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PubMed1992

Variations in tumor cell growth rates and metabolism with oxygen concentration, glucose concentration, and extracellular pH.

Tumors and multicellular tumor spheroids can develop gradients in oxygen concentration, glucose concentration, and extracellular pH as they grow. In order to calculate these gradients and assess their impact on tumor growth, it is necessary to quantify the effect of these variables on tumor cell metabolism and growth. In this work, the oxygen consumption rates, glucose consumption rates, and growth rates of EMT6/Ro mouse mammary tumor cells were measured at a variety of oxygen concentrations, glucose concentrations, and extracellular pH levels. At an extracellular pH of 7.25, the oxygen consumption rate of EMT6/Ro cells increased by nearly a factor of 2 as the glucose concentration was decreased from 5.5 mM to 0.4 mM. This effect of glucose concentration on oxygen consumption rate, however, was slight at an extracellular pH of 6.95 and disappeared completely at an extracellular pH of 6.60. The glucose consumption rate of EMT6/Ro cells increased by roughly 40% when the oxygen concentration was reduced from 0.21 mM to 0.023 mM and decreased by roughly 60% when the extracellular pH was decreased from 7.25 to 6.95. The growth rate of EMT6/Ro cells decreased with decreasing oxygen concentration and extracellular pH; however, severe conditions were required to stop cell growth (0.0082 mM oxygen and an extracellular pH of 6.60). Empirical correlations were developed from these data to express EMT6/Ro cell growth rates, oxygen consumption rates, and glucose consumption rates, as functions of oxygen concentration, glucose concentration, and extracellular pH. These empirical correlations make it possible to mathematically model the gradients in oxygen concentration, glucose concentration, and extracellular pH in EMT6/Ro multicellular spheroids by solution of the diffusion/reaction equations. Computations such as these, along with oxygen and pH microelectrode measurements in EMT6/Ro multicellular spheroids, indicated that nutrient concentration and pH levels in the inner regions of spheroids were low enough to cause significant changes in nutrient consumption rates and cell growth rates. However, pH and oxygen concentrations measured or calculated in EMT6/Ro spheroids where quiescent cells have been observed were not low enough to cause the cessation of cell growth, indicating that the observed quiescence must have been due to factors other than acidic pH, oxygen depletion, or glucose depletion.

Animals↗

PubMed1991

31P NMR spectroscopy of 9L cell line in culture: differential effects of high temperature on anchored cells and spheroids.

The differential effects of high temperature on 9L rat gliosarcoma cells cultured in two distinctive forms, namely, anchored monolayer cells and multicellular spheroids, were investigated using 31P nuclear magnetic resonance spectroscopy. The critical temperatures resulting in irreversible changes in cellular energetics were found to be significantly different: 45 degrees C for anchored cells and 43 degrees C for multicellular spheroids, respectively. Phosphomonoester levels in multicellular spheroids were found to be consistently higher than those in anchored monolayer cells regardless of the temperature to which they were exposed. The study demonstrates that tissue derived from a single cell line may exhibit different metabolic properties depending on its growth pattern.

Animals↗

PubMed1997

Oxidative stress, signal transduction, and intercellular communication in radiation carcinogenesis.

During the evolution of multicellular organisms, survival in an aerobic environment came about by adaptive responses, both to the endogenous oxidative metabolism within the cells of the organism as well as the chemicals and low-level radiation to which they are exposed. In addition to defense mechanisms shared with single-cell organisms, multicellular organisms are equipped with gap junctions which allow electrotonic and/or metabolic synchronization of processes between coupled cells. The connexin genes, which code for the proteins comprising the gap junctions, provide homeostatic regulation of cell proliferation, differentiation, and adaptive responses of individual cells through a mechanism of "gap junctional intercellular communication." The biological consequences of the response of a multicellular organism to low-level radiation exceeding the background level of oxidative damage to a cell in a tissue could be apoptosis, cell proliferation, or cell differentiation.

Animals↗

PubMed1995

1H NMR investigations of tumor spheroids grown from a human glioma biopsy or from a human malignant glioma cell line.

