In vitro approaches to identify tumour-promoting agents: cell transformation and intercellular communication.
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Molecular mechanisms of intercellular communication in the hormonal and neural systems.
This paper reviews our studies that have addressed the molecular mechanisms underlying the biosynthesis and reception of extracellular signaling molecules and integrative mechanisms of extracellular-intracellular signaling transmission in biological systems. We introduced recombinant DNA technology into the neuroendocrine system and established the concept that a single peptide precursor encompasses multiple biologically active peptides and brings about coordinate functions in various biological systems. We then developed a novel functional cloning of membrane receptors and ion channels by combining an oocyte expression system with electrophysiology. We molecularly elucidated not only various peptide receptors, including the first demonstration of the molecular entity of a G protein-coupled peptide receptor (GPCR), substance K receptor, and also diverse members of both G protein-coupled metabotropic type and NMDA type of neurotransmitter glutamate receptors. We demonstrated many novel synaptic mechanisms involving distinct types of glutamate receptors in brain function and dysfunction. These include the mechanisms underlying segregation of light-dark signals in visual transmission, discrimination and memory formation in olfactory transmission, and motor co-ordination in the cerebellum, basal ganglia and the retinal network.
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Enhancement of altered hepatic foci in rat liver and inhibition of intercellular communication in vitro by the pyrethroid insecticides fenvalerate, flucythrinate and cypermethrin.
Male Sprague-Dawley rats dosed with N-nitrosodiethylamine (NDEA) 24 h after two-thirds partial hepatectomy were treated with the pyrethroid insecticides fenvalerate, flucythrinate or cypermethrin in the diet for 20 weeks. Altered hepatic foci were analyzed by quantitative stereology from paraffin-embedded sections stained for gamma-glutamyltranspeptidase (GGT) or glutathione S-transferase P (GST-P). The present results demonstrate that the pyrethroids tested all enhance the development of NDEA-initiated, GGT-positive foci in rat liver at non-hepatotoxic doses. On the contrary, the volume fractions of GST-P-positive foci were not elevated as compared to the control group. The three pyrethroids tested all inhibited the transfer of Lucifer Yellow CH between WB-F344 rat liver epithelial cells in culture, supporting the increase of GGT-positive foci and suggesting that these substances can act as tumour promoters. The discrepancy between the results from analyses using GGT or GST-P as markers emphasizes the importance of understanding the mechanism underlying the expression of different markers for preneoplastic lesions and the importance of such effects in tumour promotion.
Animals↗
Possible anti-tumour-promoting activity of components in Japanese soybean fermented food, Natto: effect on gap junctional intercellular communication.
In order to detect any protective agent against tumor formation, we examined the anti-tumor-promoting effect of a Japanese traditional soybean fermented food, Natto. Dye transfer was employed as an assay method. When fluorescent dye was microinjected into cultured BALB/3T3 cells, the dye was transformed into the neighboring cells through the gap junction. This dye transfer was blocked by the treatment with the tumor promoters 12-O-tetra-decanoylphorbol-13-acetate (TPA), a high concentration of NaCl and lithocholic acid (LCA). This reduction of the dye transfer by TPA treatment was not observed when the cells were pretreated with retinoic acid, an anti-tumor promoter. Thus, the recovery of the dye transfer in TPA-treated BALB/3T3 cells was proven to ge a good indicator for detecting some possible anti-tumor promoters. After extraction and fractionation of Natto, we obtained an active fraction (H1) which showed recovery of the dye transfer in TPA-treated cells. The fraction contained straight-chain saturated hydrocarbons. A comparison of the fraction and the authentic samples by GC analysis suggests that the H1 fraction contained straight-chain saturated hydrocarbons from around C30 to C32. Among these hydrocarbons, hentriacontane (C31) was found at the highest concentrations, and was shown to have the highest activity. Hentriacontane at a very low concentration of 0.65 ng/ml was shown to recover the dye transfer inhibited by the treatment with TPA as well as with NaCl and LCA.
