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PubMed2005

Physiological regulation of yeast cell death in multicellular colonies is triggered by ammonia.

The existence of programmed cell death (PCD) in yeast and its significance to simple unicellular organisms is still questioned. However, such doubts usually do not reflect the fact that microorganisms in nature exist predominantly within structured, multicellular communities capable of differentiation, in which a profit of individual cells is subordinated to a profit of populations. In this study, we show that some PCD features naturally appear during the development of multicellular Saccharomyces cerevisiae colonies. An ammonia signal emitted by aging colonies triggers metabolic changes that localize yeast death only in the colony center. The remaining population can exploit the released nutrients and survives. In colonies defective in Sok2p transcription factor that are unable to produce ammonia, death is spread throughout the whole population, thus decreasing the lifetime of the colony. The absence of Mca1p metacaspase or Aif1p orthologue of mammalian apoptosis-inducing factor does not prevent regulated death in yeast colonies.

Ammonia↗
PubMed1979

Multicellular origin of fibrosarcomas in mice induced by the chemical carcinogen 3-methylcholanthrene.

The cellular origin of tumors induced by the chemical carcinogen 3-methylcholanthrene (MCA) was studied in mice with X-chromosome inactivation mosaicism. Because only one of the two X-chromosomes is active in XX somatic cells, a female heterozygous at the X-linked phosphoglycerate kinase (PGK-1) locus for the usual Pgk-1b gene and the variant Pgk-1a has two populations of cells, in the cells of one population, Pgk-1b is active and B-type enzyme is synthesized, whereas in cells of the other population, A-type enzyme is produced. Both enzyme types are found in normal tissues from these mosaic mice. A tumor developing from a single cell exhibits only one of the two PGK enzyme types, whereas a tumor with a multicellular origin expresses both enzymes (i.e., it has a double-enzyme phenotype). Five fibrosarcomas developing at the site of injection of 0.2 or 2.0 mg of MCA were analyzed. 36 of 38 fragments from the five tumors had double-enzyme PGK phenotypes. One piece from each of two tumors showed a single-enzyme phenotype. Histological, cell culture, and cloning studies indicate that the double-enzyme phenotypes reflect the presence of both types of malignant cells and not admixture of normal with neoplastic elements in the specimens tested for PGK. The results suggest strongly that these fibrosarcomas have a multicellular origin.

Animals↗
PubMed2005

On the surviving fraction in irradiated multicellular tumour spheroids: calculation of overall radiosensitivity parameters, influence of hypoxia and volume effects.

We model the heterogeneous response to radiation of multicellular tumour spheroids assuming position- and volume-dependent radiosensitivity. We propose a method to calculate the overall radiosensitivity parameters to obtain the surviving fraction of tumours. A mathematical model of a spherical tumour with a hypoxic core and a viable rim which is a caricature of a real tumour is constructed. The model is embedded in a two-compartment linear-quadratic (LQ) model, assuming a mixed bivariated Gaussian distribution to attain the radiosensitivity parameters. Ergodicity, i.e., the equivalence between ensemble and volumetric averages is used to obtain the overall radiosensitivities for the two compartments. We obtain expressions for the overall radiosensitivity parameters resulting from the use of both a linear and a nonlinear dependence of the local radiosensitivity with position. The model's results are compared with experimental data of surviving fraction (SF) for multicellular spheroids of different sizes. We make one fit using only the smallest spheroid data and we are able to predict the SF for the larger spheroids. These predictions are acceptable particularly using bounded sensitivities. We conclude with the importance of taking into account the contribution of clonogenic hypoxic cells to radiosensitivity and with the convenience of using bounded local sensitivities to predict overall radiosensitivity parameters.

Animals↗
PubMed1977

Multicellular spheroids: a new model target for in vitro studies of immunity to solid tumor allografts.

