Qualitative differences in testosterone metabolism as an indication of cellular heterogeneity in fibroblast monolayers derived from human preputial skin.
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Adult↗
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Cellular heterogeneity of granular cell tumours: a clue to their nature?
Most granular cell tumours (GCTs) are benign proliferations of purported Schwannian derivation, showing immunoreactivity for Schwann cell-related antigens. Due to incomplete agreement on the precise nature of GCTs (reactive vs neoplastic), we performed an immunohistochemical study with the alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique on 30 GCTs. The aim was to evaluate their growth patterns and the possible relationships of granular cells with other nerve sheath-related cell types (i.e., Schwann and perineurial cells, and dendritic cells displaying CD34/vimentin immunoreactivity). An expansive growth pattern was detected in five cases, a pseudoinfiltrative growth pattern in nine cases and a mixture of the above in the remaining 16 cases. Besides immunoreactivity for S-100 protein, neuron-specific enolase, vimentin, CD57, CD68, MAC 387, alpha-1-antitrypsin and alpha-1-antichymotrypsin in granular cells, we documented intimate architectural relationships between granular cells, Schwann and perineurial cells, and a third type of CD34/vimentin-positive nerve sheath-related cell in most GCTs. These results suggest that GCTs are heterogeneous lesions. Some of them show a pseudoinfiltrative growth pattern and retain close relationships with the normal components of the nerve sheath. In other lesions, granular cells grow in an expansive fashion and constitute the predominant cell component of the tumour. These architectural and immunophenotypic differences may reflect a different nature of GCTs: they may initially represent reactive or hamartomatous lesions that subsequently acquire truly neoplastic potential.
Adult↗
Cellular heterogeneity in a tissue culture cell line derived from a human bladder carcinoma.
To study heterogeneity in a cell line derived from a human bladder carcinoma (EJ), 7 clones were isolated at low passage and examined for differences in culture behaviour, ability to grow in agar and tumorigenicity in nude mice. The parent EJ line had several distinct chromosome populations (both diploid and tetraploid), grew in agar and produced tumours in nude mice. Three of the clones had pseudodiploid modes and 4 had either hypo- or hypertetraploid modes. The 7 clones had 5 marker chromosomes in common but the combination of other marker chromosomes made each clone unique. No significant difference was found between the clones in the in vitro growth rate although analysis of in vitro culture behaviour showed heterogeneity in the pattern of cell movement on plastic substratum. Three clones were composed of static cells, one clone had very mobile cells; the other clones had rates of movement intermediate between the two. Differences were also found in the packing density of the cloned cells and in the cell size. All 7 clones grew in agar but heterogeneity was seen between the clones as shown by widely varying colony-forming efficiencies (0.5-13%). One clone had a high colony-forming ability in agar but failed to produce tumours in nude mice. The other clones were tumorigenic regardless of colony-forming efficiency in agar. Specific chromosome abnormalities were found to be associated with growth in agar and tumorigenicity but not with the growth pattern or the rate of movement of the cloned cells in culture.
Animals↗
Cellular heterogeneity in tumours.
Malignant tumours contain normal cells, descendants of transformed cells, and conceivably also initiated cells which have taken some but not all of the steps toward malignancy, and hybrid cells. Tumours are propagated by multiplication of clonogenic cells, which are a subclass of the descendants of transformed cells. The clonogenic cells of a tumour may differ in respect of morphology, karyotype, metastatic capacity, sensitivity to cytotoxic drugs, expression of cell surface antigens and hormone receptors, immunogenicity, sensitivity to the immune reaction of the host, and other properties. Evidence (disputed by some) suggests that selection of particular subpopulations plays a role in tumour metastasis and recurrence. Heterogeneity may be due to pleoclonal origin, generation of phenotypic diversity within a clone, or spontaneous hybridization and chromosome loss. The possibility of interaction between different subpopulations must be taken into account in discussing tumour cell population kinetics. Heterogeneity also has important therapeutic implications and may help to explain the failure of some therapeutic regimes and the success of others.
Animals↗
Fifth Gordon Hamilton-Fairley memorial lecture. Methotrexate resistance and gene amplification: an experimental model for the generation of cellular heterogeneity.
