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Cancers
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Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy
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Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 88630

Special Issue Editor

Dr. Randall J Ruch

E-Mail Website
Guest Editor
Department of Cancer Biology, University of Toledo, Toledo, OH 43614, USA
Interests: intercellular communication; gap junctions; tumor microenvironment; nongenotoxic carcinogenesis

Special Issue Information

Dear Colleagues,

Gap junctions are clusters of aqueous channels approximately 1.5 nm in diameter that directly connect the interiors of two apposed cells. The channels enable cell-to-cell diffusion of small molecules and ions (e.g., water, amino acids, simple sugars, second messengers, and microRNAs), but not larger, more complex molecules. The channels are comprised of connexins, of which twenty human forms are known.

Cancer cells typically have defects in gap junctions for many reasons that include deficient expression of connexins, defective connexin trafficking, and poor cell–cell adhesion. The restoration of gap junctions in many types of neoplastic cells normalizes their phenotype (decreased proliferation and tumorigenicity and increased sensitivity to therapy). Connexins also have functions independent of channel formation and can play roles in signal transduction and gene transcription. Some connexins may also enhance invasion and metastasis. Newer studies also suggest connexins impact cancer stem cell number and function and cancer cell dormancy. This Special Issue will highlight recent findings on the many roles of gap junctions and connexins in cancer development, progression, and therapeutic response.

Dr. Randall J. Ruch
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gap junctions
  • connexins
  • intercellular communication
  • tumor microenvironment
  • cancer dormancy
  • cancer stem cells
  • tumor promotion

Published Papers (21 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 186 KiB  
Editorial
Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy
by Randall Ruch
Cancers 2020, 12(11), 3307; https://doi.org/10.3390/cancers12113307 - 09 Nov 2020
Cited by 9 | Viewed by 1388
Abstract
n/a Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)

