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PubMed2003

When may a nonuniform distribution of 131I be considered uniform? An experimental basis for multicellular dosimetry.

UNLABELLED: To varying degrees, radiopharmaceuticals are distributed nonuniformly in tissue. At a macroscopic level, the radiopharmaceutical may appear to be uniformly distributed throughout the tissue. However, on closer inspection, not all cells in the tissue may be labeled with the radiopharmaceutical. Furthermore, the radioactivity in the cells may be localized only in certain compartments within the cell. This work uses a cell culture model to examine the impact of nonuniformity at the multicellular level on the lethal effects of (131)I. METHODS: A 3-dimensional tissue culture model was used to investigate the biologic effects of nonuniform distributions of (131)I in a large population of mammalian cells. Chinese hamster V79 cells were labeled with (131)I-iododeoxyuridine ((131)IdU), mixed with unlabeled cells, and multicellular clusters (4 x 10(6) cells) were formed by gentle centrifugation. Thus, the labeled cells were randomly located in the cluster to achieve a uniform distribution of radioactivity at the macroscopic level, yet nonuniform at the multicellular level. The clusters were assembled as described and then maintained at 10.5 degrees C for 72 h to allow (131)I decays to accumulate. The clusters were then dismantled and the cells were plated for colony formation. RESULTS: When 100% of the cells were labeled, the surviving fraction of cells in the cluster was exponentially dependent on the cluster activity down to 0.1% survival. In contrast, when 10% of the cells were labeled, it was observed that the survival fraction begins to saturate at about 1% survival. Absorbed-dose estimates reveal that the mean lethal cluster dose is 4.5, 5.7, and 6.4 Gy for 100%, 10%, and 1% labeling, respectively. CONCLUSION: These data indicate that when the distribution of (131)I is uniform at the macroscopic level, but nonuniform at the multicellular level, the mean absorbed dose to a tissue element may not be a suitable quantity for use in predicting biologic effect. Rather, cellular and multicellular dosimetry approaches may be necessary to predict the biologic effects of incorporated (131)I.

Animals↗
PubMed2004

Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro.

Multicellular resistance, a subtype of therapeutic resistance manifested in cancer cells grown as three-dimensional multicellular masses, such as spheroids in vitro and solid tumors in vivo, occurs with respect to a variety of anticancer treatment strategies including chemotherapy, ionizing radiation, and even host-mediated antibody-dependent cellular cytotoxicity. Previous studies from our laboratory have shown that multicellular resistance to chemotherapy demonstrated by aggregates of EMT-6 murine mammary carcinoma cells can be overcome by using hyaluronidase to disrupt intercellular adhesive interactions and associated patterns of protein expression. In this proof of principle study, we explored the concept of antiadhesive chemosensitization in the context of human cancer cells by using a monoclonal antibody to disrupt E-cadherin-mediated cell-cell interactions in multicellular spheroids of HT29 human colorectal adenocarcinoma. In so doing, we found that disruption of E-cadherin-mediated adhesion sensitizes multicellular spheroids of HT29 in vitro to treatment with 5-fluorouracil, paclitaxel, vinblastine, and etoposide but not cisplatin. Furthermore, we have found that antibody-mediated blockage of E-cadherin function leads to decreased expression and activity of protein kinase C alpha and beta1, both of which have previously been implicated in chemoresistance exhibited by HT29 cells; however, we have found that the chemosensitization effects of the anti-E-cadherin antibody are independent of its influence on protein kinase C beta1.

Animals↗
PubMed1985

[Effects of anticancer drugs on multicellular spheroid of 9L rat brain tumor].

