Biomedical subjects

Jian Kang

Publications and source records attributed to Jian Kang.

At least 55 records · Page 3Linked to original sources

PubMed2004

Presynaptic inactivation of action potentials and postsynaptic inhibition of GABAA currents contribute to KA-induced disinhibition in CA1 pyramidal neurons.

Kainate-type glutamate ionotropic receptors (KAR) mediate either depression or potentiation of inhibitory transmission. The mechanisms underlying the depressant effect of KAR agonists have been controversial. Under dual patch-clamp recording techniques in synaptically coupled pairs of CA1 interneurons and pyramidal neurons in hippocampal slices, micromolar concentrations of KAR agonists, kainic acid (KA, 10 microM) and ATPA (10 microM), induced inactivation of action potentials (APs) in 58 and 50% of presynaptic interneurons, respectively. Inactivation of interneuronal APs might have significantly contributed to KA-induced decreases in evoked inhibitory postsynaptic currents (eIPSCs) that are obtained by stimulating the stratum radiatum. With controlled interneuronal APs, KAR agonists induced a decrease in the potency (mean amplitude of successful events) and mean amplitude (including failures) of unitary inhibitory postsynaptic currents (uIPSCs) without significantly changing the success rate (P(s)) at perisomatic high-P(s) synapses. In contrast, KAR agonists induced a decrease in both the P(s) and potency of uIPSCs at dendritic high-P(s) synapses. KAR agonists induced an inhibition of GABA(A) currents by activating postsynaptic KARs in pyramidal neurons; this was more prominent at dendrites than at soma. Both the exogenous GABA-induced current and the amplitude of miniature IPSCs (mIPSCs) were attenuated by KAR agonists. Thus the postsynaptic KAR-mediated inhibition of GABA(A) currents may contribute to the KAR agonist-induced decrease in the potency of uIPSCs and KA-induced disinhibition.

Action Potentials↗

PubMed2004

Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord.

Lineage-restricted progenitors of the central nervous system (CNS) are not readily expandable because their mitotic competence is limited. Here we used retroviral overexpression of human telomerase reverse transcriptase (hTERT) to immortalize progenitors from human fetal spinal cord. The hTERT-immortalized cells divided in basic fibroblast growth factor (bFGF) expressed high telomerase activity, and gave rise to phenotypically restricted subpopulations of either glia or neurons. The latter included a prototypic line, hSC11V-TERT, that gave rise only to neurons. These included both chx10(+) interneurons and Islet1(+)/Hb9(+)/ChAT(+) motor neurons; the latter were recognized by green fluorescent protein (GFP) driven by the Hb9 enhancer. The neurons were postmitotic and achieved electrophysiologic competence. Upon xenograft to both fetal rat brain and injured adult spinal cord, they matured as neurons and survived for 6 months, with no evident tumorigenesis. The cells have survived >168 doublings in vitro, with karyotypic normalcy and without replicative senescence. hTERT overexpression thus permits the generation of progenitor lines able to give rise to phenotypically restricted neurons.

Cell Culture Techniques↗

PubMed2004

Astrocyte-mediated activation of neuronal kainate receptors.

Exogenous kainate receptor agonists have been shown to modulate inhibitory synaptic transmission in the hippocampus, but the pathways involved in physiological activation of the receptors remain largely unknown. Accumulating evidence indicates that astrocytes can release glutamate in a Ca(2+)-dependent manner and signal to neighboring neurons. We tested the hypothesis that astrocyte-derived glutamate activates kainate receptors on hippocampal interneurons. We report here that elevation of intracellular Ca(2+) in astrocytes, induced by uncaging Ca(2+), o-nitrophenyl-EGTA, increased action potential-driven spontaneous inhibitory postsynaptic currents in nearby interneurons in rat hippocampal slices. This effect was blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonists, but not by selective AMPA receptor or N-methyl-d-aspartate receptor antagonists. This pharmacological profile indicates that kainate receptors were activated during Ca(2+) elevation in astrocytes. Kainate receptors containing the GluR5 subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca(2+) uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca(2+) uncaging induced a small decrease in the frequency of miniature inhibitory postsynaptic currents, which was not affected by AMPA/kainate receptor antagonists. Our data suggest that an astrocyte-derived, nonsynaptic source of glutamate represents a signaling pathway that can activate neuronal kainate receptors. By modulating the activity of interneurons, astrocytes may play a critical role in circuit function of hippocampus.

Animals↗

PubMed2004

Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission.

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca(2+) elevation in astrocytes, by photolysis of caged Ca(2+) by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca(2+) uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca(2+) uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca(2+) uncaging on mIPSCs and eIPSCs. Our results indicate that Ca(2+)-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.