Gene amplification is a mechanism whereby cultured animal cells and human tumours become resistant to cancer chemotherapeutic agents. This review of studies from the authors' laboratory describes properties of the acquisition of resistance to methotrexate in cultured mammalian cells by virtue of amplification of the dihydrofolate reductase gene. These properties result in a heterogeneous cell population with respect to many cell properties, including the number and stability of the amplified genes. Gene amplification results from overreplication of DNA in a single cell cycle as a result of inhibition of DNA synthesis. The cells surviving such overreplication constitute a heterogeneous population with multiple chromosomal changes, including partial or complete endoreduplication of chromosomes, as well as a variety of chromosomal rearrangements. A similar phenomenon may underlie the generation of aneuploidy in tumours, their malignant progression, and the generation of heterogeneity in the tumour cell population.
Animals↗
Early origin and pervasiveness of cellular heterogeneity in some malignant transformations.
Nontransformed BALB/3T3 cells were passaged weekly in monolayer culture on plastic dishes and aliquots were regularly assayed for colony production when suspended in agar. During several months of passaging, a single large colony arose once in the agar assay, and its constituent cells were isolated to form a subline of transformed cells. These cells had the fusiform and rounded morphologies characteristic of transformed cells and had a colony-forming efficiency in agar (CFEag) of approximately 10%. Five of the agar colonies were isolated at random and the cell populations of these primary subclones were further analyzed. Four of the five subclonal populations differed from each other in appearance slightly, but consistently, while the fifth had a markedly different colonial morphology. They also differed from one another in CFEag as well as in average diameter of the agar colonies. These general differences among the five subclones remained, although the CFEag and colony sizes changed recognizably in repeated weekly transfers. All of the subclones produced sarcomas in nude mice but did so at different rates. A secondary generation of five subclones was derived from each of three of the original subclonal populations. All the secondary subclones had the same morphology as the primary subclones from which they were derived. The averages of the CFEag and colony sizes of the secondary subclones from each of the subclones differed as a group from the other groups, but they also differed, to a lesser extent, among themselves. Despite the differences noted among the primary subclones in morphology, growth in agar, and tumor production in mice, they were virtually identical in their rapid growth rate on a plastic surface and all shared a high rate of glucose consumption. A second transformed clone arose among the continuously passaged nontransformed cells 5 months after the first one had appeared. Subclones of this clone did not differ recognizably from one another in morphology or in CFEag. The results indicate that recognizable heterogeneity can arise in some tumors during the earliest stages of their development and involve a high proportion of their constituent cells, while it may not become evident in other tumors until much later.
Animals↗
Vaccinia virus late transcription is activated in vitro by cellular heterogeneous nuclear ribonucleoproteins.
Vaccinia virus gene expression is temporally regulated, and three gene classes have been identified: early, intermediate, and late. Several virus-encoded proteins and an activity designated VLTF-X are required for maximum transcription in vitro of a template containing a late promoter. VLTF-X is present in both cytoplasmic and nuclear extracts prepared from uninfected mammalian cells and co-purifies with a late promoter DNA-binding activity. Here, extensive purification of VLTF-X has revealed that heterogeneous nuclear ribonucleoproteins A2/B1 and RBM3 co-purified with in vitro late transcription stimulation. Overexpression and purification of these proteins from Escherichia coli demonstrated that they both complemented for VLTF-X activity in in vitro transcription reactions. These studies identify two host cell factors potentially contributing to poxvirus replication in vivo.
Amino Acid Sequence↗
Altered cellular heterogeneity as a possible mechanism for the maintenance of organ function in senescent animals.
We tested the hypothesis that an alteration in the functional heterogeneity of cell populations (i.e., changes occurring in sensitivity and responsiveness to external stimuli among individual cells) may be a mechanism by which some organs are able to resist age-related decrements in function. To this end, changes in cytoplasmic free calcium concentration ([Ca2+]i) following glucose stimulation of individual pancreatic beta cells isolated from male F344 rats of ages 6, 12, and 26 mo were used as a model for evaluating responsiveness and sensitivity. Changes in [Ca2+]i of individual beta cells were monitored using fura-2 microspectrofluorimetry. No differences were observed in [Ca2+]i or in insulin secretion per beta cell among the age groups at any of the glucose concentrations. However, the percentage of beta cells that were responsive to a stimulatory glucose concentration (> 5.5 mM) was significantly greater in islets from the 26-mo-old rats (76%) as compared to the 6- and 12-mo-old animals (63% and 65%, respectively). Of the responsive beta cells, a significantly greater percentage of those from the 26-mo-old rats (72%) responded at the lowest stimulatory glucose concentration (7.5 mM) as compared to the 6- and 12-mo-old animals (58% and 60%, respectively). These data suggest that the maintenance of organ function in older rats at a level comparable to that of younger animals may be accomplished, in part, by an increase in the percentage of cells that are responsive to stimuli and/or by an increase in the sensitivity of the responsive cells.