The effects of the anticancer drugs Nimustine (ACNU), Aclacinomycin A (ACR), Adriamycin (ADM), Bleomycin (BLM), Cisplatin (CDDP), and 5-Fluorouracil (5-FU) on the multicellular spheroid of a chemically-induced 9L rat glioma was studied. The multicellular spheroid in which cells grow in vitro as three-dimensional aggregates represents a biological model, which is intermediate between monolayer cells in vitro and solid tumors. Spheroids were initiated in bacteriological grade petri dishes seeded with 10(6) 9L rat glioma cells, cultured for four days and thereafter transferred and further developed in a spinner flask. Spheroids of 200-400 micron diameter were sorted and exposed for 24 hours to 5-FU and one hour for other drugs. After treatment both cytotoxic effect and growth delay were analyzed. Following disaggregation using collagenase, pronase and DNAase, cytotoxic effect on multicellular spheroids was measured by colony forming assay and were compared with those effects on 9L monolayer culture cells in the exponential growth. For growth delay assay, multicellular spheroids were individually transferred to 16 mm well containing 0.4 ml agarose base and 2 ml culture medium. Spheroid size was measured twice a week and growth curves were drawn. The growth delay was determined as the treated group vs. control differences in time required to a size four times that of the initial volume. For cells both in the monolayer culture and the multicellular spheroid, the dose response curve for ADM, BLM and 5-FU was "biphasic" and that for ACNU, ACR and CDDP "shoulder-threshold" type.(ABSTRACT TRUNCATED AT 250 WORDS)

Aclarubicin↗
PubMed1996

Induction and reversal of cell adhesion-dependent multicellular drug resistance in solid breast tumors.

Although there are a number of chemotherapeutic drugs available for the treatment of breast cancer, eg. adriamycin, cyclophosphamide and taxol, their effectiveness is severely limited by expression of intrinsic resistance in some patients and by acquired resistance in others. There is thus an urgent need to develop innovative methods to try and make these drugs more effective than is currently the case. One such method is to combine them with novel "chemosensitizers", i.e., drugs which themselves lack anti-tumor cytotoxic properties but which will increase the efficacy of those which do. In this regard we hae been studying the hypothesis that the resistance of solid tumors, including breast cancer, can be expressed at the prototissue/multicellular level, and that this "multicellular resistance" can be minimized or reversed by the appropriate use of so-called "anti-adhesive" agents. RESULTS/BACKGROUND: It is well known that monolayer cultures of tumor cells-including murine breast cancer-are generally much more intrinsically chemosensitive than the same cells grown as solid tumors in vivo. However, the relative resistance of solid tumors can often be recapitulated in tissue culture simply by growth of the tumor cells as three dimensional multicellular spheroids. There are cases where this is also true with respect to acquired drug resistance. This "multicellular resistance" could be due to such factors as insufficient drug penetration, a reduced growth fraction, or a decreased sensitivity to drug induced apoptosis mediated by cell-cell interaction survival signals. Can such multicellular resistance mechanisms in solid tumors be reversed? With respect to this question, we have recently found that the relative intrinsic resistance of intact murine EMT-6 mouse mammary carcinoma spheroids can be significantly reversed by the anti-adhesive (disaggregating) effects of hyaluronidase. Moreover, this novel method of chemosensitization appears to depend on increased recruitment of disaggregated cells into the cycling pool, thus rendering them more sensitive to a cell cycle dependent drug such as cyclophosphamide. The reduced growth fraction observed in spheroids appears to be due to a marked cell contact-dependent upregulation of the cyclin dependent kinase inhibitor, p27Kipl. FUTURE OBJECTIVE: The overall goal of our current and future research is to determine whether solid tumors, including human breast cancer, express intrinsic or acquired resistance at the multicellular level to such drugs as taxol or cyclophosphamide, and if so, determine whether it can be reversed by the chemosensitizing effect of anti-adhesive agents. This will require a search for effective anti-adhesive agents for human cancers as hyaluronidase has not been found to possess anti-adhesive function against such tumors to date. In addition, the counter-intuitive and innovative idea of downregulating p27kipl in human breast cancers as a means of cytotoxic drug chemosensitization is also being evaluated.

Animals↗
PubMed1998

Reappraisal of the multicellular preparation for the in vitro physiopharmacological evaluation of myocardial performance.

In order to evaluate myocardial performance, single cardiomyocytes suffer from technical problems and from the fact that some basic functional properties vanish when one moves down the hierarchic scale from multicellularity to single cells. The isolated papillary muscle has at present proven to be superior to the isolated intact cardiomyocyte. A large number of major intra- and extracellular features required to describe myocardial performance can be derived from analyzing twitch contraction and relaxation in the multicellular isolated papillary muscle. In addition, the present paper illustrates the possibility to differentiate between effects of inotropic interventions on activating Ca2+ and Ca2+ sensitivity in multicellular preparations, from a grid analysis of isometric twitches in a coordinate system of peak rate of force development (+dF/dt; reflecting the time pattern of twitch contraction) versus time to half relaxation (tHR; reflecting the time pattern of twitch relaxation). The abundance of information about myocardial performance that can be derived from the easily accessible multicellular preparation reflects its physiological kinship with the intact ventricle.