Multicellular spheroids of EMT6 mammary sarcoma cells of BALB/c origin were incubated with normal spleen cells or alloimmune spleen cells generated in vitro in mixed leukocyte cultures (MLC). After 24 hours, spheroids were trypsinized and assayed for surviving tumor cells by use of a cloning technique. Under these conditions a 60-80% reduction in clone-forming tumor cells was observed after incubation of spheroids with immune lymphocytes as compared to normal lymphocyte controls. This cytotoxic effect occurred in situ, and alloimmune cells sensitized against unrelated antigens were much less cytotoxic than were specifically sensitized cells. In parallel autoradiographic studies, some immune lymphoid cells that had been labeled with tritiated thymidine during the proliferative phase of the MLC could be demonstrated within spheroids after 24 hours. These results suggested that multicellular spheroids will be a useful in vitro model for more detailed analysis of the factors controlling infiltration in in situ destruction of solid tumor grafts.

Animals↗
PubMed1996

Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mammary carcinoma cells.

BACKGROUND: De novo or acquired resistance to chemotherapeutic drugs continues to be one of the most important obstacles hindering the successful treatment of cancer patients. Consequently, enhancing the efficacy of conventional chemotherapeutic drugs has become an important research goal. Our previous studies using the mouse EMT-6 mammary carcinoma selected for resistance to various alkylating agents in vivo demonstrated that such acquired drug resistance may be manifested in vitro only in cells growing in a three-dimensional configuration but not in conventional monolayer culture. We also found that this phenomenon, which we refer to as "acquired multicellular resistance," is associated with an increase in intercellular adhesion or compaction of the alkylating agent-resistant cell lines grown as aggregates in three-dimensional culture. PURPOSE: The present study further investigates the impact of three-dimensional architecture on acquired multicellular drug resistance and its influence on cell cycle kinetics, cell cycle arrest, and cell survival. METHODS: To test the hypothesis that an increase in three-dimensional compaction is related to the drug resistance properties of the cells, we did the following: 1) selected clones of the EMT-6 cell line that spontaneously formed tightly or loosely adherent aggregates and assessed their respective drug resistance properties in vitro; 2) assayed tumorigenic potential of the tight and loose clones after exposure to defined concentrations of the activated form of cyclophosphamide, 4-hydroperoxycyclophosphamide (4-HC) in vitro; and 3) treated the tight clones with hyaluronidase, an agent capable of disrupting EMT-6 spheroids, and assayed what effect this treatment had on chemosensitivity. We used fluorescence-activated cell sorter analysis to monitor any potential alterations in cell cycle kinetics. RESULTS: The increase in compaction in three-dimensional culture was sufficient to confer resistance to 4-HC. This increase in intercellular adhesion was also associated with a lower proliferating fraction of tumor cells and with an almost completely diminished ability of the cells to arrest in the G2/M phase of the cell cycle after drug exposure. Furthermore, these changes were detectable only in three-dimensional culture, not in conventional monolayer culture. In conventional monolayer culture, all cell types consistently showed a high level of proliferation and arrested in G2/M after exposure to 4-HC. Moreover, hyaluronidase was able to disrupt intercellular adhesion and chemosensitize tumor cells both in vitro and in vivo in an ascites model. CONCLUSION: Earlier studies have demonstrated that hyaluronidase is able to sensitize tumor cells to various anticancer agents. Our studies now demonstrate that this sensitization can occur by a mechanism independent of increased drug penetration. This mechanism is likely to be related to the "anti-adhesive" effect of hyaluronidase, which overrides cell contact-dependent growth inhibition, recruits cells into the cycling pool, and renders tumor cells more sensitive to cytotoxic agents that preferentially kill rapidly dividing cells. IMPLICATIONS: Other tumor-specific "anti-adhesives" should be explored that can be effective chemosensitizers when used in combination with cell cycle-specific drugs for the treatment of small, solid tumors.

Animals↗
PubMed1983

The nucleotide sequences of 5S rRNAs from a multicellular green alga, Ulva pertusa, and two brown algae, Eisenia bicyclis and Sargassum fulvellum.

The nucleotide sequences of 5S rRNA from a multicellular green alga Ulva pertusa, and multicellular brown algae Eisenia bicyclis and Sargassum fulvellum, have been determined. The 5S rRNA from Ulva is composed of 120 nucleotides, and those from Eisenia and Sargassum have 118 nucleotides. The nucleotide sequence of Ulva 5S rRNA is rather similar to 5S rRNAs from unicellular green algae and higher plants, while those of Eisenia and Sargassum 5S rRNAs are unique.

