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Results for “Cellular Microenvironment”

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PubMed1989

Distribution and activity of antineoplastic drugs in a tumor model.

Antineoplastic drugs can be effective in solid tumors only if they can penetrate several cell layers and retain their activity in the tumor microenvironment. The capacity of several common chemotherapeutic agents to meet these requirements was evaluated in an in vitro tumor model, V79 Chinese hamster cells grown as spheroids. The delivery and toxicity of radioactively labeled 5-fluorouracil, lomustine, tetraplatin, and chlorambucil were determined by use of cell-sorting techniques to select cells as a function of their position (depth) within these spheroids, and the delivery and toxicity of doxorubicin (DOX) were evaluated on the basis of fluorescence intensity. Simultaneous measurement of drug level and toxicity in cells at the time of recovery from different depths within the spheroids led to the conclusion that drug delivery was a problem only for DOX. In contrast, several of the other agents showed a dissociation between cellular drug levels and activity, implicating a major role of the cellular microenvironment in modulating drug toxicity.

Animals↗

PubMed1986

Importance of critical metabolites and cellular interactions in the biology of microregions of tumors.

Heterogeneity of cellular microenvironments and associated differences in phenotypic expression of cells in solid tumors occur as a consequence of deficiencies of vascularization. Intervascular microregions of tumors and micrometastases can be modeled by multicellular spheroids in vitro. These develop concentration gradients of critical metabolites such as oxygen, glucose, and probably also other important nutrients, hormones, and growth factors. Drug penetration may also be reduced. Concentrations of these factors decrease from the periphery towards the center, but gradients develop in the opposite direction for certain metabolic and necrotic products such as lactate and pH. Such gradients significantly modify the proliferative status of the cells, viability, clonogenicity, cell cycle distribution, antigen expression, and differentiation. Stress of oxygen and glucose deprivation induces synthesis of a specific set of proteins. Cellular interactions can also modulate phenotypic expression, including oxygen and glucose consumption rates and sensitivity to radiation and drugs. The mechanisms of these are unknown, but changes in cell-cell communication and DNA damage and repair have been demonstrated in spheroids. Microenvironmental and cellular changes may be transient. Thus, the characteristics of cells in tumor microregions may be quite different from the intrinsic cellular properties observed after growth of cells in standard culture systems. These changes may have significant effects on responses to therapeutic agents.

Adenocarcinoma↗

PubMed1976

DNA synthesis and cell proliferation in the simple liver acinus of 10 to 20-day-old rats: evidence for cell fusion.

Radioautography after 3H-thymidine injection, mitotic arrest by colchicine and camera lucida drawings were used to study DNA synthesis, mitosis, formation of binucleated cells and morphogenesis in the simple liver acinus of Rappaport in 10-20-day old rats. By ten days the arrangement of hepatic cell plates had already attained the adult configuration - irregular and thick in acinar zone 1 (periportal), straight and thin in acinar zone 3 (pericentral). The DNA synthetic index of parenchymal and bile duct cells slowly decreased during the observation period. Zonal labeling remained steady in the relationship: zone 1 greater than zone 2 greater than zone 3. Mitosis of parenchymal and bile duct cells reached a peak at 12 days, decreasing slowly thereafter. Mitosis also exhibited the relationship zone 1 greater than zone 2 greater than zone 3. The number of binucleated cells remained constant until after day 14 when it increased rapidly. Zonal distribution of binucleated cells was just the reverse of that for DNA synthesis and mitosis, that is zone 3 greater than zone 2 greater than zone 1. Radioautographic studies of binucleated cells labeled with 3H-thymidine indicated that a small percentage of them were formed by fusion of mononucleated cells. Conclusions are: (1) the 10-20-day old rat liver is expanding its cell population primarily in acinar zones 1 and 2 while overt differentiation is occurring in acinar zone 3, (2) ingestion of solid food around day 16 may be related to binucleated cell production due in part to altered portal venous blood changing the cellular microenvironments, (3) binucleated cells arise by suppression of cytokinesis, cell fusion and/or other non-mitotic routes.

Animals↗

PubMed1986

Influence of growth phase, nutrition and hypoxia on heterogeneity of cellular buoyant densities in in vitro tumor model systems.