Three-dimensional spherical aggregates of cells, grown from a permanent human malignant glioma cell line (multicellular GaMG spheroids) and from a human glioma biopsy (fragment spheroids), were investigated by 1H NMR spectroscopy. In addition, 1H NMR spectra of biopsy specimens immediately after explantation and of cell monolayers from primary passage and passage 5 were acquired and compared to those of fragment spheroids. By allowing tumor cells to grow in a three-dimensional arrangement, many biological characteristics of the original tumor in vivo are preserved. A technical procedure was established, indicating that spheroids are particularly suited for NMR spectroscopic studies. Well-resolved proton NMR spectra were obtained from homogeneously reaggregated as well as from fragment spheroids which were immobilized in agar. We found that fragment spheroids closely resemble characteristic spectral patterns of the corresponding tumor tissue in vitro, thus making such tissue available for 1H NMR spectroscopic measurements under easy to standardize tissue-culture conditions. Furthermore, the effect of altering glucose supply on metabolism and growth was studied with multicellular GaMG spheroids. The spectroscopic differences found between cell suspensions and multicellular spheroids indicate that GaMG spheroids produce large amounts of lactate and that they can adapt their metabolism depending on glucose supply similar to tumors in vivo.

Biopsy↗

PubMed1987

Common origin and phylogenetic diversification of animal hormonal systems.

The comparative view leads to the following main conclusions: Hormones are intercellular messengers in multicellular organisms. However, the receptor mechanism, the ability of forming receptors to substances in the cell's environment and the ability to synthesize most of the substances which serve as hormones in metazoans, are present in unicellular organisms, too. The main achievement of multicellular organisms in evolving hormonal mechanisms is due to their ability of differentiation. Though the whole genome and the ability to synthesize certain substances is, in principle, common to all body cells, the forming of certain substances and the ability to react to them in a certain way is delegated to certain cell groups only. This may be common to many intercellular messenger substances such as chalons, prostaglandins, morphogenetic and tissue-specific growth substances. A special feature in hormonal systems is that the two sites of release and reaction are distinct and are located at a distance from each other. Possibly this is the main or even the only difference from other intercellular messengers. However, it is of great functional importance because it enables hormones to control the temporal coordination of entirely different processes in different tissues located at a distance from each other or distributed all over the body. This feature is common to all compounds presently known as hormones. While the localization of receptors in target cells, as well as the nature of the releasing tissue or the mode of transport through the blood, may be too marrow borders for a definition (for instance in animal groups without a closed blood circulation system) the fact that there is transport over a distance is not. The fact that release and reaction sites are located at a distance from each other within the multicellular body may serve as a definition of "hormones' based on a common phylogenetic root and functional importance. On this common base different animal phyla have evolved different hormonal systems in relation to the particular problems of long distance temporal control of physiological processes posed by their special type of organization.

Animals↗

PubMed1982

Microtubule function and its relation to cellular development and the yeast cell cycle in Wangiella dermatitidis.

The microtubule inhibitor nocodazole (methyl-5-[2-(thienylcarbonyl)-1H-benzimidazol-2-yl]-carbamate) prevented nuclear migration and nuclear division in yeasts and developing multicellular forms of the polymorphic fungus Wangiella dermatitidis. It did not prevent yeast bud formation during at least two or three budding cycles, and caused yeasts to accumulate as premitotic forms with one to three buds. The effects of the drug suggested that at least three control pathways were involved in the yeast cell cycle; that the nocodazole block point was separate from the execution points of two temperature-sensitive mutations which lead to multicellularity; and that microtubules were controlling neither the yeast budding process nor the development of multicellular forms.

Benzimidazoles↗

PubMed1995

Molecular phylogeny of Metazoa (animals): monophyletic origin.

The phylogenetic relationships within the kingdom Animalia (Metazoa) have long been questioned. Focusing on the lowest eukaryotic multicellular organisms, the metazoan phylum Porifera (sponges), it remained unsolved if they evolved multicellularity independently from a separate protist lineage (polyphyly of animals) of derived from the same protist group as the other animal phyla (monophyly). After having analyzed genes typical for multicellularity (adhesion molecules/receptors and a nuclear receptor), we present evidence that Porifera should be placed in the kingdom Animalia. We therefore suggest a monophyletic origin for all animals.

Amino Acid Sequence↗

PubMed2003

On the origin of differentiation.

Following the origin of multicellularity in many groups of primitive organisms there evolved more than one cell type. It has been assumed that this early differentiation is related to size the larger the organism the more cell types. Here two very different kinds of organisms are considered: the volvocine algae that become multicellular by growth, and the cellular slime moulds that become multicellular by aggregation. In both cases there are species that have only one cell type and others that have two. It has been possible to show that there is a perfect correlation with size: the forms with two cell types are significantly larger than those with one. Also in both groups there are forms of intermediate size that will vary from one to two cell types depending on the size of the individuals, suggesting a form of quorum sensing. These observations reinforce the view that size plays a critical role in influencing the degree of differentiation.