Research

Jump to: Editorial, Review, Other

19 pages, 7450 KiB  
Article
Dysregulation of Gap Junction Function and Cytokine Production in Response to Non-Genotoxic Polycyclic Aromatic Hydrocarbons in an In Vitro Lung Cell Model
by Deedee Romo, Kalpana Velmurugan, Brad L. Upham, Lori D. Dwyer-Nield and Alison K. Bauer
Cancers 2019, 11(4), 572; https://doi.org/10.3390/cancers11040572 - 23 Apr 2019
Cited by 16 | Viewed by 3197
Abstract
Polycyclic aromatic hydrocarbons (PAHs), prevalent contaminants in our environment, in many occupations, and in first and second-hand smoke, pose significant adverse health effects. Most research focused on the genotoxic high molecular weight PAHs (e.g., benzo[a]pyrene), however, the nongenotoxic low molecular weight [...] Read more.
Polycyclic aromatic hydrocarbons (PAHs), prevalent contaminants in our environment, in many occupations, and in first and second-hand smoke, pose significant adverse health effects. Most research focused on the genotoxic high molecular weight PAHs (e.g., benzo[a]pyrene), however, the nongenotoxic low molecular weight (LMW) PAHs are emerging as potential co-carcinogens and tumor promoters known to dysregulate gap junctional intercellular communication (GJIC), activate mitogen activated protein kinase pathways, and induce the release of inflammatory mediators. We hypothesize that inflammatory mediators resulting from LMW PAH exposure in mouse lung epithelial cell lines are involved in the dysregulation of GJIC. We used mouse lung epithelial cell lines and an alveolar macrophage cell line in the presence of a binary PAH mixture (1:1 ratio of fluoranthene and 1-methylanthracene; PAH mixture). Parthenolide, a pan-inflammation inhibitor, reversed the PAH-induced inhibition of GJIC, the decreased CX43 expression, and the induction of KC and TNF. To further determine the direct role of a cytokine in regulating GJIC, recombinant TNF (rTNF) was used to inhibit GJIC and this response was further enhanced in the presence of the PAH mixture. Collectively, these findings support a role for inflammation in regulating GJIC and the potential to target these early stage cancer pathways for therapeutics. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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10 pages, 1418 KiB  
Article
Connecting Exosomes and Connexins
by Joanna Gemel, John Kilkus, Glyn Dawson and Eric C. Beyer
Cancers 2019, 11(4), 476; https://doi.org/10.3390/cancers11040476 - 04 Apr 2019
Cited by 20 | Viewed by 3982
Abstract
Intercellular communication is accomplished by passage of ions and small molecules through gap junction channels in directly contacting cells or by secretion and response to transmitters, hormones and extracellular vesicles in cells that are distant from each other. Recent studies have suggested that [...] Read more.
Intercellular communication is accomplished by passage of ions and small molecules through gap junction channels in directly contacting cells or by secretion and response to transmitters, hormones and extracellular vesicles in cells that are distant from each other. Recent studies have suggested that there may be overlap of these processes; specifically, small extracellular vesicles may contain subunit gap junction proteins, connexins. We isolated and analyzed extracellular vesicles secreted by cultured microvascular endothelial cells. These vesicles had a diameter of ~120 nm. They contained four exosomal proteins (flotillin-1, CD63, CD81 and Alix) and the gap junction protein, connexin43. They did not contain an endoplasmic reticulum protein (Grp94) or an adherens junction protein (VE-cadherin). Secretion of vesicles was increased by treatment of the cells with staurosporine. Our data confirm that the gap junction protein, connexin43, can be secreted in vesicles with the properties of exosomes. Although the role of vesicular connexin is not clearly known, we speculate that it might participate in docking/fusion of the exosomes with the recipient cell, transmission of vesicular contents, or cellular signaling. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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18 pages, 4411 KiB  
Article
Cx43 Expression Correlates with Breast Cancer Metastasis in MDA-MB-231 Cells In Vitro, In a Mouse Xenograft Model and in Human Breast Cancer Tissues
by Jalal M. Kazan, Jamal El-Saghir, Jessica Saliba, Abdullah Shaito, Nour Jalaleddine, Layal El-Hajjar, Sara Al-Ghadban, Lamis Yehia, Kazem Zibara and Marwan El-Sabban
Cancers 2019, 11(4), 460; https://doi.org/10.3390/cancers11040460 - 01 Apr 2019
Cited by 30 | Viewed by 7007
Abstract
Connexins regulate multiple cellular functions and are considered tumor suppressors. Connexin43 (Cx43) is frequently down-regulated in breast tumors. However, Cx43 regulation during cancer onset and metastasis is complex and context-dependent. We investigated the effect of Cx43 over-expression or knock-down on the metastatic potential [...] Read more.