Animals↗
PubMed1984

Evolution of multicellular animals as deduced from 5S rRNA sequences: a possible early emergence of the Mesozoa.

The nucleotide sequences of 5S rRNA from a mesozoan Dicyema misakiense and three metazoan species, i.e., an acorn-worm Saccoglossus kowalevskii, a moss-animal Bugula neritina, and an octopus Octopus vulgaris have been determined. A phylogenic tree of multicellular animals has been constructed from 73 5S rRNA sequences available at present including those from the above four sequences. The tree suggests that the mesozoan is the most ancient multicellular animal identified so far, its emergence time being almost the same as that of flagellated or ciliated protozoans. The branching points of planarians and nematodes are a little later than that of the mesozoan but are clearly earlier than other metazoan groups including sponges and jellyfishes. Many metazoan groups seem to have diverged within a relatively short period.

Animals↗
PubMed2001

Tobamoviral movement protein transiently expressed in a single epidermal cell functions beyond multiple plasmodesmata and spreads multicellularly in an infection-coupled manner.

Cell-to-cell movement of a plant virus requires expression of the movement protein (MP). It has not been fully elucidated, however, how the MP functions in primary infected cells. With the use of a microprojectile bombardment-mediated DNA infection system for Tomato mosaic virus (ToMV), we found that the cotransfected ToMV MP gene exerts its effects in the initially infected cells and in their surrounding cells to achieve multicellular spread of movement-defective ToMV. Five other tobamoviral MPs examined also transcomplemented the movement-defective phenotype of ToMV, but the Cucumber mosaic virus 3a MP did not. Together with the cell-to-cell movement of the mutant virus, a fusion between the MP and an enhanced green fluorescent protein variant (EGFP) expressed in trans was distributed multicellularly and localized primarily in plasmodesmata between infected cells. In contrast, in noninfected sites the MP-EGFP fusion accumulated predominantly inside the bombarded cells as irregularly shaped aggregates, and only a minute amount of the fusion was found in plasmodesmata. Thus, the behavior of ToMV MP is greatly modulated in the presence of a replicating virus and it is highly likely that the MP spreads in the infection sites, coordinating with the cell-to-cell movement of the viral genome.

Amino Acid Sequence↗
PubMed2003

Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species.

Hypoxia in tumors is generally associated with chemoresistance and radioresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance transporter P-glycoprotein (P-gp) has not been investigated. Herein, we demonstrate that with increasing size of DU-145 prostate multicellular tumor spheroids the pericellular oxygen pressure and the generation of reactive oxygen species decreased, whereas the alpha-subunit of HIF-1 (HIF-1alpha) and P-gp were up-regulated. Furthermore, P-gp was up-regulated under experimental physiological hypoxia and chemical hypoxia induced by either cobalt chloride or desferrioxamine. The pro-oxidants H2O2 and buthionine sulfoximine down-regulated HIF-1alpha and P-gp, whereas up-regulation was achieved with the radical scavengers dehydroascorbate, N-acetylcysteine, and vitamin E. The correlation of HIF-1alpha and P-gp expression was validated by the use of hepatoma tumor spheroids that were either wild type (Hepa1) or mutant (Hepa1C4) for aryl hydrocarbon receptor nuclear translocator (ARNT), i.e., HIF-1beta. Chemical hypoxia robustly increased HIF-1alpha as well as P-gp expression in Hepa1 tumor spheroids, whereas no changes were observed in Hepa1C4 spheroids. Hence, our data demonstrate that expression of P-gp in multicellular tumor spheroids is under the control of HIF-1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1978

The multicellular spheroid as a model tumor allograft. I. Quantitative assessment of spheroid destruction in alloimmune mice.