Animals↗
PubMed1991

Freedom from wholism in multicellular organisms: a possible role of tumor suppressor genes.

Wholism, known as 'homeostasis' in multicellular organisms, is fundamentally expressed in the regulation of cell proliferation and of the metabolism of individual cells. Control mechanisms represent an overriding control of the autonomy of cells in multicellular organisms. Negative regulation by suppressor genes including tumor suppressor genes is essential to maintain homeostasis in these organisms. Without wholistic regulation, the cellular society of multicellular organisms would progress from bad to worse, with eventual destruction of the whole system. The enhancement of division and differentiation of cells transduced by water-soluble factors may be considered as the controlling structure on the tumor suppressor genes. In microevolution, cell killing by the immunosurveillance systems directed at the external environments has been avoided for the 'self' cells in general, since the multicellular organism may not be considered as only a crowd of single cells.

Animals↗
PubMed1989

Repair of sublethal damage in two human tumor cell lines grown as multicellular spheroids.

Multicellular tumor spheroids (MTS) provide a suitable in vitro model to study radiation sensitivity of tumor cells. Two cell lines of human origin, obtained from a neuroblastoma (NB-100) and a squamous cell carcinoma (HN-1), were exposed to graded doses (4-9 Gy) of radiation with 18 MV photons. Radiation was applied either as a single or as a split dose with an interval of 6 hr to determine the extent of sublethal damage repair. Treated spheroids regrew at approximately the same growth rate as control multicellular tumor spheroids, preceded by a static or regression phase. Radiation response was quantified in terms of regrowth delay, expressed as the time needed for treated spheroids to obtain an 8-fold increase of the initial volume at the time of irradiation. Data obtained from regrowth delay analysis were used to calculate the extent of sublethal damage repair, showing for the squamous cell carcinoma line a fractionally higher capacity to repair sublethal damage than the neuroblastoma line. Repair increased with larger dose fractions in both cell lines. Our results show that multicellular tumor spheroids from the two cell lines used in this study are best applicable at relatively high total radiation doses. This makes multicellular tumor spheroids a suitable model for the in vitro evaluation of clinical treatment rationales such as hyperfractionation.

Carcinoma, Squamous Cell↗
PubMed2004

Evolution of multicellularity in Metazoa: comparative analysis of the subcellular localization of proteins in Saccharomyces, Drosophila and Caenorhabditis.

A comparison of the subcellular assignments of proteins between the unicellular Saccharomyces cerevisiae and the multicellular Drosophila melanogaster and Caenorhabditis elegans was performed using a computational tool for the prediction of subcellular localization. Nine subcellular compartments were studied: (1) extracellular domain, (2) cell membrane, (3) cytoplasm, (4) endoplasmic reticulum, (5) Golgi apparatus, (6) lysosome, (7) peroxisome, (8) mitochondria, and (9) nucleus. The transition to multicellularity was found to be characterized by an increase in the total number of proteins encoded by the genome. Interestingly, this increase is distributed unevenly among the subcellular compartments. That is, a disproportionate increase in the number of proteins in the extracellular domain, the cell membrane, and the cytoplasm is observed in multicellular organisms, while no such increase is seen in other subcellular compartments. A possible explanation involves signal transduction. In terms of protein numbers, signal transduction pathways may be roughly described as a pyramid with an expansive base in the extracellular domain (the numerous extracellular signal proteins), progressively narrowing at the cell membrane and cytoplasmic levels, and ending in a narrow tip consisting of only a handful of transcription modulators in the nucleus. Our observations suggest that extracellular signaling interactions among metazoan cells account for the uneven increase in the numbers of proteins among subcellular compartments during the transition to multicellularity.

Animals↗
PubMed2004

Tissue electroporation: quantification and analysis of heterogeneous transport in multicellular environments.