Connexins regulate multiple cellular functions and are considered tumor suppressors. Connexin43 (Cx43) is frequently down-regulated in breast tumors. However, Cx43 regulation during cancer onset and metastasis is complex and context-dependent. We investigated the effect of Cx43 over-expression or knock-down on the metastatic potential of MDA-MB-231 breast cancer cells in vitro and in vivo and in human breast cancer tissues. MDA-MB-231 cells over-expressing (Cx43D) or down-regulating Cx43 (shCx43) were generated and used in proliferation, migration, and invasion assays. The regulation of genes/proteins implicated in progression, invasion and metastasis was assessed in vitro and in immune-compromized mice injected with MDA-MB-231, Cx43D or shCx43 cells. Primary tumor onset/growth, metastasis and overall survival of these animals was monitored and evaluated. In addition, Cx43 expression in human breast carcinoma samples was assessed by qPCR. Cx43 over-expression increased protein levels of epithelial markers E-cadherin and zonula occludens 1 expression and resulted in the sequestration of β-catenin at the cell membrane, while Cx43 knock-down induced protein expression of the mesenchymal marker N-cadherin and an increased invasive potential of shCx43 cells. In vivo, in mice xenografted with breast cancer cells, Cx43 over-expression decreased tumor volume, attenuated cell metastasis to lungs and liver and increased overall mice survival. Importantly, the expression of Cx43 in triple negative human breast cancer tissues is also down-regulated. Collectively, Cx43 over-expression induced an epithelial-like phenotype in MDA-MB-231 cells and suppressed tumor growth and metastasis to secondary organs in vivo. In contrast, Cx43 knock-down in MDA-MB-231 cells induced a mesenchymal phenotype with increased cell invasion leading to an enhanced metastatic phenotype. These data provide evidence for a pivotal role of Cx43 in breast cancer metastasis and support the potential targeting of connexins in breast cancer therapy. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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19 pages, 14074 KiB  
Article
Pannexin 2 Localizes at ER-Mitochondria Contact Sites
by Maxence Le Vasseur, Vincent C. Chen, Kate Huang, Wayne A. Vogl and Christian C. Naus
Cancers 2019, 11(3), 343; https://doi.org/10.3390/cancers11030343 - 11 Mar 2019
Cited by 17 | Viewed by 5613
Abstract
Endomembrane specialization allows functional compartmentalization but imposes physical constraints to information flow within the cell. However, the evolution of an endomembrane system was associated with the emergence of contact sites facilitating communication between membrane-bound organelles. Contact sites between the endoplasmic reticulum (ER) and [...] Read more.
Endomembrane specialization allows functional compartmentalization but imposes physical constraints to information flow within the cell. However, the evolution of an endomembrane system was associated with the emergence of contact sites facilitating communication between membrane-bound organelles. Contact sites between the endoplasmic reticulum (ER) and mitochondria are highly conserved in terms of their morphological features but show surprising molecular diversity within and across eukaryote species. ER-mitochondria contact sites are thought to regulate key processes in oncogenesis but their molecular composition remains poorly characterized in mammalian cells. In this study, we investigate the localization of pannexin 2 (Panx2), a membrane channel protein showing tumor-suppressing properties in cancer cells. Using a combination of subcellular fractionation, particle tracking in live-cell, and immunogold electron microscopy, we show that Panx2 localizes at ER-mitochondria contact sites in mammalian cells and sensitizes cells to apoptotic stimuli. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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28 pages, 3579 KiB  
Article
Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling
by Sabreen Fostok, Mirvat El-Sibai, Dana Bazzoun, Sophie Lelièvre and Rabih Talhouk
Cancers 2019, 11(3), 339; https://doi.org/10.3390/cancers11030339 - 08 Mar 2019
Cited by 19 | Viewed by 4138
Abstract
(1) Background: The expression of connexin 43 (Cx43) is disrupted in breast cancer, and re-expression of this protein in human breast cancer cell lines leads to decreased proliferation and invasiveness, suggesting a tumor suppressive role. This study aims to investigate the role of [...] Read more.