Animals↗

PubMed2006

A novel regulation on developmental gene expression of fruiting body formation in Myxobacteria.

Myxobacteria are Gram-negative soil microorganisms that prey on other microorganisms. Myxobacteria have significant potential for applications in biotechnology because of their extraordinary ability to produce natural products such as secondary metabolites. Myxobacteria also stand out as model organisms for the study of cell-cell interactions and multicellular development during their complex life cycle. Cellular morphogenesis during multicellular development in myxobacteria is very similar to that in the eukaryotic soil amoebae. Recent studies have started uncovering molecular mechanisms directing the myxobacterial life cycle. We describe recent studies on signal transduction and gene expression during multicellular development in the myxobacterium Myxococcus xanthus. We provide our current model for signal transduction pathways mediated by a two-component His-Asp phosphorelay system and a Ser/Thr kinase cascade.

Gene Expression Regulation, Bacterial↗

PubMed2004

Time-lapse tracking of barley androgenesis reveals position-determined cell death within pro-embryos.

Following abiotic stress to induce barley (Hordeum vulgare L.) androgenesis, the development of 794 enlarged microspores in culture was monitored by time-lapse tracking. In total, 11% of the microspores tracked developed into embryo-like structures (type-I pathway), 36% formed multicellular structures (type-II pathway) and 53% of the microspores followed gametophytic divisions, accumulated starch and died in the first days of tracking (type-III pathway). Despite the microspore fate, enlarged microspores showed similar morphologies directly after stress treatment. Ultrastructural analysis, however, revealed two morphologically distinct cell types. Cells with a thin intine layer and an undifferentiated cytoplasm after stress treatment were associated with type-I and type-II pathways, whereas the presence of differentiated amyloplasts and a thick intine layer were associated with the type-III pathway. Tracking revealed that the first morphological change associated with embryogenic potential was a star-like morphology, which was a transitory stage between uninucleate vacuolated microspores after stress and the initiation of cell division. The difference between type-I and type-II pathways was observed during the time they displayed the star-like morphology. During the transition phase, embryo-like structures in the type-I pathway were always released out of the exine wall at the opposite side of the pollen germ pore, whereas in the type-II pathway multicellular structures were unable to break the exine and to release embryo-like structures. Moreover, by combining viability studies with cell tracking, we show that release of embryo-like structures was preceded by a decrease in viability of the cells positioned at the site of exine wall rupture. These cells were also positively stained by Sytox orange, a cell death indicator. Thereby, we demonstrate, for the first time, that a position-determined cell death process marks the transition from a multicellular structure into an embryo-like structure during barley androgenesis.

Cell Death↗

PubMed1997

Origin of metazoan adhesion molecules and adhesion receptors as deduced from cDNA analyses in the marine sponge Geodia cydonium: a review.

The phylogenetic relationships of the kingdom Animalia (Metazoa) have long been questioned. Whether the lowest eukaryotic multicellular organisms, the metazoan phylum Porifera (sponges), independently evolved multicellularity from a separate protist lineage (polyphyly of animals) or whether they were derived from the same protist group as the other animal phyla (monophyly) remains unclear. Analyses of the genes that are typical for multicellularity, e.g. those coding for adhesion molecules (galectin) and adhesion receptors (receptor tyrosine kinase, integrin receptor, receptors featuring scavenger receptor cysteine-rich domains) or elements involved in signal transduction pathways (G-proteins, Ser/Thr protein kinases), especially from the marine sponge Geodia cydonium, indicate that all animals, including sponges, are of monophyletic origin.

Animals↗

PubMed2006

Nitric oxide attenuates resistance to doxorubicin in three-dimensional aggregates of human breast carcinoma cells.