Although electroporation is gaining increased attention as a technology to enhance clinical chemotherapy and gene therapy of tissues, direct measurements of electroporation-mediated transport in multicellular environments are lacking. In this study, we used multicellular tumor spheroids of DU145 prostate cancer cells as a model tissue to measure the levels and distribution of molecular uptake in a multicellular environment as a function of electrical and other parameters. These measurements, and subsequent analysis, were used to test the hypothesis that cells in a multicellular environment respond to electroporation in a heterogeneous manner that differs from isolated cells in suspension due to differences in cell state, local solute concentration, and local electric field. In support of the hypothesis, molecular uptake was consistently lower for cells within spheroids than cells in dilute suspension and was spatially heterogeneous, with progressively less uptake observed for cells located deeper within spheroid interiors. Reduced uptake and heterogeneity can be explained quantitatively by accounting for the effects of cell size on transmembrane voltage and cell volume, limited extracellular solute reservoir, heterogeneous field strength due to influence of neighboring cells, and diffusional lag times.

Biological Transport↗
PubMed2003

NADPH oxidase: an enzyme for multicellularity?

Multicellularity has evolved several times during the evolution of eukaryotes. One evolutionary pressure that permits multicellularity relates to the division of work, where one group of cells functions as nutrient providers and the other in specialized roles such as defence or reproduction. This requires signalling systems to ensure harmonious development of multicellular structures. Here, we show that NADPH oxidases are specifically present in organisms that differentiate multicellular structures during their life cycle and are absent from unicellular life forms. The biochemical properties of these enzymes make them ideal candidates for a role in intercellular signalling.

Amino Acid Sequence↗
PubMed2003

The evolution of cell death programs as prerequisites of multicellularity.

One of the hallmarks of multicellularity is that the individual cellular fate is sacrificed for the benefit of a higher order of life-the organism. The accidental death of cells in a multicellular organism results in swelling and membrane-rupture and inevitably spills cell contents into the surrounding tissue with deleterious effects for the organism. To avoid this form of necrotic death the cells of metazoans have developed complex self-destruction mechanisms, collectively called programmed cell death, which see to an orderly removal of superfluous cells. Since evolution never invents new genes but plays variations on old themes by DNA mutations, it is not surprising, that some of the genes involved in metazoan death pathways apparently have evolved from homologues in unicellular organisms, where they originally had different functions. Interestingly some unicellular protozoans have developed a primitive form of non-necrotic cell death themselves, which could mean that the idea of an altruistic death for the benefit of genetically identical cells predated the invention of multicellularity. The cell death pathways of protozoans, however, show no homology to those in metazoans, where several death pathways seem to have evolved in parallel. Mitochondria stands at the beginning of several death pathways and also determines, whether a cell has sufficient energy to complete a death program. However, the endosymbiotic bacterial ancestors of mitochondria are unlikely to have contributed to the recent mitochondrial death machinery and therefore, these components may derive from mutated eukaryotic precursors and might have invaded the respective mitochondrial compartments. Although there is no direct evidence, it seems that the prokaryotic-eukaryotic symbiosis created the space necessary for sophisticated death mechanisms on command, which in their distinct forms are major factors for the evolution of multicellular organisms.

Animals↗
PubMed2006

Synchronizing a multicellular system by external input: an artificial control strategy.

MOTIVATION: Although there are significant advances on elucidating the collective behaviors on biological organisms in recent years, the essential mechanisms by which the collective rhythms arise remain to be fully understood, and further how to synchronize multicellular networks by artificial control strategy has not yet been well explored. RESULTS: A control strategy is developed to synchronize gene regulatory networks in a multicellular system when spontaneous synchronization cannot be achieved. We first construct an impulsive control system to model the process of periodically injecting coupling substances with constant or random impulsive control amounts into the common extracellular medium, and further study its effects on the dynamics of individual cells. We derive the threshold of synchronization induced by the periodic substance input. Therefore, we can synchronize the multicellular network to a specific collective behavior by changing the frequency and amplitude of the periodic stimuli. Moreover, a two-stage scheme is proposed to facilitate the synchronization in this paper. We show that the presence of the external input may also initiate different dynamics. The multicellular network of coupled repressilators is used to show the effectiveness of the proposed method. The results not only provide a perspective to understand the interactions between external stimuli and intrinsic physiological rhythms, but also may lead to development of realistic artificial control strategy and medical therapy. AVAILABILITY CONTACT: aihara@sat.t.u-tokyo.ac.jp.

