Fractions. The results showed that the effect of the heterogeneous localization of the compound can be overridden by the amount of radioactivity administered. However, significant variations in the survival probability distributions have been observed, depending on the amount of initial activity considered, the activity configuration, the radionuclide, and the time over which the energy was deposited. It has been shown, for example, that the ability of longer-range beta emitters, such as (32)P and (90)Y, to invalidate heterogeneous dose-rate distributions may be negated by the decay rate of the radioactivity.

Dose-Response Relationship, Radiation↗
PubMed1987

Effects of doxorubicin and cisplatin on multicellular tumor spheroids from human lung cancer.

We tested the sensitivity to doxorubicin (DXR) and cisplatin (DDP) of multicellular tumor spheroids (MTS) developed from 2 human lung cancer cell lines; PC-10 squamous cell carcinoma and PC-6 small cell carcinoma. DDP was able to maintain its efficacy in MTS: PC-10 MTS were only 3-fold more resistant to DDP than in monolayer and in PC-6 cells DDP induced cell lethality was essentially unchanged irrespective of cells being in a monolayer or MTS. Atomic absorption spectrometry revealed that DDP uptake was essentially identical, irrespective of cells being in monolayer or MTS. DDP's efficient cell kill effects in MTS seems to be explained by its good penetration into the MTS core. In contrast to DDP, these 2 types of cells responded differently to DXR. Thus, PC-10 MTS became progressively more resistant to DXR when their size increased, whereas the susceptibility of PC-6 MTS tended to increase when the MTS grew larger. Fluorescent microscopic study revealed that prominent DXR fluorescence was observed only at the outer layer of PC-10 MTS. In PC-6 MTS, however, DXR fluorescence was diffusely seen in the entire MTS at low concentrations; nevertheless, owing to PC-6 cells' high sensitivity DXR was able to exert cell lethality. The differences in distribution of DXR fluorescence between PC-10 and PC-6 MTS were corroborated by flow cytometric analysis.

Cell Survival↗
PubMed1989

Effects of physiological oxygen environment on drug-induced cell lethality of multicellular tumor spheroids from human lung cancer.

Advanced malignant tumors of certain histological types contain a hypoxic and necrotic core. Multicellular tumor spheroids (MTS) have the characteristics of chronically hypoxic cells in the center. We studied the effects of physiological oxygen environment on MTS growth and the cell lethality produced by doxorubicin (DXR) and cisplatin (DDP). MTS were made from 2 human lung cancer cell lines; PC-6 small cell and PC-10 squamous cell carcinoma, and grown for 2, 3 or 4 weeks; either in 5% CO2/air or 5% 02/5% CO2/90% N2. They were exposed to graded concentrations of DXR for 1 hr and cell lethality was determined by clonogenic assay. In the physiological oxygen environment MTS growth was retarded for both cell lines. PC-6 MTS grown in physiological oxygen environment were more sensitive to DXR than those developed in air. The differential sensitivity was most pronounced with the 2 week old MTS and gradually narrowed with increasing MTS size. In contrast, PC-10 MTS developed in the physiological oxygen environment were more resistant to DXR than those in air; the differences were again most pronounced in 2 week old MTS. There were little differences in cell kill effects of DDP, irrespective of cells being in monolayer or in MTS and growing in air or in physiological oxygen environment. These observations are consistent with the interpretation that cells in PC-6 MTS are scarcely affected by the physiological oxygen environment but easily affected by DXR, whereas cells in PC-10 MTS responded vice versa.

Antineoplastic Agents↗
PubMed1999

Polymer substrate topography actively regulates the multicellular organization and liver-specific functions of cultured hepatocytes.