EMT6/Ro multicellular spheroids were sequentially dissociated into outer, middle and inner layers, and the buoyant densities of these subpopulations were compared to aerobic or exponential or plateau-phase monolayers by isopycnic density centrifugation using Percoll as the gradient medium. Spheroids were more heterogeneous in buoyant density distributions than monolayer cultures. The outer-layer cells of spheroids and fed plateau monolayers peaked at a similar density; the majority of middle-layer cells banded close to unfed plateau and exponential hypoxic monolayers, while most inner-layer cells banded where fed or unfed plateau hypoxic monolayer peaked in density. Our data suggest that metabolic heterogeneity due to growth phase, together with altered cellular microenvironment brought about by differences in oxygenation and external nutrient supplies between spheroids and monolayers, can be manifested in one biophysical parameter such as buoyant density.

Animals↗

PubMed1988

Physicochemical characterization of deposits associated with HA ceramics implanted in nonosseous sites.

Pellets of well-characterized microporous hydroxyapatite (HA) ceramic were implanted in hamsters in two nonosseous sites: (1) in the fatty tissue of the gingival crease, far from bony tissue and (2) in intraperitoneal sites. The implants in site 1 were placed directly in contact with tissues, cells, and extracellular fluids while the implants in site 2 were placed in special chambers made of plexiglass cylinders covered in both ends with millipore filters, preventing contact with tissues and cells, but not with extracellular fluids. The hamsters were sacrificed and the implants recovered after 8, 16, 30, 150, and 365 days. The pellets were characterized using x-ray diffraction, infrared absorption, thermogravimetry, scanning and transmission electron microscopy, and calcium and phosphate analyses before and after implantation. Physicochemical analyses of HA ceramic implants before and after implantation demonstrated the formation of new material which was significantly different from the HA ceramic in terms of the following: (a) morphology (size of shape) of crystals; (b) intimate association of the inorganic phase of the new material with an organic phase similar to inorganic/organic association in bone; (c) the inorganic phase of the new material is a CO3-apatite, similar to that of bone, while the HA in ceramic is CO3-free; (d) electron diffraction of apatite of new material is similar to that of bone apatite. This study also demonstrated that the new material associated with the HA ceramics implanted in two different nonosseous sites were identical in spite of the differences in their microenvironment (cellular and acellular).

Animals↗

PubMed1979

Solute compatibility with enzyme function and structure: rationales for the selection of osmotic agents and end-products of anaerobic metabolism in marine invertebrates.

The major nitrogenous osmolytes present in the cells of marine invertebrates, notably the free amino acids glycine, alanine and proline, and trimethylamine oxide and betaine, are highly compatible with proper enzyme function and structure. These nitrogenous osmolytes display either non-perturbing or, in some cases, favorable effects on enzyme-substrate and enzyme-cofactor complex formation, catalytic velocity and protein structural stability. In contrast, inorganic salts (KCl and NaCl) and certain of the free amino acids which play only a minor osmotic role, e.g., arginine and lysine, have strongly perturbing effects on one or more of these enzymic parameters. The compatible nitrogenous solutes therefore are suitable for use at high (several tenths molar) concentrations and at widely varying concentrations in osmo-conforming species. Certain nitrogenous solutes, especially trimethylamine oxide, betaine and glutamate, offset some of the perturbing effects of inorganic ions on enzyme function. The selective accumulation of osmolytes thus involves not only the concentration of non-perturbing solutes, but also a balanced accumulation of solutes with opposing effects on enzymes. The selection of end-products of anaerobic metabolism also appears to be based, in part, on considerations of solute compatibility with enzyme function. Octopine is a non-perturbing solute, whereas arginine, which is condensed with pyruvate to form octopine, is very strongly perturbing. Succinate has marked stabilizing effects on protein structure. We conclude that the composition of the intracellular fluids of marine invertebrates reflects selection for osmolytes and end-products whose net effects create a cellular microenvironment which is conducive to optimal enzyme function and structure. The accumulation of compatible solutes may preclude the necessity for widespread changes in protein structure in adapting to concentrated or highly variable osmotic environments.

Amino Acids↗

PubMed1988

Haemopoietic regulation and the role of the macrophage in erythropoietic gene expression.

The macrophage is considered as an "active" component of the haemopoietic cellular microenvironment with respect to erythropoietin (epo) production during embryonic, foetal and adult erythropoiesis. Emphasis is placed on steady-state rather than pathophysiological conditions. In addition, the signals capable of affecting the functional capacity of the macrophage with regard to colony stimulating factor and epo production are also taken into account. Evidence is given demonstrating that a subpopulation of resident macrophages in vitro and in the mouse bone marrow, under normal conditions, can express the epo gene. These results indicate that erythropoiesis can be regulated by short-range or cell-to-cell interactions within the bone marrow.