Compared with monolayer culture, tumour cells cultured as multicellular aggregates (spheroids) exhibit much higher levels of resistance to chemotherapeutic agents, a phenomenon known as multicellular resistance (MCR). Associated with multicellular aggregates is a heterogeneous microenvironment characterised by gradients in oxygen, pH, and nutrients. We previously showed that nitric oxide (NO) signalling plays an important role in the regulation of chemosensitivity in cancer cells cultured as monolayer, and that hypoxia increases resistance to anti-cancer agents largely through a mechanism involving the inhibition of NO signalling. The goal of the present study was to determine whether NO mimetics chemosensitize breast cancer cells in spheroid cultures. Survival of MDA-MB-231 breast carcinoma cells was determined by clonogenic assay following spheroid culture, doxorubicin exposure, and NO mimetic administration. When spheroids were incubated for 24 h with the NO mimetics diethylenetriamine/nitric oxide adduct (DETA/NO) and glyceryl trinitrate (GTN), cell survival after doxorubicin (200 microM) exposure was decreased by 33% (p<0.006) and by up to 47% (p<0.02), respectively. Nitric oxide-mediated signalling involves the generation of the second messenger cyclic guanosine monophosphate (cGMP). Administration of a non-hydrolysable cGMP analogue, 8-Bromo-cGMP, significantly decreased MCR (p<0.04). The effect of NO mimetic exposure on tumour cell chemosensitivity was not due to increased penetration of doxorubicin into spheroids, nor was it associated with an increase in cell proliferation. These results suggest that NO mimetics attenuate MCR to doxorubicin through a mechanism involving cGMP-dependent signalling. Therefore, NO-mimetics may potentially be used as chemosensitizers in cancer therapy.

Antibiotics, Antineoplastic↗

PubMed1997

Three-dimensional endothelial-tumor epithelial cell interactions in human cervical cancers.

The purpose of this study is to understand the multicellular interaction between tumor epithelial (TEC) and human umbilical vein endothelial cells (HUVEC). The development of in vitro systems in which to coculture these cells as multicellular aggregates is very critical. Cell lines were established from cervical tumor cells (n = 6) and two from HUVEC (n = 2) and they were cultured as three-dimensional (3-D) multicellular-cultures using Cytodex-3 microcarrier beads in the rotating wall vessel (RWV). After a 240-h incubation, TEC and HUVEC proliferated exponentially to 4.2 x 10(7) and 2.2 x 10(7) cells/ml, respectively, without requiring a feeder layer; in contrast to the two-dimensional (2-D) cultures that average about 8 x 10(5) cells/ml. Phase contrast microscopy indicated formation of 3-D aggregates that varied in size from 0.5 to 5 mm. The size of the aggregates (1-5 mm, 6-14 microcarriers) increased over time; however, the number of aggregates (0.5-1 mm, 2-5 microcarriers) decreased over a long-term incubation (240 h) because the cells merged to form large clumps. Maximum aggregation was observed with TEC at 120 h and HUVEC at 96 h. The culture of TEC in the absence of HUVEC produced minimal differentiation in contrast to cocultures. The TEC and HUVEC as cocultures in RWV proliferated at an accelerated rate (1.3 x 10(7) cells/ml, 96 h). The TEC-HUVEC coculture presented tubular structures penetrating the tumor cell masses, forming aggregates larger in size than the monocultures and typically with greater cell mass and number. The cells were viable (trypan blue exclusion) and metabolically active (glucose utilization) until 240 h. These data suggest that RWV provides a new model that allows us to investigate the regulatory factors that govern tumor angiogenesis.

Adenocarcinoma↗

PubMed1995

Darwin's selection within the human body.

It has been widely accepted that Darwin's natural selection plays a basic role in carcinogenesis and some other disease processes, but is not relevant to the normal multicellular life within the human body. The hypothesis proposed here is that selection and other evolutionary mechanisms not only normally or physiologically exist within the body of human beings and other multicellular organisms, but also persist and 'function' throughout the entire life span of the organism, from the embryo development to the aging process. This is based on the concept of cell individuality and the fact that there are a great deal of variations in cell populations, in particular possible existence of somatic genetic variations within the body. To realize the existence of natural selection in the multicellular life and study how it operates within organisms in both physiological and pathological conditions are fundamentally important to our understanding of human biology and medicine.

Cell Division↗

PubMed1990

Radiosensitivity of human melanoma spheroids influenced by growth rate.

The radiosensitivity of human melanoma cell line BRO was investigated using the multicellular tumor spheroid system. By adding different concentrations of bovine serum to the tissue culture medium, two different growth rates could be obtained. Spheroids (200-250 microns) were irradiated with graded single doses of X rays (2-8 Gy). The radiation response was quantified using specific growth delay, clonogenic cell survival, and spheroid cure. All three assays showed a growth rate dependent radiation response. At both growth rates the spheroid growth fraction and critical cell number were of comparable magnitude. There was a strong correlation between the radiation response of spheroid regenerating units and clonogenic cells from dispersed spheroids. Cell survival curves indicated a decreased ability to accumulate sublethal damage in fast growing multicellular tumor spheroids. From this study it appears that the intrinsic radiosensitivity of human melanoma cell line BRO cells in multicellular spheroids is modulated by intratumoral conditions.