(1) Background: The expression of connexin 43 (Cx43) is disrupted in breast cancer, and re-expression of this protein in human breast cancer cell lines leads to decreased proliferation and invasiveness, suggesting a tumor suppressive role. This study aims to investigate the role of Cx43 in proliferation and invasion starting from non-neoplastic breast epithelium. (2) Methods: Nontumorigenic human mammary epithelial HMT-3522 S1 cells and Cx43 shRNA-transfected counterparts were cultured under 2-dimensional (2-D) and 3-D conditions. (3) Results: Silencing Cx43 induced mislocalization of β-catenin and Scrib from apicolateral membrane domains in glandular structures or acini formed in 3-D culture, suggesting the loss of apical polarity. Cell cycle entry and proliferation were enhanced, concomitantly with c-Myc and cyclin D1 upregulation, while no detectable activation of Wnt/β-catenin signaling was observed. Motility and invasion were also triggered and were associated with altered acinar morphology and activation of ERK1/2 and Rho GTPase signaling, which acts downstream of the noncanonical Wnt pathway. The invasion of Cx43-shRNA S1 cells was observed only under permissive stiffness of the extracellular matrix (ECM). (4) Conclusion: Our results suggest that Cx43 controls proliferation and invasion in the normal mammary epithelium in part by regulating noncanonical Wnt signaling. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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20 pages, 5714 KiB  
Article
Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis
by Trond Aasen, Irene Sansano, Maria Ángeles Montero, Cleofé Romagosa, Jordi Temprana-Salvador, Alexandre Martínez-Marti, Teresa Moliné, Javier Hernández-Losa and Santiago Ramón y Cajal
Cancers 2019, 11(3), 320; https://doi.org/10.3390/cancers11030320 - 06 Mar 2019
Cited by 22 | Viewed by 5411
Abstract
Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and [...] Read more.
Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p = 0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0.002) but not in the squamous carcinoma subtype (p = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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17 pages, 6608 KiB  
Article
Spatial Arrangements of Connexin43 in Cancer Related Cells and Re-Arrangements under Treatment Conditions: Investigations on the Nano-Scale by Super-Resolution Localization Light Microscopy
by Götz Pilarczyk, Franziska Papenfuß, Felix Bestvater and Michael Hausmann
Cancers 2019, 11(3), 301; https://doi.org/10.3390/cancers11030301 - 04 Mar 2019
Cited by 5 | Viewed by 3435
Abstract
Cancer studies suggest that the spatial localization of connexin43 (Cx43) could play an important role during tumor genesis and the formation of metastasis. Cx43 has been shown to be upregulated in cancer cells; thereby a shift from Cx43 normal localization in gap junctions [...] Read more.
Cancer studies suggest that the spatial localization of connexin43 (Cx43) could play an important role during tumor genesis and the formation of metastasis. Cx43 has been shown to be upregulated in cancer cells; thereby a shift from Cx43 normal localization in gap junctions in the cell membrane towards a primarily cytoplasmic localization was observed in many studies. So far neither the spatial arrangements of Cx43 in breast cancer cells nor the effects of treatment outcome (ionizing radiation and antibody therapy) on the spatial arrangements of Cx43, have been microscopically studied on the nanoscale. This has brought up the idea to study the micro- and nanoscaled spatial Cx43 arrangements in a model of breast cancer-related cell types, i.e., SkBr3 breast cancer cells, BJ fibroblasts, and primary human internal mammary artery endothelial cells (HIMAECs). The cells were treated with neuregulin1 (NRG1), trastuzumab (Herceptin), or 6MeV-photon irradiation at a dose of 4 Gy. NRG1 stimulates further NRG1 release in the tumor endothelium that may lead to an enhanced tumor protective effect whereas Herceptin, used in antibody treatment, works in an antagonistic fashion to NRG1. After fluorescent labelling with specific antibodies, the molecular positions of Cx43 in the perinuclear cytosol and in the cell periphery at the membrane were determined for the three treatment related applications (NRG1, trastuzumab, 4 Gy irradiation) using confocal laser scanning microscopy (CLSM) and single molecule localization microscopy (SMLM). These techniques enable investigations of Cx43 enrichment and topological arrangements of Cx43 molecules from the micro-scale of a whole cell to the nano-scale of single molecules. In SkBr3 cells with and without radiation treatment high density accumulations were detected which seem to be diluted after NRG1 and trastuzumab treatment although the SMLM distance frequency distributions did not significantly vary. In BJ fibroblasts and HIMAECs differences between periphery and perinuclear cytosol were observed after the different treatment processes. HIMAECs showed significant Cx43 accumulation after NRG1, trastuzumab, and radiation treatment in the perinuclear region whereas in the periphery radiation has less influence as compared to the control. BJ cells were reacting to the treatments by Cx43 accumulations in the perinuclear region but also in the periphery. In conclusion, it was shown that by using CLSM and super-resolution SMLM, treatment effects on the spatial and thus functional arrangements of Cx43 became detectable for investigations of tumor response mechanisms. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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Graphical abstract