3T3 Cells↗
Tumor promoter inhibition of intercellular communication between cultured mammalian cells.
Cocultures were established of a cell line deficient in hypoxanthine-guanine phosphoribosyltransferase (PG-19; HPRT-) and a mouse epidermal cell line (HEL-37; HPRT+). The cocultures were incubated in a medium containing hypoxanthine, aminopterin and thymidine (HAT). HPRT- cells die in HAT medium unless rescued by metabolic cooperation with HPRT+ cells. The extent of cell death was measured by the release of radioactivity from PG-19 cells previously labelled with [3H]thymidine, and expressed as the lytic index. The lytic index was significantly increased (decreased metabolic cooperation) by tumor-promoting phorbol esters but not by non-promoting esters. The enhanced lytic index was obtained when promoters were incubated with cocultures for 10 h in a total incubation time of 48 h.
Animals↗
Inhibition of intercellular communication by nickel(II): antagonistic effect of magnesium.
The level of gap-junctional (cell-cell) communication was studied by the radioisotope transfer technique in NIH 3T3 cells exposed to NiSO4, MgSO4, or both salts combined. Monolayered NIH 3T3 donor cells were labeled with [3H]-uridine for 3 h and then co-cultured with non-labeled recipient NIH 3T3 cells for 3 h in the presence of 0.5-20 mM NiSO4, 1.0-100 mM MgSO4, or 5 mM NiSO4 plus 1.0-100 mM MgSO4. 12-O-tetradecanoylphorbol-13-acetate (TPA), 16-160 pM, served as a positive control. The exposed cells were fixed with 2.5% glutaraldehyde and processed for autoradiography. The cell-cell communication rate was based on the number of radioactive recipient cells in relation to the total number of recipient cells for 100 donor cells. NiSO4 disrupted cell-cell communication in a dose-related manner from 98% of the base value at 0.5 mM NiSO4 to 2% at 5 mM NiSO4. Cell viability was not affected by 0.5-5 mM NiSO4. The inhibitory action of 5 mM NiSO4 could be partially prevented by 5.0-100 mM MgSO4. However, MgSO4 did not prevent the inhibition by TPA. The results indicate that NiSO4 is capable of inhibiting cell-cell communication at concentrations that do not cause cytotoxic effects in NIH 3T3 cells during a 3-h period. In this respect NiSO4 resembles such classical tumor promoters like TPA. The antagonism by magnesium of the nickel-induced inhibition of cell-cell communication may indicate a contributory mechanism by which magnesium counteracts the carcinogenicity of nickel in vivo.
Cell Communication↗
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) does not inhibit intercellular communication in Chinese hamster V79 cells.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental pollutant which has been shown to be both a potent teratogen and carcinogen and also to have tumor-promoting activity. We have compared TCDD with the proto-type phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) using the metabolic cooperation assay as a measure of tumor promotional competence. Unlike TPA, TCDD was found to be ineffective in inhibiting metabolic cooperation at concentrations which elicit many of TCDD's biological responses. These results suggest that TPA and TCDD elicit tumor promotion by different pathways. We discuss these results in the context of cell-type-specific and TCDD receptor-mediated biological responses to tumor promoters.
Animals↗
Metsovo-tremolite asbestos fibres: in vitro effects on mutation, chromosome aberration, cell transformation and intercellular communication.
Samples of Metsovo-tremolite asbestos, previously found to be the causative agent of endemic pleural calcification and an increased level of malignant pleural mesothelioma in a rural area of north-western Greece (Metsovo area), were tested in various in vitro toxicity test systems. It was found that asbestos fibres of this type were strong inducers of micronuclei and numerical chromosomal abnormalities while they induced low levels of chromosomal aberrations in mammalian cells in culture. Furthermore, this type of asbestos can induce a low level of in vitro transformation of Syrian hamster embryo cells. The fibres had no effect on gap-junctional cell-cell communication (followed by the dye-transfer method) and did not induce any mutations in the Salmonella typhimurium strain TA102 which is known to be sensitive to the action of various oxidative agents. These results support the hypothesis generated from studies on other types of asbestos that such fibres induce tumours by causing chromosomal mutations.
