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PubMed1998

Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines.

Tumor cells expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene become sensitive to ganciclovir (GCV), and the phenomenon by which tumor cells surrounding the HSV-tk expressing cells also become sensitive to GCV is known as the "bystander effect." The purpose of this study was to investigate the bystander effect in human lung-cancer cell lines, and the role of gap-junctional intercellular communication as the mechanism responsible for it. Gap-junctional intercellular communication was measured both with a dye-transfer assay involving single-cell microinjection of Lucifer Yellow and with a PKH26/calcein-AM double-dye-transfer assay. Significant bystander tumoricidal effect was observed in lung-cancer cell lines when cultured cells contained only 10% HSV-tk expressing cells. This was also observed to occur with cell lines of different origin or from different species. Although gap-junctional intercellular communication characterized by rapid transfer of Lucifer Yellow was not observed, we did detect gap-junctional communication marked by the slow transfer of calcein-AM in lung-cancer cell lines. However, neither an inhibitor (1-octanol) nor an enhancer (all trans-retinoic acid [ATRA]) of gap-junctional communication affected the extent of the bystander effect. These findings suggest that low levels of gap-junctional communication may be efficient for producing the bystander effect in lung-cancer cells, or that other mechanisms may underlie this effect. Although gap-junctional communication may play an important role in generating the bystander effect in tumor cells expressing the HSV-tk gene, further knowledge of the mechanism of this effect may help improve the treatment of lung cancer with an HSV-tk system.

1-Octanol↗
PubMed1998

Deficient epithelial-fibroblast heterocellular gap junction communication can be overcome by co-culture with an intermediate cell type but not by E-cadherin transgene expression.

Epithelial, fibroblast and intermediate cell lines were employed to examine the mechanism(s) essential for heterocellular gap junction intercellular communication in vitro. These cell lines were characterized extensively for cell type based on morphology, intermediate cytoskeletal proteins, cell adhesion molecules and their associated proteins, tight junction proteins as well as functional differentiation. All cell types expressed connexin43 and were dye-coupled in homocellular culture. Epithelial and intermediate cells or fibroblasts and intermediate cells readily assembled heterocellular connexin43-positive gap junction plaques when co-cultured, while gap junction plaques in mixed cultures of epithelial cells and fibroblasts were rare. Dye microinjection studies were used to show that there was little gap junction intercellular communication between epithelial cells and fibroblasts. However, intermediate cells were able to communicate with epithelial cells and, to a lesser extent, fibroblasts and could transfer dye to both epithelial cells and fibroblasts when all three cell types were cultured together. Fibroblasts that were stably transfected with a cDNA encoding E-cadherin had a greater tendency to aggregate and exhibited a more epithelial-like phenotype but heterocellular gap junction intercellular communication with epithelial cells, which endogenously express E-cadherin, was not enhanced. These results suggest that mutual expression of E-cadherin is insufficient to stimulate gap junction formation between epithelial cells and fibroblasts. Moreover, our results also demonstrate that communication gaps between epithelial cells and fibroblasts can be bridged by intermediate cells, a process that may be important in mammary gland development, growth, differentiation and cancer.

Animals↗
PubMed1999

Consequences of impaired gap junctional communication in glial cells.

Astrocytes are characterized by extensive gap junctional intercellular communication (GJIC) mediated by channels composed primarily of connexin43. To examine some of the functions of this intercellular communication in glial cells, we have used three approaches. The first involves transfection of glioma cells, which are deficient in connexin expression and gap junctional communication, with connexin cDNAs to examine changes in cellular phenotype following increased gap junctional communication. Using differential display, we have identified several genes which appear to be regulated by GJIC. The second is to study astrocytes cultured from embryonic mice with a null mutation in the connexin43 gene. These homozygous null astrocytes are devoid of connexin43 and also deficient in intercellular dye transfer. Markers of glial differentiation appear similar in all genotypes. Measurement of intercellular calcium concentration following mechanical stimulation of confluent astrocytes revealed that the number of cells affected by a rise in intracellular calcium was reduced in homozygous cultures compared to wild type. The growth rate of astrocytes lacking connexin43 was reduced compared to wild-type astrocytes. The third approach employs the use of gap junction blockers in a model of neuronal and glial differentiation, namely P19 mouse embryonal carcinoma cells treated with retinoic acid. In this case, blocking GJIC during the differentiation protocol prevents the appearance of neuronal and astrocytic phenotypes. Taken together, these data suggest an important role for GJIC in glial function and differentiation.