Journal Article↗

PubMed2004

Enteroaggregative Escherichia coli flagellin-induced interleukin-8 secretion requires Toll-like receptor 5-dependent p38 MAP kinase activation.

Enteroaggregative Escherichia coli (EAEC) is an emerging enteric pathogen that causes acute and chronic diarrhoea in a number of clinical settings. EAEC diarrhoea involves bacterial aggregation, adherence to intestinal epithelial cells and elaboration of several toxigenic bacterial mediators. Flagellin (FliC-EAEC), a major bacterial surface protein of EAEC, causes interleukin (IL)-8 release from several epithelial cell lines. The host response to flagellins from E. coli and several other bacteria is mediated by Toll-like receptor 5 (TLR5), which signals through nuclear factor kappa B (NF-kappaB) to induce transcription of pro-inflammatory cytokines. p38 mitogen-activating protein (MAP) kinase (MAPK) is a member of a family of stress-related kinases that influences a diverse range of cellular functions including host inflammatory responses to microbial products. We studied the role of p38 MAPK in FliC-EAEC-induced IL-8 secretion from Caco-2 human intestinal epithelial cells and THP-1 human monocytic cells. We found that IL-8 secretion from both cell types is dependent on p38 MAPK, which is phospho-activated in response to FliC-EAEC. The role of TLR5 in p38 MAPK-dependent IL-8 secretion was verified in HEp-2 cells transiently transfected with a TLR5 expression construct. Activation of interleukin-1 receptor-associated kinase (IRAK) was also observed in Caco-2 and TLR5-transfected HEp-2 cells after exposure to FliC-EAEC. Finally, we demonstrated that pharmacological inhibition of p38 MAPK reduced IL-8 transcription and mRNA levels, but did not affect NF-kappaB activation. Collectively, our results suggest that TLR5 mediates p38 MAPK-dependent IL-8 secretion from epithelial and monocytic cells incubated with FliC-EAEC, and that this effect requires IL-8 promoter activation independent of NF-kappaB nuclear migration.

Caco-2 Cells↗

PubMed2004

Experimental treatment of human neuroblastoma using live-attenuated poliovirus.

Neuroblastoma, originated from neural crest cells, is the most common extracranial solid tumor in childhood. In the present study, we evaluated in vitro the oncolytic effect of live-attenuated poliovirus on human neuroblastoma cell lines, and in vivo its therapeutic efficacy in human neuroblastoma-bearing athymic mice. Live-attenuated poliovirus killed 27 (93%) of 29 established neuroblastoma cell lines in vitro. It induced cleavage of eukaryotic translation initiation factor 4G, leading to cell death through a mechanism involving activation of caspase-9, caspase-3 and poly(ADP-ribose)polymerase. For the in vivo experiments, an animal model was established using athymic mice xenotransplanted with SJ-N-JF neuroblastoma cells on both flanks. Inoculation of live-attenuated poliovirus into one of the two tumors caused a dramatic and complete regression of both the inoculated and contralateral tumors. Live-attenuated poliovirus has potent oncolytic activity against human neuroblastomas in vitro and in vivo and it may be useful for the treatment of advanced and refractory neuroblastomas, however, further studies are necessary to evaluate the safety of method.

Animals↗

PubMed2004

[Change of prostaglandin E2 and interleukin-12, interleukin-13 in the bronchoalveolar lavage fluid and the serum of the patients with idiopathic pulmonary fibrosis].

OBJECTIVE: To detect the levels of prostaglandin E2 (PGE2) and interleukin-12 (IL-12), IL-13 in the bronchoalveolar lavage fluid (BALF) and the serum of patients with idiopathic pulmonary fibrosis (IPF) and to investigate the significance of their change in the pathogenesis of IPF. METHODS: Radioimmunoassay (RIA) and enzyme-linked immunoadsorbent assay (ELISA) were used to detect the levels of PGE2 and IL-12, IL-13 in the BALF and the serum of patients with IPF. RESULTS: In the BALF of patients with IPF, the levels of PGE2 (591 +/- 88) ng/L and IL-13 (38 +/- 5) ng/L were higher than that of the control group (P < 0.01), and the level of IL-12 (1.34 +/- 0.25) ng/L was lower than that of control group. In the patients with IPF, the change of IL-13 in the serum was consistent with the change in the BALF. But the levels of PGE2 (235 +/- 13) ng/L and IL-12 (2.35 +/- 0.14) ng/L in the serum showed no significant difference between the patients with IPF and the control group. CONCLUSIONS: In the patients with IPF the increase of PGE2 may be correlated with the increase of IL-13 and the decrease of IL-12. It suggests that disequilibrium of Th1/Th2 plays an important role in the development of IPF. The increase of PGE2 in IPF is a local event rather than a systemic effect.