21 pages, 3441 KiB  
Article
Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival
by Nicole L. Jacobsen, Tasha K. Pontifex, Paul R. Langlais and Janis M. Burt
Cancers 2019, 11(2), 188; https://doi.org/10.3390/cancers11020188 - 06 Feb 2019
Cited by 9 | Viewed by 2580
Abstract
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined [...] Read more.
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined use of deletion and site specific (de)phospho-mimetic Cx37-CT mutants, our data suggest a phosphorylation-dependent interaction between the mid-tail (aa 273–317) and end-tail (aa 318–333) portions of the Cx37-CT that regulates cell survival. As detected by mass spectrometry, Cx37 was phosphorylated at serines 275, 321, and 328; phosphomimetic mutations of these sites resulted in cell death when expressed in rat insulinoma cells. Alanine substitution at S328, but not at S275 or S321, also triggered cell death. Cx37-S275D uniquely induced the death of only low density, non-contact forming cells, but neither hemichannel open probability nor channel conductance distinguished death-inducing mutants. As channel function is necessary for cell death, together the data suggest that the phosphorylation state of the Cx37-CT controls an intra-domain interaction within the CT that modifies channel function and induces cell death. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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17 pages, 3825 KiB  
Article
Connexin43 Suppresses Lung Cancer Stem Cells
by Randall J. Ruch
Cancers 2019, 11(2), 175; https://doi.org/10.3390/cancers11020175 - 02 Feb 2019
Cited by 18 | Viewed by 3630
Abstract
Alterations in gap junctions and their protein components, connexins, have been associated with neoplastic transformation and drug resistance, and more recently have been shown to play important roles in cancer stem cells (CSCs). However, there is less knowledge of connexins and gap junctions [...] Read more.
Alterations in gap junctions and their protein components, connexins, have been associated with neoplastic transformation and drug resistance, and more recently have been shown to play important roles in cancer stem cells (CSCs). However, there is less knowledge of connexins and gap junctions in lung CSCs. To address this, Connexin43 (Cx43), the major human lung epithelial gap junction protein, was expressed ectopically in poorly expressing National Cancer Institute-125 (NCI-H125) metastatic human lung adenocarcinoma cells, and phenotypic characteristics of malignant cells and abundance of CSCs were evaluated. The ectopic expression of Cx43 resulted in the formation of functional gap junctions; a more epithelial morphology; reduced proliferation, invasion, colony formation, tumorsphere formation, pluripotency marker expression, and percentage of aldehyde dehydrogenase (ALDH)-positive cells; and increased cisplatin sensitivity. Similarly, in NCI-H522 (human lung adenocarcinoma) and NCI-H661 (human lung large cell carcinoma) cell lines, which express Cx43 and functional gap junctions endogenously, the Cx43 content was lower in tumorspheres and ALDH-positive cells than in bulk cells. These results demonstrate that Cx43 can reverse several neoplastic characteristics and reduce the abundance of human lung CSCs. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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21 pages, 8808 KiB  
Article
Exploring Differential Connexin Expression across Melanocytic Tumor Progression Involving the Tumor Microenvironment
by Gergo Kiszner, Peter Balla, Barna Wichmann, Gabor Barna, Kornelia Baghy, Istvan Balazs Nemeth, Erika Varga, Istvan Furi, Bela Toth and Tibor Krenacs
Cancers 2019, 11(2), 165; https://doi.org/10.3390/cancers11020165 - 01 Feb 2019
Cited by 10 | Viewed by 3319
Abstract
The incidence of malignant melanoma, one of the deadliest cancers, continues to increase. Here we tested connexin (Cx) expression in primary melanocytes, melanoma cell lines and in a common nevus, dysplastic nevus, and thin, thick, and metastatic melanoma tumor progression series involving the [...] Read more.