This study examines the role of topography of porous synthetic polymer substrates in regulating the tissue-specific morphogenesis of cultured hepatocytes. Porous foams of amorphous 50/50 poly(D,L glycolic-co-lactic acid) (PGLA) with a wide range of controlled pore-size distributions ( approximately 1 to 100 microm) were used as culture model surfaces. We found that the induction of microporosity in PGLA substrates significantly improved cell attachment and viability in comparison to those observed on non-porous PGLA films. A detailed evaluation of cellular morphogenesis on the microporous matrices showed that hepatocellular organization was sensitively dependent on the topographical feature size of the foam surfaces. Foams with subcellular size voids ( approximately 3 microm) induced kinetics of two-dimensional hepatocyte reorganization, yet limited the extent of three-dimensional aggregation. In contrast, foams with supercellular size voids ( approximately 67-microm) restricted hepatocyte motility, thereby promoting the kinetics of 3D aggregation. At intermediate void sizes ( approximately 17 microm), both 2D and 3D reorganization kinetics were promoted. Albumin secretory kinetics progressively increased on all void size configurations, the most rapid and sustained kinetics observed in supercellular sized voids, which may serve to minimize cell-polymer contacts and maximize cell-cell contacts in 3D. Overall, these studies demonstrate that void topography of porous polymer substrates is a critical textural feature to induce short-term cell adhesion and viability, and to also selectively regulate the kinetics and extent of multicellular spreading versus 3D aggregation. By virtue of its effects on cell adhesion and morphogenesis, the void topography of nonphysiological polymer scaffolds also is a powerful variable to microengineer hepatospecific activity of tissue analogs.

Albumins↗
PubMed1997

Characteristics of multicellular spheroids formed by primary cultures of human thyroid tumor cells.

Features of multicellular tumor spheroids (MCTS) differed depending on their types of cells. MCTS formed by 4000 human thyroid primary culture epithelial tumor cells displayed diameters between 0.31 and 0.33 mm within 2 days regardless of the stage of malignancy of the originating tumors. Their cellular composition reflected that of the originating tumor in regard to DNA content and the expression of cytokeratin, vimentin, as well as thyroglobulin. During the following 3 weeks, their sizes increased up to diameters of 0.42 mm when their cells had been derived from carcinomas, and MCTS originating from adenomas stopped growing within the next 2 days. After 8 days of incubation, proliferating cells were only found in carcinoma MCTS. The cells were randomly distributed over the total volume of the spheroids, which displayed irregular cell arrangements but not concentric cell layers and did not form necrotic centers.

Antigens, Neoplasm↗
PubMed2003

Hepatocyte growth factor switches orientation of polarity and mode of movement during morphogenesis of multicellular epithelial structures.

Epithelial cells form monolayers of polarized cells with apical and basolateral surfaces. Madin-Darby canine kidney epithelial cells transiently lose their apico-basolateral polarity and become motile by treatment with hepatocyte growth factor (HGF), which causes the monolayer to remodel into tubules. HGF induces cells to produce basolateral extensions. Cells then migrate out of the monolayer to produce chains of cells, which go on to form tubules. Herein, we have analyzed the molecular mechanisms underlying the production of extensions and chains. We find that cells switch from an apico-basolateral polarization in the extension stage to a migratory cell polarization when in chains. Extension formation requires phosphatidyl-inositol 3-kinase activity, whereas Rho kinase controls their number and length. Microtubule dynamics and cell division are required for the formation of chains, but not for extension formation. Cells in the monolayer divide with their spindle axis parallel to the monolayer. HGF causes the spindle axis to undergo a variable "seesaw" motion, so that a daughter cells can apparently leave the monolayer to initiate a chain. Our results demonstrate the power of direct observation in investigating how individual cell behaviors, such as polarization, movement, and division are coordinated in the very complex process of producing multicellular structures.

Actins↗
PubMed2005

Nuclear DNA content estimates in multicellular green, red and brown algae: phylogenetic considerations.

BACKGROUND AND AIMS: Multicellular eukaryotic algae are phylogenetically disparate. Nuclear DNA content estimates have been published for fewer than 1 % of the described species of Chlorophyta, Phaeophyta and Rhodophyta. The present investigation aims to summarize the state of our knowledge and to add substantially to our database of C-values for theses algae. METHODS: The DNA-localizing fluorochrome DAPI (4', 6-diamidino-2-phenylindole) and RBC (chicken erythrocyte) standard were used to estimate 2C values with static microspectrophotometry. KEY RESULTS: 2C DNA contents for 85 species of Chlorophyta range from 0.2-6.1 pg, excluding the highly polyploidy Charales and Desmidiales with DNA contents of up to 39.2 and 20.7 pg, respectively. 2C DNA contents for 111 species of Rhodophyta range from 0.1-2.8 pg, and for 44 species of Phaeophyta range from 0.2-1.8 pg. CONCLUSIONS: New availability of consensus higher-level molecular phylogenies provides a framework for viewing C-value data in a phylogenetic context. Both DNA content ranges and mean values are greater in taxa considered to be basal. It is proposed that the basal, ancestral genome in each algal group was quite small. Both mechanistic and ecological processes are discussed that could have produced the observed C-value ranges.

