Increased invasive capacity of connexin43-overexpressing malignant glioma cells

Zhang, Wei; Nwagwu, Chiedozie I.; Le, Duc Minh; Yong, V. Wee; Song, Hua; Couldwell, William T.

doi:10.3171/jns.2003.99.6.1039

Cited by 74 publications

(63 citation statements)

References 27 publications

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“…Kamibayashi et al [36] demonstrated that even though the expression of Cx26 and Cx43 was reduced in the early stages of mouse skin carcinogenesis, both connexins were expressed on the plasma membranes of cells invading the lymph nodes. Similar observations were made for breast cancer [35], prostate cancer [37,38] and glioma cell populations [39]. In melanoma cells residing in the basal layer, Cx26 levels remained unchanged, but were significantly up-regulated in the cells invading the dermis.…”

Section: The Effect Of Gap Junctions On the Invasive Potential Of Tumsupporting

confidence: 70%

The stage-specific function of gap junctions during tumourigenesis

Czyż

2008

Cellular and Molecular Biology Letters

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Tumour development is a process resulting from the disturbance of various cellular functions including cell proliferation, adhesion and motility. While the role of these cell parameters in tumour promotion and progression has been widely recognized, the mechanisms that influence gap junctional coupling during tumorigenesis remain elusive. Neoplastic cells usually display decreased levels of connexin expression and/or gap junctional coupling. Thus, impaired intercellular communication via gap junctions may facilitate the release of a potentially neoplastic cell from the controlling regime of the surrounding tissue, leading to tumour promotion. However, recent data indicates that metastatic tumour cell lines are often characterized by relatively high levels of connexin expression and gap junctional coupling. This review outlines current knowledge on the role of connexins in tumorigenesis and the possible mechanisms of the interference of gap junctional coupling with the processes of tumour invasion and metastasis. GAP JUNCTIONS -THEIR STRUCTURE AND BASIC FUNCTIONS IN TISSUE HOMEOSTASISGap junctions are aqueous intercellular channels which directly link the cytoplasmic compartments of adjacent cells (Fig. 1). These channels are formed upon the docking of two connexons, hexameric hemichannels built of proteins belonging to the connexin family [1]. Gap junctions are present in almost all vertebrate tissues, where they permit the intercellular exchange of small (< 1 kDa) metabolites and second messengers, and thus synchronise cellular functions in tissues [2][3][4]. Representative examples of the synchronising function of gap junctional coupling in tissues include electrical and metabolic coupling. In the former, gap junctions take part in the intercellular spreading of membrane depolarisation by permitting the rapid cell-to-cell transfer of calcium ions between cardiac muscle cells [1], or by constituting electrical synapses in the nervous system [5]. Metabolic coupling is established when the stimulation of one cell is propagated to a cluster of cells through the spreading of active substances, such as monosaccharides and cyclic nucleotides [2,6]. While electrical coupling predominantly synchronizes cell functions in excitable tissues, metabolic coupling affects the homeostasis of a spectrum of multicellular systems, including both excitable and non-excitable tissues. The crucial role of gap junctions in the regulation of tissue homeostasis is illustrated by the functional impairment of many vertebrate tissues occurring when there is deficient gap junctional communication [7,8]. For instance, disruption of the function of the gene encoding Cx32 is associated with the progressive degeneration of the peripheral nerves, resulting from the impairment of the diffusion of nutrients and signalling molecules between the perinuclear and periaxonal Schwann cell cytoplasm [for review see [9]. Furthermore, abnormalities have been observed in Cx32-deficient mouse livers: Cx32 disruption leads to a decrease in the disc...

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Section: The Effect Of Gap Junctions On the Invasive Potential Of Tumsupporting

confidence: 70%

The stage-specific function of gap junctions during tumourigenesis

Czyż

2008

Cellular and Molecular Biology Letters

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“…Substantial evidence from various models implicates cell-cell communication in the ability of tumor cells to invade and metastasize. Intercellular communication between glioma tumor cells and astrocytes or endothelial cells was shown to increase tumor invasion and to increase vascular endothelial growth factor secretion and vascular tube formation, respectively (9,15,16). In prostate cancer, a direct correlation between increased connexin 26 expression levels and cancer progression was observed (17).…”

Section: Discussionmentioning

confidence: 94%

Monoclonal Antibodies to Six-Transmembrane Epithelial Antigen of the Prostate-1 Inhibit Intercellular Communication In vitro and Growth of Human Tumor Xenografts In vivo

Challita-Eid¹,

Morrison²,

Etessami³

et al. 2007

Cancer Research

110

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Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein highly expressed in primary prostate cancer, with restricted expression in normal tissues. In this report, we show STEAP-1 expression in prostate metastases to lymph node and bone and in the majority of human lung and bladder carcinomas. We identify STEAP-1 function in mediating the transfer of small molecules between adjacent cells in culture, indicating its potential role in tumor cell intercellular communication. The successful generation of two monoclonal antibodies (mAb) that bind to cell surface STEAP-1 epitopes provided the tools to study STEAP-1 susceptibility to naked antibody therapy. Both mAbs inhibited STEAP-1-induced intercellular communication in a dosedependent manner. Furthermore, both mAbs significantly inhibited tumor growth in mouse models using patientderived LAPC-9 prostate cancer xenografts and established UM-UC-3 bladder tumors. These studies validate STEAP-1 as an attractive target for antibody therapy in multiple solid tumors and provide a putative mechanism for mAb-induced tumor growth inhibition. [Cancer Res 2007;67(12):5798-805]

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“…Adjacent glioma cells physically interact via adhesion proteins, microtubes, membrane fusing, microvesicles, and by gap junctions [34][35][36][37]. Although the mechanisms by which adjacent tumor cells interact are numerous, substantial evidence indicates that gap junctions play key roles in intercellular communication, and can regulate both glioma proliferation and invasion [36,[38][39][40]. Indeed, even cell-to-cell interactions via microtubes, adherens, and microvesicles are modulated by gap junctions [34,41,42].…”

Section: Resultsmentioning

confidence: 99%

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

Katakowski

Charteris

Chopp

et al. 2016

Cancer Microenvironment

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The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR-9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1α) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor.

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Increased invasive capacity of connexin43-overexpressing malignant glioma cells

Abstract: The overexpression of gap junction proteins in glioma cells and the intercellular communication between tumor and nontumor glia cells may play important roles in the facilitation of glioma cell invasion.

Cited by 74 publications

References 27 publications

The stage-specific function of gap junctions during tumourigenesis

The stage-specific function of gap junctions during tumourigenesis

Monoclonal Antibodies to Six-Transmembrane Epithelial Antigen of the Prostate-1 Inhibit Intercellular Communication In vitro and Growth of Human Tumor Xenografts In vivo

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

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