A quantitative model for the assessment of in situ immunity to solid tumor allografts has been developed. Multicellular spheroids of murine EMT6 mammary sarcoma cells were implanted in the peritoneal cavity of normal or specifically alloimmune mice. Damage to spheroids was quantitatively assessed at various times by trypsinizing the recovered spheroids and assaying for surviving EMT6 cells by a cloning technique. In alloimmune mice, significant destruction of spheroids was observed within 24 hr of implantation, and a 99% reduction in the number of clonogenic MT6 cells in spheroids was consistently found after 48 hr. In contrast, little or no cytotoxic effect was observed when spheroids were implanted for 48 hr in nonimmune mice or in mice immunized against unrelated alloantigens. Implantation of spheroids in alloimmune athymic (nu/nu) mice did not result in appreciable spheroid damage as compared with littermate controls. Histological analysis of spheroids taken from alloimmune mice at the time of maximum tumor cell destruction indicated that large numbers of mononuclear cells had infiltrated the spheroid. These results suggests that multicellular spheroids will be a useful model for quantitative studies of the cellular mechanisms responsible for tissue-damaging reactions in vivo.

Animals↗
PubMed1992

Analysis of G alpha 4, a G-protein subunit required for multicellular development in Dictyostelium.

The Dictyostelium G alpha 4 gene encodes a G-protein alpha subunit that is primarily expressed during the multicellular stages of development. g alpha 4 null mutants, created by gene disruption, show aberrant morphological differentiation, reduced levels of prespore gene expression, and a loss of the ability to produce spores. These developmental phenotypes can be rescued by complementation with the wild-type gene. Cells that overexpress the G alpha 4 gene (G alpha 4HC) also show reduced spore production but display an aberrant morphological phenotype distinct from that of g alpha 4 cells. The g alpha 4 phenotype can be partially rescued by the presence of wild-type or G alpha 4HC cells in chimeric organisms, suggesting that G alpha 4-expressing cells produce an intercellular signal that is essential for multicellular development.

Animals↗
PubMed2000

Origin of complexity in multicellular organisms.

Through extensive studies of dynamical system modeling cellular growth and reproduction, we find evidence that complexity arises in multicellular organisms naturally through evolution. Without any elaborate control mechanism, these systems can exhibit complex pattern formation with spontaneous cell differentiation. Such systems employ a "cooperative" use of resources and maintain a larger growth speed than simple cell systems, which exist in a homogeneous state and behave "selfishly." The relevance of the diversity of chemicals and reaction dynamics to the growth of a multicellular organism is demonstrated. Chaotic biochemical dynamics are found to provide the multipotency of stem cells.

Cell Communication↗
PubMed2005

Induction of multicellular 3-D spheroids of MCF-7 breast carcinoma cells by neutrophil-derived cathepsin G and elastase.

In tumor metastasis, multicellular aggregates of tumor cells form and disseminate into the blood or lymph vessels from the tumor mass, following the formation of tumor cell emboli in distant vessels. However, the mechanism by which aggregates form in the tumor mass is unknown. Neutrophils often exist in tumors and are considered to affect tumor development. We observed that neutrophils had the capacity to induce the aggregation of MCF-7 human breast carcinoma cells adhering to culture substrates. When MCF-7 cells were cultured with rat inflammatory neutrophils, the soluble fraction of their lysate, and the conditioned medium of neutrophils stimulated with N-formyl-Met-Leu-Phe plus cytochalasin B, multicellular aggregates formed within 16 h, and tightly aggregated 3-D spheroids formed when the cultures were prolonged. The spheroid-inducing reaction was reversible and energy-dependent. The MCF-7 cells induced to aggregate by the neutrophil extract showed growth potential, although the growth rate of the cells was slightly reduced. The aggregation was dependent on E-cadherin, because the spheroids dispersed into isolated cells on incubation with EGTA or anti-E-cadherin antibody following pipetting. The aggregation-inducing activity in neutrophils was completely inhibited by soybean trypsin-chymotrypsin inhibitor. Moreover, the commercially available human neutrophil elastase and cathepsin G induced the aggregation of MCF-7 cells and formation of spheroids. The proteases secreted by infiltrated neutrophils in tumors are implicated in the dissemination of tumor aggregates from primary tumor sites.