Aging↗
The conundrum posed by cellular heterogeneity in analysis of human neuroblastoma.
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Cell Line, Tumor↗
Transcriptional noise and cellular heterogeneity in mammalian macrophages.
Transcriptional noise is known to play a crucial role in heterogeneity in bacteria and yeast. Mammalian macrophages are known to exhibit cell-to-cell variation in their responses to pathogens, but the source of this heterogeneity is not known. We have developed a detailed stochastic model of gene expression that takes into account scaling effects due to cell size and genome complexity. We report the results of applying this model to simulating gene expression variability in mammalian macrophages, demonstrating a possible molecular basis for heterogeneity in macrophage signalling responses. We note that the nature of predicted transcriptional noise in macrophages is different from that in yeast and bacteria. Some molecular interactions in yeast and bacteria are thought to have evolved to minimize the effects of the high-frequency noise observed in these species. Transcriptional noise in macrophages results in slow changes to gene expression levels and would not require the type of spike-filtering circuits observed in yeast and bacteria.
Animals↗
The toxic effect of double-stranded RNA for interferon-treated cells: evidence for a heterogeneous cellular response and the role of the cell nucleus.
When L929 cells were treated with interferon and subsequently with poly(rI).poly(rC), there was a pronounced toxic effect. Most of the cells lysed, but some survived and grew at the same rate as control cells to yield cells which were as sensitive to the effects of interferon and poly(rI).poly(rC) as the original population. The proportion of surviving cells did not vary with either the cell cycle or the cell density. The treated cells produced interferon and some of the interferon was produced by the resistant cells. Cells which had been X-irradiated before treatment with interferon and poly(rI).poly(rC) behaved similarly so cell division was not necessary for the development of toxicity. The toxic effect also developed when cells were enucleated with the aid of cytochalas in B after treatment with interferon, but not if they were enucleated before treatment. It is concluded that the nucleus is essential for interferon to exert its effect on the cells, but not for the development of cytotoxicity after the addition of poly(rI).poly(rC).
Animals↗
Cellular heterogeneity in lung cancer.
Sixty-six lung carcinomas have been examined by light and electron microscopy, as well as by immunocytochemical techniques using a panel of monoclonal antibodies. There was considerable heterogeneity with regard to cell type and in only 18 cases was it possible to classify the tumour as a solely small cell, squamous or adenocarcinoma. In the remaining cases there was evidence of two or three cell types. These findings support the thesis that all lung cancers are derived from a pluripotential basal or reserve cell in the bronchial mucosa which may proliferate along one or more lines of differentiation. This view of the histogenesis of lung cancer would account for the heterogeneous appearance of many tumours and the difficulty experienced in placing them in one of the standard classifications.
Adenocarcinoma↗
Cellular heterogeneity in giant cell tumour of bone (osteoclastoma): an immunohistological study of 16 cases.
Sixteen cases of giant cell tumour of bone (osteoclastoma) were analysed by immunohistochemical techniques using various monoclonal antibodies specific for macrophages, monocytic and granulocytic cells, T- and B-lymphocytes and other cell types. The multinucleate osteoclastic giant cells failed to react with the majority of antibodies specific for myeloid cells and HLA-DR. In contrast to previous findings, giant cells in some tumours reacted with a rat, but not mouse, antibody to leucocyte common (CD45) antigen. Macrophages were detected in all tumours, though their numbers varied considerably; small numbers of T- and B-lymphocytes were identified in four of 16 cases. The neoplastic, spindle-shaped, stromal cells were largely unreactive with the monoclonal antibodies used in this study, further supporting the view that they are not the precursors of the characteristic giant cells, nor are they of haemopoietic origin.
Antibodies, Monoclonal↗
Infantile (juvenile) capillary hemangioma: a tumor of heterogeneous cellular elements.
Infantile (juvenile) capillary hemangiomas are vascular neoplasms which can appear quite infiltrative histologically and are characterized by cords of cells with areas of marked cellularity. While vessels can be distinguished in most cases, there are many cells which do not appear to be endothelial in origin. We labeled 5 such cases with antibodies directed against factor VIII-related antigen, CD34, alpha actin, factor XIIIa and PC-10. Anti-factor VIII-related antigen labeled all endothelial cells and did not label cells away from vessels. Anti-CD34 recognized similar cells and also stained a subset of interstitial cells. Anti-alpha muscle defined pericytes and stained few interstitial cells and none of the endothelial cells. Many of the interstitial spindled and cuboidal cells stained strongly with anti-factor XIIIa. The majority of the mitotic activity was concentrated in the interstitial cells. These observations lend support to the concept that infantile (juvenile) capillary hemangioma is a tumor of primitive cells with capabilities for differentiating toward endothelial cells and pericytes. It is not clear whether a similar stem cell population gives rise to dermal dendrocytes, or whether these represent an immune response to the neoplasm.