Animals↗

PubMed1990

Contrary effect of lactic acid on expression of neuron-specific enolase and glial fibrillary acidic protein in human glioma cells.

We examined the effect of lactic acid on cultured human glioma cell lines expressing glial fibrillary acidic protein (GFAP), vimentin and neuron-specific enolase (NSE). The growth of the cells was inhibited by the lactic acid in a dose-dependent manner. At 56 mM of lactic acid, the surviving cells of the KNS-42-c2 cell line developed slender processes and increasingly formed bizzar giant cells. In an immunofluorescence study of the lactic acid-resistant cells, the GFAP-positive cells prominently decreased in number, while the NSE-positive cells clearly increased. The vimentin was not affected throughout the experiment. After removing lactic acid from the medium, the GFAP-positive cells gradually increased in number. The method of dot immunoassay was useful for quantifying GFAP in cellular extracts. It indicated that the amount of GFAP decreased in the cells cultured with lactate-containing media and increased to the primary values after removing the lactic acid. These results may suggest that the morphological and immunochemical diversities of glioma cells are secondarily affected by cellular microenvironments such as lactic acid.

Cell Line↗

PubMed1987

Multicellular spheroids. A review on cellular aggregates in cancer research.

Cellular aggregates have been used in developmental biology and in experimental cancer research for several decades. Spherical aggregates of malignant cells, i.e. multicellular tumor spheroids, may serve as in vitro models of tumor microregions and of an early, avascular stage of tumor growth. The similarities between the original tumor and the respective spheroids include volume growth kinetics, cellular heterogeneity, e.g. the induction of proliferation gradients and quiescence, as well as differentiation characteristics, such as the development of specific histological structures or the expression of antigens. Research using cell aggregates has been focussed on mechanisms involved in the control of proliferation, invasion and metastasis. Immunological studies with spheroids have resulted in the characterization of defense cells which are responsible for specific host-versus-tumor reactions. The vast majority of investigations on spheroids concerns the simulation of therapy with regard to various treatment modalities, combination treatments and systematic analyses of using various endpoints in predictive assays. Only a few pathophysiological studies on the interrelationship among tumor-specific micromilieu, cellular metabolism, proliferative status, and cellular viability have been undertaken with the spheroid model up to now. Since these studies are indicative of a large influence of the cellular microenvironment on basic biological properties of cancer cells, investigations of these epigenetic mechanisms should be intensified in future research on cell aggregates. Similarly, the molecular basis of the biological peculiarities found in malignant cells grown as three-dimensional aggregates has to be investigated more intensively.

Animals↗

PubMed1990

Studies on human CFU-Mix microvolume culture by use of limiting dilution assay.

By use of limiting dilution assay we investigated the bipotent and pluripotent hemopoietic progenitor cells (CFU-Mix) from 21 normal adults, cultured for 32 times. The CFU-Mix counts were 35.7 colonies/10(6) bone marrow cells. According to different cellular elements they could be divided into 5 groups, namely GEMM, GE, GL, GMeg and GM phi. It was suggested that differentiation of the stem cell is of stochastic process, influenced by different hemopoietic growth factors and cellular microenvironment. Our model seems to be suitable for studying differentiation of the stem cells. The rates of 3H-TdR and 55 + 59Fe incorporation were determined, and the 2nd day of culture was found to be the delayed stage of cell growth.

Adolescent↗

PubMed1987

Functional analysis of an electromechanical spinal cord injury device.

Feedback control in our injury device allowed the impactor to be sensitive to the biomechanical characteristics of the spinal cord and produce mechanically predictable injuries. We tested the hypotheses that (i) extracellular calcium [( Ca2+]e) in the rat spinal cord recovers with a time course dependent on the magnitude of injury intensity, (ii) [Ca2+]e is initially depressed at the injury epicenter to the same degree independent of injury severity, and (iii) acute (less than 3.0 h) recovery of [Ca2+]e to normal values occurs in that group of animals that shows only transient neurologic deficits in the postinjury period. Three levels of injury (light, intermediate, and heavy) were produced by controlling spinal displacement during the injury process. After injury, [Ca2+]e at the injury site decreased to values less than 0.1 mM and then recovered during the next 3 h. Incomplete recoveries occurred in the intermediate- and heavy-injury groups (0.72 +/- 0.01 and 0.58 +/- 0.01 mM, respectively). [Ca2+]e activity in the lightly injured group recovered to normal values by 3 h. Specific injury protocols therefore resulted in reproducible responses in the cellular microenvironment. Behavioral recovery could be predicted from mechanical impact parameters. Animals in the light-injury group had transient neurologic deficits in some behavioral tests (open-field walking) with no alteration in others (inclined-plane analysis). Neurologic tests that required coordination between fore and hind limbs (grid walking) did not reveal significant deficiencies until 14 days postinjury. Those animals in the intermediate and heavy groups showed initial and continuing neurological effects in all behavioral measures. It is therefore probable that acute mechanical descriptors and hypocalcia transients are predictive of the ongoing and subsequent pathology of spinal cord injury.