The incidence of malignant melanoma, one of the deadliest cancers, continues to increase. Here we tested connexin (Cx) expression in primary melanocytes, melanoma cell lines and in a common nevus, dysplastic nevus, and thin, thick, and metastatic melanoma tumor progression series involving the tumor microenvironment by utilizing in silico analysis, qRT-PCR, immunocyto-/histochemistry and dye transfer tests. Primary melanocytes expressed GJA1/Cx43, GJA3/Cx46 and low levels of GJB2/Cx26 and GJC3/Cx30.2 transcripts. In silico data revealed downregulation of GJA1/Cx43 and GJB2/Cx26 mRNA, in addition to upregulated GJB1/Cx32, during melanoma progression. In three melanoma cell lines, we also showed the loss of GJA1/Cx43 and the differential expression of GJB1/Cx32, GJB2/Cx26, GJA3/Cx46 and GJC3/Cx30.2. The dominantly paranuclear localization of connexin proteins explained the ~10–90 times less melanoma cell coupling compared to melanocytes. In melanocytic tumor tissues, we confirmed the loss of Cx43 protein, fall of cell membrane and elevated paranuclear Cx32 with moderately increased cytoplasmic Cx26 and paranuclear Cx30.2 positivity during tumor progression. Furthermore, we found Cx43, Cx26 and Cx30 proteins upregulated in the melanoma adjacent epidermis, and Cx43 in the tumor flanking vessels. Therefore, differential connexin expression is involved in melanocytic tumor progression where varying connexin isotypes and levels reflect tumor heterogeneity-related bidirectional adaptive interactions with the microenvironment. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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17 pages, 3129 KiB  
Article
Gap Junction Intercellular Communication Positively Regulates Cisplatin Toxicity by Inducing DNA Damage through Bystander Signaling
by Sanjeevani Arora, Joshua R. Heyza, Elaine C. Chalfin, Randall J. Ruch and Steve M. Patrick
Cancers 2018, 10(10), 368; https://doi.org/10.3390/cancers10100368 - 02 Oct 2018
Cited by 28 | Viewed by 4119
Abstract
The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and [...] Read more.
The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and ovarian cancer cell lines, we showed that cisplatin cytotoxicity is mediated by cellular density. This effect is ablated when GJA1 or Connexin 43 (Cx43) is targeted, a gap junction gene and protein, respectively, leading to cisplatin resistance but only at high or gap junction forming density. We also observed that the cisplatin-mediated bystander effect was elicited as DNA Double Strand Breaks (DSBs) with positive H2AX Ser139 phosphorylation (γH2AX) formation, an indicator of DNA DSBs. These DSBs are not observed when gap junction formation is prevented. We next showed that cisplatin is not the “death” signal traversing the gap junctions by utilizing the cisplatin-GG intrastrand adduct specific antibody. Finally, we also showed that cells deficient in the structure-specific DNA endonuclease ERCC1-ERCC4 (ERCC1-XPF), an important mediator of cisplatin resistance, further sensitized when treated with cisplatin in the presence of gap junction forming density. Taken together, these results demonstrate the positive effect of GJIC on increasing cisplatin cytotoxicity. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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17 pages, 2863 KiB  
Article
Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling
by Katarzyna Piwowarczyk, Edyta Kwiecień, Justyna Sośniak, Eliza Zimoląg, Emiliana Guzik, Jolanta Sroka, Zbigniew Madeja and Jarosław Czyż
Cancers 2018, 10(10), 363; https://doi.org/10.3390/cancers10100363 - 28 Sep 2018
Cited by 8 | Viewed by 3761
Abstract
Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect [...] Read more.
Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect of fenofibrate (FF) on their activity. A549 cells induced the disruption and local activation of endothelial continuum. These events were accompanied by epidermal growth factor (EGF) up-regulation in endothelial cells. Impaired A549 diapedesis and HUVEC activation were seen upon the chemical inhibition of connexin(Cx)43 functions, EGF/ERK1/2-dependent signaling, and RhoA/Rac1 activity. A total of 25 μM FF exerted corresponding effects on Cx43-mediated gap junctional coupling, EGF production, and ERK1/2 activation in HUVEC/A549 co-cultures. It also directly augmented endothelial barrier function via the interference with focal adhesion kinase (FAK)/RhoA/Rac1-regulated endothelial cell adhesion/contractility/motility and prompted the selective transmigration of epithelioid A549 cells. N-acetyl-L-cysteine abrogated FF effects on HUVEC activation, suggesting the involvement of PPARα-independent mechanism(s) in its action. Our data identify a novel Cx43/EGF/ERK1/2/FAK/RhoA/Rac1-dependent signaling axis, which determines the efficiency of lung cancer cell diapedesis. FF interferes with its activity and reduces the susceptibility of endothelial cells to A549 stimuli. These findings provide the rationale for the implementation of FF in the therapy of malignant lung cancers. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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Review