Actins↗
In vitro cultivation of rabbit aortic media and the development of the cultures in relation to cellular heterogeneity.
Explants of rabbit aortic media were transferred to tissue culture and the development of the characteristic regions of the cultures was followed. With a new technique the explants were instantly immobilized in the culture flasks, by which the temporal development was strictly defined. The culture developed along the following four major lines: (1) cells migrated from the explant and some cells formed a network of large, attenuated cells, while other, smaller and poorly flattened cells formed clusters attached to the plastic or the network; (2) with continuing growth the network of larger and attenuated cells expanded, grew denser and formed the monolayered component of the culture; (3) multilayered thickenings formed at sites where poorly flattened small cells were numerous either within or at the outer margin of the monolayer or (4) at the margin of the explant where profuse emigration of cells had occurred. Thus, the development of the culture was dependent upon the growth behaviour and expansion of two subpopulation of cells. In the electron microscope the smaller, poorly flattened type of cell with multilayered growth pattern had features of a highly metabolically active cell and had numerous attachment sites of fibronexus type. The attenuated larger cell type growing as monolayers had very abundant microfilaments. The differences may reflect a functional segregation among different cell subpopulations in arterial smooth muscle tissue.
Animals↗
Cellular heterogeneity in malignant neoplasms and the therapy of metastases.
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Animals↗
Cellular heterogeneity in cathepsin D distribution in equine articular cartilage.
The distribution of cathepsin D in normal equine growth cartilage has been examined immunocytochemically using an antiserum raised against human cathepsin D. The cross-reactivity and specificity of the antiserum for equine cathepsin D was confirmed, and its lysosomal localisation was demonstrated in horse skin fibroblasts by confocal scanning microscopy. Cultured horse chondrocytes were heterogenous in their expression of cathepsin D. Heterogeneity of distribution of the enzyme was also seen in chondrocytes in cartilage from different anatomical sites. A high level of cathepsin D was observed in the deep layer of cartilage from the lateral trochlear ridge of the distal femur. Cathepsin D was absent in the hypertrophic zone of the distal radial growth plate.
Animals↗
Calcium signaling in endothelia: cellular heterogeneity and receptor internalization.
The vasoactive factors thrombin, bradykinin (BK), and ATP are released in response to tissue damage and inflammation and act on endothelium to modulate vascular perfusion. We have investigated the second messenger response of endothelium activated by these agonists and, in particular, the mechanism of desensitization to BK. Fura-2 fluorescence ratio imaging of calf pulmonary artery endothelial cells (CPAE) revealed 5- to 10-fold increases on intracellular Ca (Cai) in response to these agents. Maximal doses caused Cai to increase from 52 to 248 nM (thrombin), 556 nM (BK), and 643 nM (ATP). Agonists elicited a rapid (within 30 s) increase of Cai due to release of Ca from intracellular stores followed by a secondary elevation of Cai dependent on entry of external Ca. The temporal characteristics of the Cai responses to all agonists were heterogeneous from cell to cell, and, interestingly, repeated stimulation gave identical signature responses from individual cells, although the amplitude of the Cai response decreased to thrombin and especially bradykinin but not for ATP. This decrease was agonist specific because ATP elicited large increases of Cai after thrombin or BK desensitization. Maximal desensitization was obtained with BK applied for 5-10 min followed by a rest of < 10 min before restimulation. Although desensitization primarily reduced the elevation of Cai due to the release of the internal store, entry of extracellular Ca was also reduced. Cells responded heterogeneously to desensitization in that those with prominent extracellular Ca entry responded most strongly upon a second stimulation with BK. Because desensitized cells still responded to ATP with an increase of Cai, the desensitization was controlled at a step prior to the activation of phospholipase C. Desensitization occurred by a reduction of BK receptor number; a 10-min BK pretreatment reduced [3H]BK binding to receptors by 70% (from 14,600 receptors/cell, Km = 5 nM, to 5,300). As surface receptor numbers decreased, internalized receptors increased as assayed by an acetic acid wash. The time course of the receptor internalization was similar to the decrease in Cai response to BK. We conclude that the vasoactive agonists thrombin, BK, and ATP increase the second messenger Cai in endothelial cells and that a desensitized Cai response occurs with BK, but not with ATP, due to downregulation and endocytosis of the BK receptor.
Adenosine Triphosphate↗