Animals↗
PubMed2001

Physiological levels of melatonin enhance gap junction communication in primary cultures of mouse hepatocytes.

Gap junction communication is known to be involved in controlling cell proliferation and differentiation, and seems to play a crucial role in suppression of tumor promotion. Melatonin, a hormone secreted by the pineal gland, has putative oncostatic properties. Intercellular communication through gap junctions was assessed by microinjecting Lucifer yellow fluorescent dye into primary hepatocytes and visualizing the spread of the dye to adjacent neighboring cells using phase contrast/fluorescent microscopy. Treatment of primary hepatocyte cultures with a physiological range of melatonin concentrations for 24 h prior to microinjection resulted in significant enhancement in intercellular communication at 0.2 and 0.4 nmol/L but not at lower (0.1 nmol/L) or higher (0.8 or 1.0 nmol/L) concentrations. A time-dependent study showed that the changes in intercellular communication began 10 h after melatonin treatment and reached a maximum at 12 h of treatment. This nonlinear, functional gap junction response to melatonin occurred in the physiological concentration range detected in blood of mammals during nightly releases of the hormone by the pineal gland. These melatonin levels may affect the ability of gap junction communication to exert cell growth control in vivo. The uneven decline between individuals in nocturnal release of melatonin that occurs with age could identify potentially sensitive subpopulations susceptible to developing pathologies involving alterations in biological processes dependent on gap junction communication.

Analysis of Variance↗
PubMed1985

Effects of 6-thioguanine on communication competence and factors affecting reversibility of phorbol ester inhibition in V79 cells measured by the metabolic cooperation assay and by dye coupling.

One assay used to study the role of intracellular communication in tumor promotion examines chemically-induced inhibition of metabolic cooperation between 6-thioguanine (6-TG) sensitive (HGPRT+) V79 Chinese hamster cells in co-culture with 6-TG resistant (HGPRT-) cells. In the present study metabolic cooperation and Lucifer Yellow dye coupling were applied to detect intercellular communication. HGPRT+ cells were still communication competent when pre-incubated with 6-TG for up to 48 h before HGPRT- cells were plated. In both assays the phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu) inhibited intercellular communication completely at 1 ng/ml. Using 6-TG metabolic cooperation, extensive washing of cells failed to reverse the inhibition caused by 100 ng TPA/ml after exposure for as little as 1 h. However, the effect of PDBu was completely eliminated if the drug was removed within 24 h. Complete blockade of dye coupling by 1, 10 or 100 ng TPA/ml was reversible after washing only at 1 ng/ml. Cells cultured in the presence of these TPA concentrations displayed significant reversal of dye coupling inhibition after 40 h. The results indicate that the onset of communication competence impairment between V79 cells by 6-TG is much slower than hitherto implied. Failure of intercellular communication to recover even from short exposure to 100 ng TPA/ml appears to be attributable to its lipophilic nature. Not enough TPA can be removed by washing to overcome its potent inhibitory action. These observations indicate that the physicochemical properties of a chemical must be taken into consideration before making judgements about the duration of inhibition.

Animals↗
PubMed1998

Intercellular calcium signalling between chondrocytes and synovial cells in co-culture.

Intercellular communication allows the co-ordination of cell metabolism between tissues as well as sensitivity to extracellular stimuli. Paracrine stimulation and cell-to-cell coupling through gap junctions induce the formation of complex cellular networks that favour the intercellular exchange of nutrients and second messengers. Heterologous intercellular communication was studied in co-cultures of articular chondrocytes and HIG-82 synovial cells by measuring mechanically induced cytosolic changes in Ca2+ ion levels by digital fluorescence video imaging. In confluent co-cultures, mechanical stimulation induced intercellular Ca2+ waves that propagated to both cell types with similar kinetics. Intercellular wave spreading was inhibited by 18alpha-glycyrrhetinic acid and by treatments inhibiting the activation of purinoreceptors, suggesting that intercellular signalling between these two cell types occurs both through gap junctions and ATP-mediated paracrine stimulation. In rheumatoid arthritis the formation of the synovial pannus induces structural changes at the chondrosynovial junction, where chondrocyte and synovial cells come into close apposition: these results provide the first evidence for direct intercellular communication between these two cell types.