Aneuploidy↗
Effects of general anesthetics on intercellular communications mediated by gap junctions between astrocytes in primary culture.
BACKGROUND: Astrocytes represent a major nonneuronal cell population in the central nervous system (CNS) and are actively involved in several brain functions. These cells are coupled by gap junctions (GJ) into a syncytial-like network resulting in cellular communication through ionic and metabolic exchange between adjacent astrocytes. Whether anesthetics affect astrocyte function is not known. In the present study, the effects of general anesthetics on GJ permeability were investigated in primary cultures of mouse striatal astrocytes. METHODS: Junctional permeability was determined by using the fluorescent probe Lucifer yellow and the scrape loading/dye transfer technique. Confluent cells were preincubated 5 min with various concentrations of anesthetic agents and GJ permeability was estimated by measuring the area occupied by the dye from digitalized images taken 8 min after cell loading. RESULTS: Of the intravenous anesthetics tested, only propofol (P: 10(-4) M, P < 0.01 and 10(-5) M, P < 0.05) and etomidate (ET: 10(-4) M, P < 0.05, but not 10(-5) M) induced a significant reduction of GJ permeability. In contrast, diazepam (10(-5) M), morphine (10(-4) M), ketamine (10(-4) M), thiopental (10(-4) M), and clonidine (10(-7) M) did not affect junctional permeability. In addition, the halogenated anesthetics halothane, enflurane, and isoflurane induced a dose-dependent closure of GJ. For halothane, enflurane, and isoflurane, the maximum effect was achieved with a 10(-4) M, 1.6 x 10(-3) M, and 10(-3) M anesthetic concentration, respectively. Removal of volatile anesthetics resulted in the restoration of the control fluorescence area between 15 and 45 min. The time course of recovery of GJ permeability was examined more precisely for shorter periods of halothane administration (5 min, 1 mM). Under these conditions, the rate of dye spread returned to control values following anesthetic washout, while, during the same period of time, complete uncoupling of GJ was still observed in the presence of a 1 mM halothane concentration. CONCLUSIONS: These results indicate that general anesthetics differentially affect GJ permeability in cultured astrocytes. This uncoupling effect (closure of gap junctions) may contribute to the mechanisms of action of some anesthetic agents (primarily volatile anesthetics) at the level of the CNS by altering astrocyte communication.
Anesthetics↗
Hepatic intercellular communication in shock and inflammation.
The liver is well recognized as a target for injury during low flow or inflammatory states. Functionally, the result is both metabolic and host defense dysfunction. Although the liver is clearly responsive to changes in systemic levels of various mediators, it is becoming apparent that substantial changes occur within the liver that are not directly dependent on extrahepatic factors. This is the result of complex interactions among the various cell types that exist in a highly organized arrangement within the functional subunit of the liver. The purpose of this review is to summarize the structural relationships which form the basis for this system of cell-cell communication and their functional implications both in the normal liver and during both low-flow and normal-flow inflammatory states.
Animals↗
Different consequences of beta1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation, and intercellular communication.
There are conflicting reports of the consequences of deleting beta1 integrins from the epidermis of transgenic mice. Epidermal thinning with normal differentiation and lack of inflammation has been observed; conversely, epidermal thickening, abnormal differentiation, and dermal fibrosis can occur. beta1 integrin deletion results in decreased epidermal proliferation, yet on wounding the proliferative defect is overcome. To distinguish primary from secondary consequences of beta1 integrin loss, we compared epidermal beta1 deletion at E14.5 via K5Cre and 4-hydroxy-tamoxifen induced deletion in adulthood via K14CreER. As reported previously, there was dermo-epidermal splitting, inflammation, reduced proliferation, and hair follicle and sebaceous gland loss in 30-d-old K5Cre beta1-null mice. These changes were not observed 30 d after beta1 integrin deletion in adult epidermis, however, and there were no changes in the hair follicle stem cell compartment. Deletion in adult epidermis revealed a previously unreported correlation between the level of beta1 integrins and proliferation in the interfollicular epidermis that was remarkably consistent with human epidermis. In addition, the number of melanocytes in interfollicular epidermis was greatly increased. Our results highlight the context-dependent effects of beta1 integrin deletion and suggest that inflammation may be responsible for some of the K5Cre beta1-null phenotype.