Adolescent↗

PubMed2004

[Respiratory control in obstructive sleep apnea hypopnea syndrome].

OBJECTIVE: To evaluate the role of ventilatory control in obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: Thirty-five patients with OSAHS were compared with 15 obese controls in pulmonary function, hypoxic ventilatory response (HVR), hypercapnic ventilatory response (HCVR) and polysomnography (PSG). RESULTS: (1) There were no differences in HVR and HCVR between patients with OSAHS and the control (t = 1.28, 0.57; P > 0.05). In OSAHS patients, HVR was correlated with nadir nocturnal oxygen saturation (MmS(P)O(2)) (r = -0.54, P < 0.01) and HCVR (r = 0.57, P < 0.01). (2) Patients with mild and moderate OSAHS had higher HVR than those with severe OSAHS (t = 2.74, P < 0.01). When 5 < or = apnea and hypopnea index (AHI) < 40, HVR was negatively correlated to forced expiratory volume in one second (FEV(1))/peak expiratory flow (PEF) (r = -0.42, P < 0.05) and AHI (r = -0.68, P < 0.01). For those whose AHI > or = 40, HVR was negatively correlated with MmSpO(2) (r = -0.58, P < 0.05) and positively correlated with HCVR (r = 0.59, P < 0.05). CONCLUSION: In OSAHS patients, HCVR did not show significant change, but HVR showed two phasic change-increase first and then decrease-following the elevation of AHI, which was also related to MmSpO(2) and HCVR.

Adult↗

PubMed2004

[Ventilatory control in familial obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To investigate the genetic abnormality of ventilatory control may play a role in the familial aggregation of obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Ten severe patients with OSAHS, 16 first relatives of them and 14 obese subjects were studied and the hypoxic ventilatory response (HVR), the hypercapnic ventilatory response (HCVR) and the results of PSG were analyzed. HVR and HCVR of OSAHS patients were re-examined in the first, second and third month of continuous positive airway pressure(CPAP) treatment. RESULTS: (1) For the relatives of the OSAHS patients, the apnea-hypopnea index (AHI) was (28.4 +/- 39.1)/h, the incidences of snoring and daytime sleepiness were 100% and 90%, They were higher than those of the control (P < 0.05, P < 0.01, P < 0.01). OSAHS had familial aggregation. (2) The HVR and HCVR were (-19 +/- 24) cm H2O and (0.31 +/- 0.35) cm H2O/mm Hg for the relatives.Neither HVR nor HCVR showed difference between the relatives and the control (P > 0.05). Only two of the relatives with severe OSAHS had lower HVR, while the others, whether accompanied with OSAHS or not, had similar HVR and HCVR to the control. (3) HVR and HCVR returned to normal after CPAP therapy in patients of OSAHS. CONCLUSION: OSAHS had familial aggregation, but it was not related to genetic abnormality of ventilatory control.

Adult↗

PubMed2003

Protein kinase C and protein tyrosine kinase mediate lipopolysaccharide- and cytokine-induced nitric oxide formation in vascular smooth muscle cells of rats.

Rat aorta media, adventitia and cultured vascular smooth muscle cells (VSMCs) were used in this study to identify the source of nitric oxide (NO) generation from various cell types of vascular tissues and to elucidate the mechanisms involved in NO formation. Treatment of vascular media and VSMCs with lipopolysaccharide (LPS) or cytokines [tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta)] resulted in a dose-dependent increase of NO release. Inducible nitric oxide synthase (iNOS) in the stimulated VSMCs was significantly upregulated as shown by Western blot analysis. Protein kinase C (PKC) inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) prevented LPS-, TNF-alpha- and IL-1beta-induced NO production, whereas N-(2-guanidinoethyl)-5-isoquinoline-sulfonamide (HA1004), an H7 analogue with little activity towards PKC, had no inhibition effect. The role of PKC in LPS- and cytokine-induced changes on NO formation was confirmed by using another structurally distinct PKC inhibitor chelerythrine. Treatment of VSMCs with protein tyrosine kinase (PTK) inhibitor genistein or tyrphostin AG18 also reduced the NO production evoked by LPS, TNF-alpha or IL-1beta, which was associated with inhibition of iNOS protein expression. In contrast, PKC inhibitor chelerythrine did not affect iNOS expression. These results suggest that PTK mediates LPS- and cytokine-induced NO formation by upregulation of iNOS expression. PKC may be involved in the post-translational modification of iNOS or the regulation of the availability of iNOS substrates and cofactors.