Adenocarcinoma↗
PubMed1994

Analysis of growth of multicellular tumour spheroids by mathematical models.

We wished to determine the applicability of previously proposed deterministic mathematical models to description of growth of multicellular tumour spheroids. The models were placed into three general classes: empirical, functional and structural. From these classes, 17 models were applied systematically to growth curves of multicellular tumour spheroids used as paradigms of prevascular and microregional tumour growth. The spheroid growth curves were determined with uniquely high density of measurements and high precision. The theoretical growth curves obtained from the models were fitted by the weighted least-squares method to the 15 measured growth curves, each corresponding to a different cell line. The classical growth models such as von Bertalanffy, logistic and Gompertz were considered as nested within more general models. Our results demonstrate that most models fitted the data fairly well and that criteria other than statistical had to be used for final selection. The Gompertz, the autostimulation and the simple spheroid models were the most appropriate for spheroid growth in the empirical, functional and structural classes of models, respectively. We also showed that some models (e.g. logistic, von Bertalanffy) were clearly inadequate. Thus, contrary to the widely held belief, the sigmoid character of a three or more parameter growth function is not sufficient for adequate fits.

Cell Division↗
PubMed2004

Disruption of the peroxisomal citrate synthase CshA affects cell growth and multicellular development in Dictyostelium discoideum.

Non-mitochondrial citrate synthase catalyses citrate synthesis in the glyoxylate cycle in gluconeogenesis. Screening Dictyostelium discoideum mutants generated by insertional mutagenesis isolated a poor-growing mutant that displayed aberrant developmental morphology on bacterial lawns. Axenically grown mutants developed normally and formed mature fruiting bodies on buffered agar. The affected locus encoded a novel protein (CshA) that was homologous to glyoxysomal citrate synthase. cshA was expressed maximally during vegetative growth and gradually decreased through subsequent developmental stages. An in vitro citrate synthase assay revealed that cshA disruption resulted in a 50% reduction in enzyme activity, implicating CshA as an active citrate synthase. The amino-terminus of CshA was found to have an atypical mitochondrial targeting signal, instead containing a unique nonapeptide sequence (RINILANHL) that was homologous to the conserved peroxisomal targeting signal 2 (PTS2). CshA protein was shown to be localized in the peroxisomes, and the RINILANHL sequence only efficiently targeted the peroxisomal green fluorescent protein. The growth defect of cshA(-) cells was associated with the impairment of phagocytosis and fluid-phase endocytosis, independent from cytokinesis. Disrupted multicellular development on bacterial lawns resulted from the abnormal susceptibility to the environmental conditions, perhaps because of citrate insufficiency. Taken together, these results provide new insights into the function of peroxisomal citrate synthase in cell growth and multicellular development.

Amino Acid Sequence↗
PubMedDate not supplied

Melanized and non-melanized multicellular form mutants of Wangiella dermatitidis in mice: mortality and histopathology studies.

One melanized (Mc3) and one non-melanized (Mc3W) multicellular form mutant of W. dermatitidis were compared with parental wild type in NYLAR mice. Each mutant grows as multicellular (muriform-like) forms in vitro at 37 degrees C and as yeasts at less than or equal to 30 degrees C. Yeast cells of all three strains were injected intravenously at concentrations of 1 x 10(4), 1 x 10(6), 1 x 10(7), 3 x 10(7) and 1 x 10(8) cells/mouse in groups of 10 mice. There was no virulence difference between wild type and Mc3, with 100% mortality obtained with each strain at greater than or equal to 1 x 10(7) cells/mouse. In contrast, Mc3W was less virulent, with mortality being obtained only at 1 x 10(8) cells/mouse. Histopathological study of brains, lungs, livers and spleens of moribund mice revealed that both Mc3 and Mc3W persisted in tissue as muriform cells, and in some cases as yeast, pseudohyphal and hyphal forms. There was no major difference between Mc3 and Mc3W in terms of histopathological response. These data support the association between melanin and virulence in W. dermatitidis and provide a model for the study of muriform cells in vivo.

Animals↗