Adenosine Triphosphate↗
PubMed2003

Intercellular calcium communication regulates platelet aggregation and thrombus growth.

The ability of platelets to form stable adhesion contacts with other activated platelets (platelet cohesion or aggregation) at sites of vascular injury is essential for hemostasis and thrombosis. In this study, we have examined the mechanisms regulating cytosolic calcium flux during the development of platelet-platelet adhesion contacts under the influence of flow. An examination of platelet calcium flux during platelet aggregate formation in vitro demonstrated a key role for intercellular calcium communication (ICC) in regulating the recruitment of translocating platelets into developing aggregates. We demonstrate that ICC is primarily mediated by a signaling mechanism operating between integrin alpha IIb beta 3 and the recently cloned ADP purinergic receptor P2Y12. Furthermore, we demonstrate that the efficiency by which calcium signals are propagated within platelet aggregates plays an important role in dictating the rate and extent of thrombus growth.

Adenosine Diphosphate↗
PubMed2005

Pharmacology of gap junctions. New pharmacological targets for treatment of arrhythmia, seizure and cancer?

Intercellular communication in many organs is maintained via intercellular gap junction channels composed of connexins, a large protein family with a number of isoforms. This gap junction intercellular communication (GJIC) allows the propagation of action potentials (e.g., in brain, heart), and the transfer of small molecules which may regulate cell growth, differentiation and function. The latter has been shown to be involved in cancer growth: reduced GJIC often is associated with increased tumor growth or with de-differentiation processes. Disturbances of GJIC in the heart can cause arrhythmia, while in brain electrical activity during seizures seems to be propagated via gap junction channels. Many diseases or pathophysiological conditions seem to be associated with alterations of gap junction protein expression. Thus, depending on the target disease opening or closure of gap junctions may be of interest, or alteration of connexin expression. GJIC can be affected acutely by changing gap junction conductance or--more chronic--by altering connexin expression and membrane localisation. This review gives an overview on drugs affecting GJIC.

Animals↗
PubMed2005

Down-regulation of Cx43 by retroviral delivery of small interfering RNA promotes an aggressive breast cancer cell phenotype.

Connexins are gap junction proteins that assemble into channels that mediate direct intercellular communication. Connexins are well-documented tumor suppressors and are thought to regulate both cell growth and differentiation. As previously reported, most human breast tumors and cell lines down-regulate gap junctions or have defective gap junctional intercellular communication. Furthermore, overexpression of connexins in breast cancer cells inhibits tumor growth in vivo. In this study, we hypothesize that controlled Cx43 down-regulation would induce breast tumor cells to acquire a more aggressive phenotype. Here we report that Cx43 was down-regulated in both normal rat kidney (NRK) cells and human breast cancer cell lines (MDA-MB-231 and Hs578T) by transfection with chemically synthesized small interfering RNA (siRNA) or short hairpin RNA generated from a retroviral infection. Furthermore, we show that retroviral delivery and expression of siRNA directed to different coding regions of Cx43 resulted in differential levels of Cx43 silencing and impaired gap junctional intercellular communication. Cx43-silenced Hs578T cells grew faster and were more migratory. Finally, Western blot analysis revealed that down-regulation of Cx43 resulted in decreased expression of thrombospondin-1, an antiangiogenesis molecule, and increased expression of vascular endothelial growth factor. Taken together, these results suggest that Cx43 is required for maintaining cell differentiation and the regulation of molecules important in angiogenesis.

Animals↗
PubMed1995

Gap junctional communication in primary culture of cells derived from human aortic intima.