Animals↗

PubMed2003

[Bone marrow stromal cells of adult mice differentiate into smooth muscle cells in vitro].

OBJECTIVE: To explore the potential of murine bone marrow stromal cells (MSCs) to differentiate into vascular smooth muscle cells so as to contribute to neointimal formation after vascular injury. METHODS: Murine MSCs were isolated from bone marrow and cultured in M199 with 10% FBS supplemented with medium conditioned from human smooth muscle cell culture to induce differentiation. Immunofluorescent technique was used to observe the morphology of cells to examine the smooth muscle characters. Vasoactive substance was added onto the cultured smooth muscle-like cells. Inverted microscopy was used to observe the contractile changes of the cells. RESULTS: After 6 passages of subculture in differentiation medium, MSCs demonstrated smooth muscle cell-like spindle-shaped morphology and assumed a hill-and-valley growth pattern. Immunofluorescent technique revealed positive signals for alpha-smooth muscle actin, calponin and smooth muscle myosin heavy chains. The smooth muscle cell-like cells displayed robust calcium transients. In response to stimulation of vasoactive substance the [Ca(2+)] of the cells instantaneously increased which was coupled by prominent cell contraction. CONCLUSION: MSCs can differentiate into vascular smooth muscle cells with contractile ability. This model may be useful in study of smooth muscle cell differentiation and the origin of neointimal cells after vascular injury.

Actins↗

PubMed2003

Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain.

The subcortical white matter of the adult human brain harbors a pool of glial progenitor cells. These cells can be isolated by fluorescence-activated cell sorting (FACS) after either transfection with green fluorescent protein (GFP) under the control of the CNP2 promoter, or A2B5-targeted immunotagging. Although these cells give rise largely to oligodendrocytes, in low-density culture we observed that some also generated neurons. We thus asked whether these nominally glial progenitors might include multipotential progenitor cells capable of neurogenesis. We found that adult human white-matter progenitor cells (WMPCs) could be passaged as neurospheres in vitro and that these cells generated functionally competent neurons and glia both in vitro and after xenograft to the fetal rat brain. WMPCs were able to produce neurons after their initial isolation and did not require in vitro expansion or reprogramming to do so. These experiments indicate that an abundant pool of mitotically competent neurogenic progenitor cells resides in the adult human white matter.

Adolescent↗

PubMed2003

[Efficacy and safety of cefditoren pivoxil in treatment of respiratory infections, a clinical study].

OBJECTIVE: To evaluate the efficacy and safety of cefditoren pivoxil in treatment of respiratory infections. METHODS: 199 cases of respiratory infection confirmed by etiological and clinical examinations were treated with cefditoren pivoxil tablets taken orally. Therapeutic evaluation was conducted among 196 cases and safety evaluation was conducted among 199 cases. RESULTS: The total effective rate was 94.9%, and the causative bacteria -elimination rate was 96.7%. Clinical adverse events, including moderate diarrhea, mild nausea and vomiting, and stomach discomfort, were seen in 9 cases with an incidence rate of 4.5%. Laboratory adverse events, including increase of with an incidence rate of 3.5%. CONCLUSION: Cefditoren pivoxil is effective and safe in treatment of mild and moderate respiratory infections. The resistance rate to cefditoren pivoxil of pathogens of respiratory infections and the efficacy of cefditoren pivoxil show no difference from those tested 7 years ago.

Adolescent↗

PubMed2003

Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL-induced apoptosis signalling pathway in a panel of B-lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor-2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS-associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase-8 was recruited to FADD and only sensitive cells showed increased caspase-8 activity upon TRAIL stimulation. The caspase-8 specific inhibitor, Z-IETD, impaired caspase-8 activation and completely abrogated TRAIL-induced apoptosis. These results suggest that TRAIL resistance in B-lymphocytic leukaemia cells is due to negative regulation at the level of caspase-8 activation and that caspase-8 activation is an indispensable process in TRAIL-induced apoptosis. However, FADD-like interleukin-1 beta-converting enzyme inhibitory protein (c-FLIPL) was similarly expressed and down-regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase-8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X-linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down-regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B-lymphocytic leukaemia cells.

Apoptosis↗

PubMed2003

Expression of short-form caspase 8 correlates with decreased sensitivity to Fas-mediated apoptosis in neuroblastoma cells.