Cell Nucleus↗
PubMed1994

The role of swarm cell differentiation and multicellular migration in the uropathogenicity of Proteus mirabilis.

The uropathogenic bacterium Proteus mirabilis displays a form of multicellular behavior called swarming, in which typical vegetative rods differentiate into long hyperflagellate swarm cells that undergo rapid and coordinated population migration across surfaces. Such behavior might inherently assist ascending colonization of the urinary tract, and it has also been shown that swarming differentiation in vitro is central to the expression of conventional virulence factors. This study provides support for a role of swarming in vivo. Mortality rates of mice inoculated intravenously with 2.5 x 10(8) vegetative cells were lower than rates for those inoculated with wild type strains in the case of motile transposon mutants either completely unable to swarm (< 1%) or able to undergo only aberrant swarming migration (< 40%, P < .001). Histologic analysis of renal tissues from mice infected by wild type Proteus strains showed that long differentiated cells were the major cell type, whereas the extracellular inflammatory exudate contained primarily short vegetative cells. Following intravesical (bladder) inoculation with 2.0 x 10(7) vegetative cells, kidney infection was not established by any of the three motile swarm-defective mutants; indeed, the nonswarming mutant was not retained in the bladder. In contrast, the wild type strain and a normally swarming but nonhemolytic mutant achieved a high incidence of ascending infection to the kidney.

Animals↗
PubMed2006

Overview: membrane traffic in multicellular systems: more than just a housekeeper.

Membrane traffic is a fundamental cellular function by which molecules are transported between organelles in the post-Golgi network. Accumulating evidence supports the notion that membrane traffic is not only indispensable for normal cellular function and maintenance of cellular viability by playing housekeeping roles, but also critical for various functions characteristic of multicellular organisms. This Minireview series will focus on the latter aspects of membrane traffic. The topics discussed are: the pathophysiological impact of clathrin-associated adaptor protein (AP) complexes, the significance of membrane traffic in Alzheimer's disease, regulated exocytosis of insulin, secretory lysosomes in immune response, exosomes in physiology and pathology, viral and mammalian ubiquitin ligases modulating immune response, membrane traffic of bacterial toxins, and containment of bacterial infection by autophagy.

Alzheimer Disease↗
PubMed1990

Damage to multicellular human H-2 glioma spheroids incubated with LAK cells: an ultrastructural study.

Local brain tumor therapy using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) has not proved to be effective in preliminary clinical trials. One obstacle to effective use of this therapy is ignorance about the events that follow contact of the LAK cells with glioma tissue. We used multicellular spheroids grown from human glioma cell lines as targets to study, in vitro, the effect of LAK cells against three-dimensional glioma tissue. Here we describe the ultrastructural changes in spheroids of H-2 glioma cells incubated in pellets of LAK cells for up to 24 hours. In H-2 spheroids, cellular damage was not restricted to the effector cell-target cell (effector-target) contact; it extended farther, at least partly because of nonspecific changes in the spheroid micromilieu. Formation of cytoplasmic blebs, a characteristic effect of T cells, natural killer cells, and LAK cells on single target cells, also occurs in H-2 spheroids, and it is not limited to the effector-target contact area either. These findings suggest that LAK cells release membrane-damaging agents that remain active outside the effector-target area, in the micromilieu of H-2 spheroid tissue.

Cytotoxicity, Immunologic↗
PubMed2005

Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-Only, and BNip families of apoptotic regulators.