Animals↗
Enhanced tumorigenicity of rat bladder squamous cell carcinoma cells after abrogation of gap junctional intercellular communication.
We previously demonstrated a clear tendency for actively communicating rat bladder carcinoma cell lines with elevated expression of connexin 43 mRNA to possess strong tumorigenicity. In the present study, immunohistochemical analysis established that normal bladder epithelium did not express connexin 43 protein, but bladder carcinomas often expressed the protein, particularly on the membranes of cells within areas of squamous cell differentiation. To investigate the role of connexin 43 overexpression in rat bladder carcinoma cells, an anti-sense connexin 43 expression vector was transfected into BC31 cells having a high communication capacity. In the resultant transfectants, there was little or no communication capacity and connexin 43 expression. The growth rate in vitro was not changed compared to that of cells treated with the vector alone (without the anti-sense sequence), but tumorigenicity in nude mice was dramatically enhanced. The results indicate that connexin 43 overexpression in rat bladder carcinogenesis is related to squamous cell differentiation, and the protein can have tumor suppressor characteristics, as in other organs.
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The role of tumor promoters on phenotypic alterations affecting intercellular communication and tumorigenesis.
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Animals↗
The evolutionary origins of intercellular communication and the Maginot Lines of the mind.
By extending the evolutionary age of the vertebrate hormones from the vertebrates to include the metazoans, we expand their phyletic distribution about 30-fold. By tracing these molecules into the unicellular range including both eukaryotes and prokaryotes, the distribution of these molecules becomes very wide indeed. While "universal" or "ubiquitous" is probably not yet warranted, their recognition as "cosmic" molecules rather than "parochial" molecules does seem appropriate. Interestingly, the breakdown of the barriers for the hormonal molecules between the vertebrates and the rest of the metazoans, between the metazoans and the unicellular organisms, between the eukaryotes and prokaryotes, or the eubacteria and archebacteria is concordant with findings in multiple other systems. For example, hemoglobin or myoglobin is present in higher plants, Protozoa, and insects. The photosynthetic proteins of higher plants have their homologues in the photosynthetic bacteria, and the heat shock proteins of eukaryotes have their equivalents in the prokaryotes as well.
Animals↗
Regulation of intercellular communication and growth by the cellular src gene.
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Vasoactive intestinal peptide as a mediator of intercellular communication in the cerebral cortex. Release, receptors, actions, and interactions with norepinephrine.
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Animals↗
Biochemistry of breast cyst fluid. An approach to understanding intercellular communication in the terminal duct lobular units.
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Breast↗
Influence of the sodium pump on intercellular communication in heart fibres: effect of intracellular injection of sodium ion on electrical coupling.
1. The effect of intracellular sodium injection on the electrical coupling between cardiac Purkinje cells was investigated. 2. It was found that an increase in the intracellular sodium concentration produces uncoupling in about 500 sec and increases the input resistance of the injected cell. Both effects were completely reversible. 3. Inhibition of the sodium pump by ouabain (6-8 x 10(7) M) also causes electrical uncoupling. 4. The decoupling of heart cells achieved by sodium injection was considerably accelerated in fibres treated with ouabain. 5. The influence of sodium injection on cell communication seems to be related to the intracellular calcium concentration 6. The above results indicate that the maintenance of a low intracellular sodium concentration by the sodium pump is essential for the preservation of a high junctional conductance in cardiac fibres.
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