Cell Aggregation↗

PubMed1995

Heterogeneity in the fractionation sensitivities of human tumor cell lines: studies in a three-dimensional model system.

PURPOSE: Current concepts to optimize the therapeutic gain of radiotherapy by hyperfractionation assume that human tumors are less sensitive to fractionation than late reacting normal tissues. The aim of this study was to investigate the extent of the intercell line heterogeneity of fractionation sensitivity of a wide variety of human tumor cell lines in a three-dimensional model system under fully oxic conditions using schedules with one to eight fractions. Biological characteristics of the tumors that correlate with fractionation sensitivity should be identified. METHODS AND MATERIALS: A total of 21 cell lines from human tumors maintained as multicellular spheroids consisting of 1000-1500 cells were given fractionated irradiation within a total treatment time of maximally 50 h. Complete dose-spheroid control curves were determined for each fractionation scheme. The spheroid control data were adequately described by the linear quadratic model assuming Poisson statistics. In addition, the induction of a G2 block by a fractionated test dose of seven 3 Gy fractions given at 6-h intervals was determined in spheroid cells using flow cytometry of propidium bromide stained cell nuclei. RESULTS: The fractionation sensitivities of human tumor cells in multicellular spheroids could be characterized by alpha/beta values, ranging from 2.8-37 Gy in dependence on the cell line. The log normally distributed alpha/beta values were positively correlated with the percentage increase in G2/M phase after the fractionated test dose compared to the controls (r = 0.72, p < 0.01), and were associated with the degree of tumor differentiation (p = 0.01, ANOVA F-test). No significant correlation between the log (alpha/beta) values and the surviving fractions at 2 Gy (SF2) or the total doses with 2 Gy per fraction necessary to control 50% of the spheroids (SCD50) was observed. Despite the intercell line variability of the alpha/beta values, the SCD50 values of the different cell lines, given with one and eight fractions or one fraction and 2 Gy per fraction, were closely associated (Spearman rank correlation coefficients: r = 0.89 or r = 0.90, p < 0.0001). CONCLUSION: Human tumor cell lines showed a marked heterogeneity in the fractionation sensitivity when irradiated as multicellular spheroids and assayed in situ using the spheroid control end point. Therefore, the therapeutic gain of altered fractionation also depends on those biological characteristics of each individual tumor that affects its fractionation sensitivity. Parameters that correlate with fractionation sensitivity of the tumor lines in the spheroid system were identified as grade of tumor differentiation and percentage increase in G2/M cells at the end of an eight-fraction schedule.

Humans↗

PubMed1992

Positional information in cells and organisms.

The processes of pattern formation are usually considered to be quite different in unicellular and multicellular organisms. The only unifying ideas have been very general, such as those concerning regional differences and organization along a polar axis. Concepts like induction, fields and gradients have generally been applied only to the development of multicellular organisms. Here, Joseph Frankel suggests that pattern formation by multicellular organisms evolved in their progenitors in response to multiplication of cytoplasmic structural units rather than of nuclei. Ciliates provide a living example of complex patterning in a compound uninucleate organism.

Journal Article↗

PubMed2005

Evolutionary history of the retinoblastoma gene from archaea to eukarya.

The retinoblastoma gene product (Rb protein) has a role in progression through the cell cycle, regulating the activities of several transcription factors such as E2F. Since its functional loss results in impaired differentiation in the nervous, hematopoietic, and muscular systems, the Rb protein is very important for cell regulation in multicellular eukaryotes. To gain an insight into the evolutionary history of the Rb gene, I have compared the amino acid sequences of Rb proteins in multicellular eukaryotes and unicellular organisms including yeast, archaeotes, and viruses. Two short amino acid sequences, in the N-terminal and pocket A regions of human Rb protein, found to be well conserved, also in a single protein of Saccharomyces cerevisiae. These sequences were also found in proteins of two archaeotes, Archaeoglobus fulgidus and Methanococcus jannaschii. Further, the most conserved sequence in the pocket B region among multicellular eukaryotic Rb proteins was also conserved in several poxviruses. From these data, I conclude that the pocket A and B regions, backbones of the Rb protein, are derived from different organisms, respectively, the ancestors of archaeote and poxvirus, and that the ancestral pocket B region has been lost during evolutionary history of unicellular eukaryotes.

Amino Acid Sequence↗