Animals↗
PubMed1991

Closely linked genetic loci required for swarm cell differentiation and multicellular migration by Proteus mirabilis.

The pathogenic bacterium Proteus mirabilis exhibits a form of multicellular behaviour called swarming migration. This involves the differentiation of vegetative cells at the colony margin into swarm cells which are long, aseptate, multinucleate, hyper-flagellated filaments able to undergo repeated cycles of co-ordinated population migration and consolidation (reversion to vegetative cells). Transposon mutagenesis of uropathogenic P. mirabilis strain U6450 with Tn5 generated 4860 chromosomal insertions and, of these, 75 (1.6%) caused visibly abnormal swarming behaviour, indicating that at least 45 genes are involved in directing motility, cell differentiation and multicellular behaviour. While about one fifth of the swarm-defective mutants lacked flagella and were non-motile non-swarming (NMNS) the majority were normally flagellated and motile but were unable to form swarm cells (motile non-swarming, MNS), or were motile and able to form swarm cells but displayed aberrant patterns of multicellular migration (dendritic swarming, DS) or consolidation (frequent and infrequent consolidation, FC and IC). Restriction enzyme mapping of representative mutant DNAs by Southern hybridization with transposon DNA probes identified eight different mutated genetic loci within the five phenotypic classes. Subsequent Southern analysis of large restriction fragments separated by pulsed-field electrophoresis showed that these eight mutated loci required for motility, cell differentiation and multicellular migration were clustered on a region of DNA spanning approximately 8% of the 4.2 mbp P. mirabilis chromosome. Further linkage analysis showed that the DS locus involved in the ordered migration of the swarm cell population mapped separately from two main clusters of swarm loci, one cluster containing, within 112 kbp, genetic determinants of motility (NMNS) and also differentiation into swarm cells (MNS1, MNS2), and a second within a neighbouring 95 kbp DNA sequence containing three loci involved in the control of consolidation (FC, IC1, IC2).

Base Sequence↗
PubMed1978

Temperature-sensitive multicellular mutants of Wangiella dermatitidis.

Three temperature-sensitive morphological mutants of Wangiella dermatitidis were isolated and characterized. The mutants grew in the yeastlike morphology at the permissive temperature (25 degrees C) but expressed a multicellular (Mc) phenotype at the restrictive temperature (37 degrees C). Cultures of Mc 2 and 3 incubated at the restrictive temperature showed rapid reductions in the percentage of budded cells in the population. In contrast, budding continued for several generations in cultures of Mc 1. Incubation of cultures of Mc 2 and 3 at the restrictive temperature for 48 h resulted in nearly total conversion of yeastlike cells to the multicellular form; about 50% of the cells of Mc 1 had converted to multicellular forms after 48 h at the restrictive temperature. Studies using radiolabeled compounds documented that DNA, RNA, and protein synthesis continued at the restrictive temperature. The results suggest that multicellularity is the result of inhibition of bud emergence and cell separation without inhibition of growth nuclear division, and cytokinesis.

DNA↗
PubMed1998

Thinking about bacterial populations as multicellular organisms.

It has been a decade since multicellularity was proposed as a general bacterial trait. Intercellular communication and multicellular coordination are now known to be widespread among prokaryotes and to affect multiple phenotypes. Many different classes of signaling molecules have been identified in both Gram-positive and Gram-negative species. Bacteria have sophisticated signal transduction networks for integrating intercellular signals with other information to make decisions about gene expression and cellular differentiation. Coordinated multicellular behavior can be observed in a variety of situations, including development of E. coli and B. subtilis colonies, swarming by Proteus and Serratia, and spatially organized interspecific metabolic cooperation in anaerobic bioreactor granules. Bacteria benefit from multicellular cooperation by using cellular division of labor, accessing resources that cannot effectively be utilized by single cells, collectively defending against antagonists, and optimizing population survival by differentiating into distinct cell types.