Intercellular communication via gap junctions plays an important role in the regulation and homeostasis. The presence of gap junctions and the efficiency of their function directly correlates with the degree of cell differentiation in a tissue. In the present study, gap junctional communication has been investigated in a primary culture of highly differentiated mesenchymal cells (subendothelial smooth muscle cells isolated from grossly normal and atherosclerotic areas of human aorta) and in poorly differentiated cells of mesenchymal origin (adult human skin fibroblasts as well as skin fibroblasts and aortic smooth muscle cells, derived from human fetus). The fluorescent dye transfer technique was used in this study. In cell cultures isolated from grossly normal and atherosclerotic aorta, the number of cells coupled via gap junctions increased with cell density and reached a plateau at a cell density of 50 to 70 cells/mm2. In cultures of normal aortic cells the number of coupled cells was 23.0 +/- 4.1 per injected cell and was significantly higher than in cultures of atherosclerotic cells (16.4 +/- 2.1, p < 0.05). Gap junctional communication between cells loaded with lipid inclusions was 2.4-fold lower than between cells free of excess intracellular lipids. In cultures of human skin fibroblasts the rate of intercellular communication was lower than in cultures of normal aortic cells and was comparable to that in cultures of atherosclerotic cells. There was practically no cell-to-cell communication in cultures of fetal cells. It is hypothesized that the reduced gap junctional communication in atherosclerotic human aorta is associated with the alterations in the degree of smooth muscle cell differentiation and impairs the function of the intima in atherosclerosis.

Aorta↗
PubMed1999

Spatial and temporal regulation of gap junction connexin43 in vascular endothelial cells exposed to controlled disturbed flows in vitro.

Hemodynamic regulation of the endothelial gap junction protein connexin43 (Cx43) was studied in a model of controlled disturbed flows in vitro. Cx43 mRNA, protein expression, and intercellular communication were mapped to spatial variations in fluid forces. Hemodynamic features of atherosclerotic lesion-prone regions of the vasculature (flow separation and recirculation) were created for periods of 5, 16, and 30 h, with laminar shear stresses ranging between 0 and 13.5 dynes/cm2. Within 5 h, endothelial Cx43 mRNA expression was increased in all cells when compared with no-flow controls, with highest levels (up to 6- to 8-fold) expressed in regions of flow recirculation corresponding to high shear stress gradients. At 16 h, Cx43 mRNA expression remained elevated in regions of flow disturbance, whereas in areas of fully developed, undisturbed laminar flow, Cx43 expression returned to control levels. In all flow regions, typical punctate Cx43 immunofluorescence at cell borders was disrupted by 5 h. After 30 h of flow, disruption of gap junctions persisted in cells subjected to flow separation and recirculation, whereas regions of undisturbed flow were substantially restored to normal. These expression differences were reflected in sustained inhibition of intercellular communication (dye transfer) throughout the zone of disturbed flow (84.2 and 68.4% inhibition at 5 and 30 h, respectively); in contrast, communication was fully reestablished by 30 h in cells exposed to undisturbed flow. Up-regulation of Cx43 transcripts, sustained disorganization of Cx43 protein, and impaired communication suggest that shear stress gradients in regions of disturbed flow regulate intercellular communication through the expression and function of Cx43.

Animals↗
PubMed1997

Paracrine and intracellular signaling mechanisms of calcium waves in cultured human uterine myocytes.

OBJECTIVE: To establish mechanisms of intercellular communication in human myometrium other than action potential propagation. METHODS: Monolayer cultured human myometrium was used as a model system. The calcium-sensitive fluorescent dye, calcium green-1, was used as a probe for the concentration of intracellular free calcium. Intercellular calcium waves were initiated by mechanical stimulation and observed with video spectrofluorimetry. This technique allowed initiation of calcium waves from a known location at a known time while simultaneously controlling the flow rate of the bathing solution across the surface of the cells. Intercellular calcium waves were observed at bath flow rates between 0 and 5.1 mL/minute through a 0.4 mL chamber. Experiments were performed using low calcium, high potassium bathing solutions to eliminate the possibility of action potential signaling. RESULTS: In still bathing solution, calcium waves radiated symmetrically from the site of initiation. With the bathing solution flowing, two mechanisms of intercellular calcium wave propagation were observed-one dependent on and one independent of the direction of bath flow. The calcium waves that were independent of bath flow used an intracellular mechanism for intercellular communication, were only observed within 100 microns of the site of wave initiation, and demonstrated mean (+/- standard deviation [SD]) wave speeds of 14.1 +/- 2.6 microns/second. The waves dependent on bath flow used an extracellular signaling mechanism, were observed at distances much greater than 100 microns, and exhibited downstream biasing. Mean (+/- SD) wave speeds of flow-dependent calcium waves were faster under flow conditions than still bath conditions (36.0 +/- 4.7 versus 6.2 +/- 1.3 microns/second; P < .001). By exposing the cells to flurbiprofen, a water soluble prostaglandin synthetase inhibitor, both types of calcium waves were inhibited. CONCLUSION: Human myocytes demonstrate paracrine and intracellular signaling mechanisms for intercellular communication that are distinctly different from action potential propagation.