Animals↗

PubMed1988

Lactate-induced inhibition of tumor cell proliferation.

Culture medium that was recovered from tumor cell or fibroblast cultures during the plateau phase, and that was replenished by addition of glucose, glutamine, and serum and readjustment of pH had a distinct growth-inhibiting effect on monolayer cell cultures. The effect, which was not specific for a given cell strain, may be partially responsible for the "density inhibition" commonly observed in malignant cells grown in monolayer cultures. By modifying fresh growth media, it was shown that the growth inhibition observed can be partly attributed to the accumulation of lactate in the culture medium of plateau phase cells. This substance reduced the plating efficiency and the number of cells per petri dish in the plateau phase. It is concluded that this effect may be used for inducing growth inhibition in tumors in vivo by manipulating the cellular production of lactate and/or by impeding its removal from the cellular microenvironment.

Amino Acids↗

PubMed1991

Effects of oxygenation and pH on tumor cell response to alkylating chemotherapy.

In the present investigations we evaluated the consequence of changing the cellular microenvironment on the treatment efficacy of the alkylating chemotherapeutic agent melphalan. Human A549 adenocarcinoma and mouse KHT/iv sarcoma cells were treated with melphalan under aerobic or hypoxic conditions at pH 6.6 or 7.4. Both low oxygenation and acidic pH individually were found to increase tumor cell killing by this chemotherapeutic agent. However, the magnitude of the enhanced toxic effect was greatest when hypoxic conditions and acidic pH were combined during treatment. For example, A549 cells treated with melphalan under hypoxic conditions at pH 6.6 were approximately 3 times more sensitive to this anticancer drug than were cells exposed in air at pH 7.4. Conditions of low oxygen and pH also increased the chemosensitization potential of the nitroimidazole misonidazole (MISO) when combined with this chemotherapeutic agent. Thus, when KHT/iv cells were treated with the combination of melphalan plus MISO, the resulting enhancement ratio increased from 1.8 to 2.5, when the pH maintained during the treatment was changed from physiologic (7.4) to acidic (6.6).

Adenocarcinoma↗

PubMed1986

Primary active sodium transport, oxygen consumption, and ATP: coupling and regulation.

Several metabolic aspects of primary active transport have been explored in this communication. One emphasized theme entailed the need to investigate the properties of the mitochondria and the active transport systems within the intact cell. Several methodological and conceptual approaches were described that permitted such an analysis. The answers provided were sometimes qualitative or quantitative. Qualitative information was provided regarding the cytosolic signal linking active transport with respiration, suggesting that the cytosolic ADP concentration was an important element in that link. The intact renal cell was found to work normally at 50 to 60% of its maximal respiratory capacity, indicating that sufficient reserve capacity was present for increased metabolic demands. Several examples were described in which a combination of qO2 measurements and/or optical techniques were used to differentiate between effects of agents which act primarily on transport or metabolic events. Finally, the control of transport by metabolism was discussed, primarily emphasizing the role of ATP and Pi. One of the overall conclusions from these studies is that, in general, the mitochondria and the transport systems seem to display similar properties in the intact cell as they do in isolated form. However, uncertainties concerning the cellular microenvironment surrounding the mitochondria and the plasma membrane transporters have produced some interesting surprises concerning their function in the intact cell. More quantitative information on the energy compartmentation of the renal cell would be helpful to clarify numerous aspects of metabolic function.

Adenosine Diphosphate↗

PubMed1990

Anticopper treatment inhibits pseudopodial protrusion and the invasive spread of 9L gliosarcoma cells in the rat brain.