Bacillus subtilis↗
PubMed1997

Role of the matrixin MMP-2 in multicellular organization of adipocytes cultured in basement membrane components.

Primary rat adipocytes cultured in basement membrane component gels migrated and organized into large, three-dimensional, multicellular clusters. Gross morphological changes seen during this reorganization are described. The rate of cluster formation decreased with age of the rats and was stimulated by insulin in older, but not in younger rats. Echistatin, a disintegrin, partially inhibited the formation of multicellular clusters in a concentration-dependent fashion (50% inhibitory concentration approximately 10 nM). The original extracellular matrix was initially remodeled and eventually destroyed by the time large multicellular clusters were observed. This implied that one or more matrix-degrading protease(s) were being secreted. Adipocyte-conditioned medium was found to contain a divalent cation-sensitive gelatinase activity at approximately 72 and/or approximately 62 kDa. The elution profile of this activity from gelatin-Sepharose 4B was similar to matrix metalloproteinase 2 (MMP-2, a 72-kDa matrixin with a 62-kDa mature form), and the dimethyl sulfoxide eluant from these columns contained MMP-2 immunoreactivity. MMP-2 concentration and activity were greater in conditioned medium from young than from older animals; however, insulin did not affect the amount of MMP-2 in adipocyte-conditioned media. The matrixin inhibitor 1,10-phenanthroline not only blocked gelatinase activity in zymograms but also prevented extracellular matrix remodeling and destruction, as well as adipocyte migration and the formation of cell-cell contacts in adipocyte cultures. These observations are consistent with the hypothesis that the matrixin MMP-2 is secreted by adipocytes. Whereas matrixin activity alone may not be sufficient for the formation of multicellular clusters, the data indicate that it may have a requisite role in this process.

Adipocytes↗
PubMed1998

Emergence of multicellular organisms with dynamic differentiation and spatial pattern.

The origin of multicellular organisms and the mechanism of development in cell societies are studied by choosing a model with intracellular biochemical dynamics allowing for oscillations, cell-cell interaction through diffusive chemicals on a two-dimensional grid, and state-dependent cell adhesion. Cells differentiate due to a dynamical instability, as described by our "isologous diversification" theory. A fixed spatial pattern of differentiated cells emerges, where spatial information is sustained by cell-cell interactions. This pattern is robust against perturbations. With an adequate cell adhesion force, active cells are release that form the seed of a new generation of multicellular organisms, accompanied by death of the original multicellular unit as a halting state. It is shown that the emergence of multicellular organisms with differentiation, regulation, and life cycle is not an accidental event, but a natural consequence in a system of replicating cells with growth.

Animals↗
PubMed2005

Idarubicin and idarubicinol effects on breast cancer multicellular spheroids.

Despite extensive preclinical evaluation in several experimental models, no studies have determined the effect of idarubicin and its metabolite idarubicinol on multicellular spheroids, a model which mimics the microregions of solid tumors. The principal aim of the present study was to investigate the in vitro cytotoxicity of idarubicin and its metabolite idarubicinol on MCF-7 breast cancer cells growing as monolayers or multicellular spheroids and to evaluate the influence of the length of exposure on the cytotoxic effect of both drugs. Cytoxicity was evaluated on monolayer and spheroid cultures exposed to idarubicin and idarubicinol 0.01-1000 ng/ml for 24 h or treated for 6, 12, 24 and 48 h to 100 ng/ml of both drugs. The IC50 of idarubicin and idarubicinol were 3.3+/-0.4 and 3.6+/-0.7 ng/ml, respectively, on MCF-7 monolayers and 7.9+/-1.1 and 5.3+/-0.7 ng/ml in multicellular spheroids, respectively. The antiproliferative effects of 100 ng/ml idarubicin and idarubicinol on MCF-7 spheroids was characterized by a marked time-dependence, which was less evident on MCF-7 growing as monolayer. In conclusion, the present experimental data demonstrate, for the first time, that idarubicin and idarubicinol have significant cytotoxic activity against multicellular spheroids, comparable to the antiproliferative effects on monolayer cells. In contrast, spheroids displayed substantial resistance after short exposure times that was not present in the two dimensional cultures.

Antibiotics, Antineoplastic↗