Calcium↗
PubMed1994

Hormonal regulation of connexin 43 expression and gap junctional communication in human osteoblastic cells.

We have recently shown that connexin 43 (Cx43), a major gap junction protein in osteoblasts, is expressed with an increase in cell density (CHIBA, H. et al. (1993). Cell Struc. Funct., 18: 419-426). In the present study, we examined what kinds of hormones and cytokines regulate the gap junction protein in osteoblastic cells, using a human osteoblastic cell line (SV-HFO) after reaching a confluent density to avoid influence of cell proliferation. Either retinoic acid (RA) or transforming growth factor-beta 1 (TGF-beta 1) induced the Cx43 expression of SV-HFO cells, as revealed by Northern blot analysis and immunocytochemistry. These modulators also increased gap junctional intercellular communication, in terms of the extent of dye transfer. On the other hand, 1 alpha, 25-dihydroxyvitamin D3 did not influence the Cx43 expression and gap junctional intercellular communication of the cells. These results suggest that RA and TGF-beta might maintain bone tissue as an organized tissue in vivo by increasing intercellular communication of osteoblastic cells.

Calcitriol↗
PubMed1984

Inhibition of metabolic cooperation in Chinese hamster V79 cells by various organic solvents and simple compounds.

Gap-junctional intercellular communication is a biological process implicated in the regulation of cell proliferation and differentiation. Metabolic cooperation between 6-thioguanine-sensitive and resistant Chinese hamster cells, in vitro, has been used as a means to detect chemicals which can inhibit this form of intercellular communication. To further characterize this in vitro system as a potential screening assay for potential teratogens, tumor promoters and reproductive toxicants, a series of common solvents as well as other chemicals representing eight different functional groups, i.e., alcohols with straight or side chains, glycols, ketones, esters, ethers, phenols, aldehydes, amines and amino compounds and oxygen-heterocyclic compounds, were tested for their ability to inhibit colony-formation and to inhibit metabolic cooperation. A wide range of effects were observed which suggested a structure/activity relationship between a chemical's ability to inhibit gap junction-mediated intercellular communication and the cytotoxicity of a chemical. Possible mechanisms affecting the modulation of gap junctional communication by these chemicals are discussed.

Animals↗
PubMed1995

Immunohistochemistry of gap junctions in normal and diseased gastric mucosa of humans.

BACKGROUND & AIMS: Intercellular communication through gap junctions has been proposed to be an important mechanism for the maintenance of tissue homeostasis. However, few studies have considered the role of gap junctions in gastric mucosa. The purpose of this study was to evaluate the distribution of gap junction-specific proteins in normal and diseased gastric mucosa of humans. METHODS: Biopsy specimens were obtained endoscopically. Immunohistochemical staining was performed by standard immunoperoxidase techniques using an anti-connexin 32 monoclonal antibody. RESULTS: In normal gastric mucosa, connexin 32 was present chiefly in the foveolar cells and in a decreasing staining gradient extending down to the necks of the glands. Connexin 32 also was observed in the epithelial cells of atrophic mucosa in a pattern similar to that observed in normal controls. Conversely, the majority of the foveolar cells adjacent to erosions had reduced or absent staining. Connexin 32 also was reduced significantly or absent from metaplastic epithelial cells. No malignant cells from patients with carcinoma contained detectable connexin 32. CONCLUSIONS: Intercellular communication likely is impaired in precancerous or paracancerous lesions of the stomach. Abnormal intercellular communication thus may play an important role in the progression from mucosal injury to intestinal metaplasia and/or gastric carcinoma.