The copper ion, a cofactor of angiogenesis, is sequestered in human brain tumors and the adjacent brain. The invasive spread of neoplastic cells has been linked to angiogenesis and involves similar mechanisms of migration and tumor-matrix interaction. In this report, copper depletion inhibited the infiltrative spread of the normally invasive 9L gliosarcoma. Twenty made Fischer 344 rats were each injected with 1 X 10(5) 9L cells; 10 rats were treated with a low-copper diet and penicillamine. In the normocupremic control rats, a "diffuse" invasive pattern was observed in all 10 animals. In the hypocupremic group, a "nodular" pattern, with a discrete border between tumor and brain, was found in 7 of 10 rats (P less than 0.01). In a second experiment, the brains of 16 tumor-bearing rats were studied by electron microscopy. In the 8 normocupremic control rats, cytoplasmic extensions and pseudopodial protrusions, cytological markers of invasive cells, were prominent at the tumor-brain interface. In striking contrast, pseudopodia were absent along the border of the tumors in the 8 hypocupremic rats. These findings suggest a biological role of copper in the neoplastic spread of brain tumor cells. Pharmacological and metabolic alteration of the cellular microenvironment to inhibit invasiveness represents a novel therapeutic approach, especially for tumors of the brain in which malignancy is a function of regional invasiveness.

Animals↗

PubMed2025

Stereo-cell: Spatial enhanced-resolution single-cell sequencing with high-density DNA nanoball-patterned arrays.

Single-cell sequencing technologies have advanced our understanding of cellular heterogeneity and biological complexity. However, existing methods face limitations in throughput, capture uniformity, cell size flexibility, and technical extensibility. We present Stereo-cell, a spatial enhanced-resolution single-cell sequencing platform based on high-density DNA nanoball (DNB)-patterned arrays, which enables scalable and unbiased cell capture at a wide input range and supports high-fidelity transcriptome profiling. Stereo-cell further allows integration with imaging-based modalities and multiomics strategies, including immunofluorescence and epitope profiling. This platform is also compatible with profiling extracellular vesicles, microstructures, and large cells, whereas its spatial resolution facilitates in situ analysis of cell-cell interactions, cellular microenvironments, and subcellular transcript localization. Together, Stereo-cell provides a flexible framework for expanding single-cell research applications.

Animals↗

PubMed1987

Human thymocyte subpopulations: maturational stages defined by the expression of the T3-T cell receptor complex.

Using sensitive fluorescence flow-cytometric techniques, human thymocyte subpopulations were fractionated according to their surface expression of the T3-T cell receptor (T3-Ti) complex. Two major subpopulations, one expressing low (immature subpopulation) and one high T3 antigen surface density (mature fraction) were characterized in detail with respect to surface antigen expression, right-angle scatter and proliferative capacity. Thymocyte subpopulations were activated through the T11 molecule (alternate pathway) and compared with regard to interleukin-2 (IL-2) receptor expression, changes in right-angle scatter and 3H-thymidine incorporation. We report that both populations could be activated through the T11 pathway to undergo nuclear activation and express IL-2 receptors. Moreover, in the absence of accessory cells, only the most mature population, expressing high T3 density, could be induced to proliferate, whereas immature cortical thymocytes required accessory cells for proliferation. These findings suggest that the cellular microenvironment may have a critical role in regulating the activation of immature cortical thymocytes.

Antigen-Presenting Cells↗

PubMed1990

Alveolar type II cell responses to chronic inhalation of chrysotile asbestos in rats.

The effects of chronic exposure to chrysotile asbestos on alveolar type II cells were examined in the lungs of Fischer 344 rats. Morphometric and three-dimensional analyses were used to characterize the alveolar type II cell and to determine the relationship of asbestos fiber localization to ultrastructural change in these cells. During the 2-yr period of study, type II cell number and volume increased to values more than 4 times those seen in controls. Ultrastructurally, cisternal dilations of the rough endoplasmic reticulum (RER) composed 12% of the total cell volume after 12 mo of exposure to asbestos and was still 15% of the total cell volume 1 yr after fiber exposure had ended compared to less than 1% in control cells. Asbestos fiber density surrounding these cells was directly proportional to the degree of cisternal dilatation in the cell; however, lamellar body volume and number in these cells were not different from that found in control type II cells. The incidence of a subset of type II cells with large lamellated inclusions was 10-fold greater in regions near bronchiolar-alveolar duct junctions, compared to more distal gas exchange regions of the lungs. Normal-sized lamellar bodies were fused to these large lamellated inclusions. These cells also contained significantly greater numbers of lamellar bodies and multivesicular bodies than those type II cells in more distal lung regions. These ultrastructural changes observed in type II cells may be a simple dose response to inhaled asbestos or the manifestation of two distinct populations of cells in the lungs that respond to asbestos in different ways. Asbestos fiber dose, cellular microenvironment, and aberrations of the cell plasma membrane and/or cell cytoskeleton (i.e., microtubules and filaments) are discussed as potential factors in the changes noted in type II cells.

Administration, Inhalation↗