Disruption of apoptotic death signal transduction pathways may be responsible for tumor formation, progression and resistance to treatment in neuroblastoma. Caspase 8, one of the initiator caspases, plays an important role in the Fas-Fas ligand pathway. This caspase signals through the formation of a death-inducing signaling complex in response to Fas activation by its ligand. In this study, we evaluated the sensitivity of a series of human neuroblastoma cell lines to membrane-bound Fas ligand induced-cell death, as well as the expression of Fas, caspase 3 and caspase 8. Sensitivity to Fas-mediated cell death did not correlate with the expression of Fas in neuroblastoma cells, but was directly associated with the pattern of caspase 8 protein expression. We found that the majority of neuroblastoma cell lines we evaluated lacked caspase 8 expression, and these cell lines were invariably resistant to Fas-mediated cell death. In contrast, cell lines expressing normal caspase 8 protein were quite sensitive to Fas-mediated cell death. More interestingly, a group of cell lines expressing a distinct short form of caspase 8 with splicing out of exon 3 consistently showed moderate sensitivity to Fas-mediated cell death. These results indicate that the profile of caspase 8 expression is an important determinant of the response of neuroblastoma cells to Fas-mediated cell death.

Alternative Splicing↗

PubMed2003

[Tracheoesophageal shunt for voice reconstruction after total laryngectomy to prevent from deglutition disorders].

OBJECTIVE: To observe the effect of tracheoesophageal shunt on voice reconstruction after total laryngectomy. METHODS: Seventy-nine patients with laryngeal cancer of T3 and T4 stages were conducted an operation of tracheoesophageal shunt after total laryngectomy. The vertical voiced slit with a length of 0.8-0.12 cm was made between the posterior wall of trachea and the frontal wall of esophagus, while the cricoid cartilage flap with the length of 2.0 cm and width of 1.2 cm was reserved to form cartilage mucosa flap as an edge to prevent deglutition disorders. Finally, membranous part of trachea was sutured together with the neck skin as an inclination edge. RESULTS: In this series, 71 of 79 patients kept good voice function, and 65 of 71 patients avoided deglutition disorders, but other patients failed to do so. The 3-year survival rate was 66.7% (14/21, for stage T3) and 64.9% (24/37, for stage T4), respectively. The 5-year survival rate was 6/10 (for stage T3) and 50.0% (10/20, for stage T4), respectively. CONCLUSION: The operation of tracheoesophageal shunt is advantageous to prevent deglutition disorders as well as to restore the voice function of larynx.

Adult↗

PubMed2002

Intercellular calcium signaling mediated by point-source burst release of ATP.

Calcium signaling, manifested as intercellular waves of rising cytosolic calcium, is, in many cell types, the result of calcium-induced secretion of ATP and activation of purinergic receptors. The mechanism by which ATP is released has hitherto not been established. Here, we show by real-time bioluminescence imaging that ATP efflux is not uniform across a field of cells but is restricted to brief, abrupt point-source bursts. The ATP bursts emanate from single cells and manifest the transient opening of nonselective membrane channels, which admits fluorescent indicators of < or = 1.5 kDa. These observations challenge the existence of regenerative ATP release, because ATP efflux is finite and restricted to a point source. Transient efflux of cytosolic nucleotides from a subset of cells may represent a conserved pathway for coordinating local activity of electrically nonexcitable cells, because identical patterns of ATP release were identified in human astrocytes, endothelial cells, and bronchial epithelial cells.

Adenosine Triphosphate↗

PubMed2002

Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells.

A hallmark of astrocytic tumors is their infiltrative nature. Although their aggressive and typically widespread dispersal in the adult brain differs fundamentally from that of other brain tumors, little is known about their cellular basis. Astrocytic tumors express the gap junction protein connexin 43 (Cx43), and we show here that Cx43 expression induced the morphological transformation of glioma cells into an epithelial phenotype. In a short-term aggregation assay, Cx43 expression was associated with a several-fold increase in the competence of glioma cells to aggregate. Antibodies directed against the extracellular domain of Cx43 restored the connexin-deficient phenotype, as manifested by a dose-dependent reduction in aggregation. Apart from their role in gap junction formation, connexins may therefore be considered a distinct class of membrane proteins with adhesive properties. Moreover, implanted Cx43-expressing glioma cells established functional gap junction channels with host astrocytes and dispersed through a substantially greater volume of brain parenchyma than mock- and mutant Cx43-transfected sister cells. Cx43 expression therefore may modulate not only the adhesion of astrocytes to one another, but the spread of glial tumor cells throughout astrocytic syncytia. These observations widen our concept of the potential interactions between tumor cells and their surroundings and suggest that both connexin proteins and their derived gap junctions are critical determinants of the invasiveness of central gliomas.

Animals↗