Adult↗
PubMed2002

Connexins and cancer.

The hypothesis, that gap junctional intercellular communication plays a key role in carcinogenesis and more generally in growth control was formulated nearly 40 years ago. From this time, data accumulated, showing that this type of communication is frequently decreased or absent in cells treated with tumor promoting agents, among transformed cells or between transformed/tumor cells and normal cells. This observation has been made on various cell types and whatever their tissue and species origins, by using in vitro and in vivo models. It led to the general assumption that the inhibition of gap junctional intercellular communication may play a role in carcinogenesis at two levels: (1) during tumor promotion by favoring the clonal expansion of initiated cells and (2) after the phenotypic transformation of cells by preventing the diffusion of putative "normalizing" factors between tumor cells and surrounding normal cells. During the past decade, the discovery that gap junction proteins, the connexins (Cx), may act as tumour suppressors, by reverting the phenotype of transformed cells confirmed the idea that their lack of function would be actively involved in carcinogenesis. However, we still do not know precisely what are the molecular processes that gap junctional intercellular communication may regulate and still do have very few data concerning the gap junction situation in human cancers. All these aspects are presented from an historical point of view and discussed below.

Animals↗
PubMed1987

Gap junctions and synchronization of polarization process during epithelial reorganization.

The formation of intercellular communication during epithelial reorganization of LLC-PK1 cells was studied with a new, nondisruptive flow cytometric technique. The assembly of these junctions, as demonstrated by cell-to-cell transfer of the fluorescent dye carboxy dimethyl fluorescein, occurs very early during epithelial reorganization. Close cell-to-cell interaction is required for the assembly to occur. Low temperature, treatment with 10(-3) M ouabain, or treatment with the Ca2+ ionophore A23187 inhibits assembly of these junctions. Removal of Ca2+ from the incubation medium, on the other hand, has no effect. Cycloheximide (10(-6) M) is also without effect, suggesting that protein synthesis is not required during the assembly of the junctions and that either the trypsin used to disperse the cells does not affect the junctional components or the cells have a rather extensive reserve pool of junctional precursors. The concomitant delay in the development of intercellular communication and the reorganization of the epithelial membrane, as previously observed with cells in asynchronous growth [Am. J. Physiol. 251 (Renal Fluid Electrolyte Physiol. 20): F978-F987, 1986], is consistent with the theory that junctional intercellular communication coordinates cellular activity during epithelial reorganization.

Animals↗
PubMed2003

The expression of the tumor suppressor gene connexin 26 is not mediated by methylation in human esophageal cancer cells.

Gap junctional intercellular communication is thought to play an important role in cell differentiation and tissue homeostasis. Gap junctional intercellular communication is mediated by intercellular channels connecting adjacent cells and composed of connexin (Cx) proteins. Until now, approximately 20 different Cx have been characterized in mammals, and they are expressed in a tissue-specific manner. The downregulation of Cx expression is often observed in tumors and transformed cell lines and is believed to contribute to the loss of proliferating control. Connexin 26 (Cx26) is a Cx constitutively expressed in the normal epithelial esophageal tissue. In the majority of esophageal tumors, Cx26 expression is low or totally absent. CpG island hypermethylation is known to be associated with gene silencing in cancer. Because the promoter and exon 1 region of Cx26 are rich in CpG dinucleotides, we examined whether the loss of Cx26 expression in human esophageal TE cell lines was related to the hypermethylation of this region. We analyzed several TE cell lines derived from different human esophageal carcinomas and exhibiting different levels of Cx26 expression by using methylation-sensitive restriction digestion and Southern blot analysis. We did not find any correlation between the Cx26 expression and the methylation level of the promoter region of the Cx26 gene. Our results suggest that methylation was probably not involved as a primary mechanism of Cx26 regulation in human esophageal cancer cell lines.

Connexin 26↗