In this report, we conducted a comprehensive survey of Bcl-2 family members, a divergent group of proteins that regulate programmed cell death by an evolutionarily conserved mechanism. Using comparative sequence analysis, we found novel sequences in mammals, nonmammalian vertebrates, and in a number of invertebrates. We then asked what conclusions could be drawn from phyletic distribution, intron/exon structures, sequence/structure relationships, and phylogenetic analyses within the updated Bcl-2 family. First, multidomain members having a sequence pattern consistent with the conservation of the Bcl-X(L)/Bax/Bid topology appear to be restricted to multicellular animals and may share a common ancestry. Next, BNip proteins, which were originally identified based on their ability to bind to E1B 19K/Bcl-2 proteins, form three independent monophyletic branches with different evolutionary history. Lastly, a set of Bcl-2 homology 3-only proteins with unrelated secondary structures seems to have evolved after the origin of Metazoa and exhibits diverse expansion after speciation during vertebrate evolution.

Amino Acid Sequence↗
PubMed2006

'Genome design' model and multicellular complexity: golden middle.

Human tissue-specific genes were reported to be longer than housekeeping genes (both in coding and intronic parts). The competing neutralist and adaptationist models were proposed to explain this observation. Here I show that in human genome the longest are genes with the intermediate expression pattern. From the standpoint of information theory, the regulation of such genes should be most complex. In the genomewide context, they are found here to have the higher informational load on all available levels: from participation in protein interaction networks, pathways and modules reflected in Gene Ontology categories through transcription factor regulatory sets and protein functional domains to amino acid tuples (words) in encoded proteins and nucleotide tuples in introns and promoter regions. Thus, the intermediately expressed genes have the higher functional and regulatory complexity that is reflected in their greater length (which is consistent with the 'genome design' model). The dichotomy of housekeeping versus tissue-specific entities is more pronounced on the modular level than on the molecular level. There are much lesser intermediate-specific modules (modules overrepresented in the intermediately expressed genes) than housekeeping or tissue-specific modules (normalized to gene number). The dichotomy of housekeeping versus tissue-specific genes and modules in multicellular organisms is probably caused by the burden of regulatory complexity acted on the intermediately expressed genes.

Gene Expression Regulation↗
PubMed1985

Codon usage and tRNA content in unicellular and multicellular organisms.

Choices of synonymous codons in unicellular organisms are here reviewed, and differences in synonymous codon usages between Escherichia coli and the yeast Saccharomyces cerevisiae are attributed to differences in the actual populations of isoaccepting tRNAs. There exists a strong positive correlation between codon usage and tRNA content in both organisms, and the extent of this correlation relates to the protein production levels of individual genes. Codon-choice patterns are believed to have been well conserved during the course of evolution. Examination of silent substitutions and tRNA populations in Enterobacteriaceae revealed that the evolutionary constraint imposed by tRNA content on codon usage decelerated rather than accelerated the silent-substitution rate, at least insofar as pairs of taxonomically related organisms were examined. Codon-choice patterns of multicellular organisms are briefly reviewed, and diversity in G+C percentage at the third position of codons in vertebrate genes--as well as a possible causative factor in the production of this diversity--is discussed.

Animals↗
PubMed1993

Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis.

Blood platelets represent the first line of host defense when normal vessels are injured. Platelet adhesion to subendothelium, aggregation, and further platelet recruitment culminate in hemostatic plug formation, which is accompanied by the consolidating effect of fibrin deposition on and between platelets. The process is multicellular in that erythrocytes promote and neutrophils inhibit platelet plug formation. Endothelial cells in proximity possess three protective mechanisms (thrombo-regulators) for limiting the size of the hemostatic plug-ADPase, eicosanoids, endothelium-dependent relaxing factor/NO. We propose that in advanced atherosclerotic blood vessels such as coronary arteries, an ulcer or fissure in the fibrous cap of the atheroma serves as an agonist that transforms the platelet into a major prothrombotic offender. Induction of excessive platelet activation overcomes the normal thromboregulatory mechanisms. Erythrocytes further activate platelets, even in the presence of aspirin, and neutrophil blockage of platelet reactivity is insufficient to prevent impending vascular occlusion. Appreciating that multiple cell types and metabolic pathways are involved in modulation of platelet reactivity in vascular occlusion is a relatively recent concept. Strategies designed to restore processes such as thromboregulation may serve to improve therapeusis in thrombosis, which at present is far from optimal.

Animals↗
PubMed2001

Tumor-induced angiogenesis studied in confrontation cultures of multicellular tumor spheroids and embryoid bodies grown from pluripotent embryonic stem cells.

Tumor vascularization is the rate-limiting step for the progression of cancer. Differential steps of tumor-induced angiogenesis were studied by a novel in vitro confrontation culture of avascular multicellular prostate tumor spheroids and embryoid bodies grown from pluripotent embryonic stem (ES) cells. Vascularization in embryoid bodies started on day 5 of cell culture and was paralleled by down-regulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). In parallel, a dissipation of gradients in the pericellular oxygen pressure was observed as measured by O(2)-sensitive microelectrodes. After 24--48 h of confrontation culture, cells positive for platelet endothelial cell adhesion molecule (PECAM-1) became visible in the contact region between the embryoid body and the tumor spheroid and sprouted within the confrontation cultures during subsequent days. Tumor-induced angiogenesis resulted in growth stimulation of tumor spheroids, disappearance of central necrosis and a reduction of the pericellular oxygen pressure. Furthermore, tumor vascularization resulted in elevated levels of HIF-1 alpha, VEGF, heat shock protein 27 (HSP27), and P-glycoprotein. Tumor-induced angiogenesis may augment the oxygen consumption in tumors resulting in an increased expression of hypoxia-related, proangiogenic genes as well as of HSP27 and P-glycoprotein, which are involved in a multidrug resistance phenotype.

Animals↗
PubMed2001

Activation of p90RSK and growth stimulation of multicellular tumor spheroids are dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP.

Mitogenic stimulation by growth factors may be mediated through intracellular reactive oxygen species (ROS) acting as signaling molecules. Incubation of multicellular prostate tumor spheroids with adenosine 5' triphosphate (ATP) dose-dependently stimulated tumor growth. ATP, uridine 5'-triphosphate (UTP), adenosine 5'-diphosphate (ADP), and 2-methylthio-ATP (2-MeS-ATP) increased intracellular ROS levels significantly. ROS generation by ATP was inhibited by the P2 receptor antagonist suramin, by the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), as well as by the Ca2+-dependent phospholipase A2 (PLA2) inhibitors indomethacin and methyl arachidonyl fluorophosphonate (MAFP). The generation of ROS was dependent on the intracellular Ca2+ response evoked by ATP. Exogenous ATP activated the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) pathway, which was blunted by the MAPK/ERK kinase 1/2 (MEK1/2) antagonist PD98059. The radical scavengers vitamin E, dimethyl thiourea (DMTU), and N-acetyl cysteine (NAC) failed to inhibit ERK1/2 activation but abolished p90 ribosomal S6 kinase (p90RSK) activation downstream of ERK1/2, as well as the growth stimulation of tumor spheroids. Our data indicate that p90RSK downstream of ERK1/2 is the molecular target for ROS generated through stimulation of purinergic receptors by ATP.

Acetylcysteine↗
PubMed1997

Evaluation of Taxol in head and neck squamous carcinoma multicellular tumor spheroids.

Taxol cytotoxicity was evaluated in human head and neck squamous carcinoma cell lines growing as multicellular tumor spheroids (MTS) and compared with monolayered culture using conventional clonogenic assays. End points were respectively the concentration inhibiting 50% of the cellular growth (IC50) in clonogenic assays and the concentration required to induce a 50% decrease in the MTS volume (ID50) or number in the overall spheroid population (SCC50). A significant difference was observed when the cells were exposed for 10 days to Taxol as a consequence of the different growth kinetics of the spheroids. After 16 day exposure of spheroids to Taxol, no difference remained between ID50 and IC50. In addition, a significant correlation was found between individual spheroid sensitivity to Taxol (ID50) and the spheroid population sensitivity (SCC50). Both parameters (ID50 and SCC50) defined in cell models appear useful for the evaluation of chemosensitivity of three-dimensional structures known to be closer to in vivo tumor models.

Antineoplastic Agents, Phytogenic↗