Jump to: Editorial, Research, Other

16 pages, 345 KiB  
Review
Direct Intercellular Communications and Cancer: A Snapshot of the Biological Roles of Connexins in Prostate Cancer
by Catalina Asencio-Barría, Norah Defamie, Juan C. Sáez, Marc Mesnil and Alejandro S. Godoy
Cancers 2019, 11(9), 1370; https://doi.org/10.3390/cancers11091370 - 14 Sep 2019
Cited by 17 | Viewed by 3632
Abstract
Tissue homeostasis is the result of a complex intercellular network controlling the behavior of every cell for the survival of the whole organism. In mammalian tissues, cells do communicate via diverse long- and short-range communication mechanisms. While long-range communication involves hormones through blood [...] Read more.
Tissue homeostasis is the result of a complex intercellular network controlling the behavior of every cell for the survival of the whole organism. In mammalian tissues, cells do communicate via diverse long- and short-range communication mechanisms. While long-range communication involves hormones through blood circulation and neural transmission, short-range communication mechanisms include either paracrine diffusible factors or direct interactions (e.g., gap junctions, intercellular bridges and tunneling nanotubes) or a mixture of both (e.g., exosomes). Tumor growth represents an alteration of tissue homeostasis and could be the consequence of intercellular network disruption. In this network, direct short-range intercellular communication seems to be particularly involved. The first type of these intercellular communications thought to be involved in cancer progression were gap junctions and their protein subunits, the connexins. From these studies came the general assumption that global decreased connexin expression is correlated to tumor progression and increased cell proliferation. However, this assumption appeared more complicated by the fact that connexins may act also as pro-tumorigenic. Then, the concept that direct intercellular communication could be involved in cancer has been expanded to include new forms of intercellular communication such as tunneling nanotubes (TNTs) and exosomes. TNTs are intercellular bridges that allow free exchange of small molecules or even mitochondria depending on the presence of gap junctions. The majority of current research shows that such exchanges promote cancer progression by increasing resistance to hypoxia and chemotherapy. If exosomes are also involved in these mechanisms, more studies are needed to understand their precise role. Prostate cancer (PCa) represents a type of malignancy with one of the highest incidence rates worldwide. The precise role of these types of direct short-range intercellular communication has been considered in the progression of PCa. However, even though data are in favor of connexins playing a key role in PCa progression, a clear understanding of the role of TNTs and exosomes is needed to define their precise role in this malignancy. This review article summarizes the current view of the main mechanisms involved in short-range intercellular communication and their implications in cancer and delves into the biological, predictive and therapeutic role of connexins in PCa. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
12 pages, 1846 KiB  
Review
Connexins and Gap Junctions in Cancer of the Urinary Tract
by Thomas Tschernig
Cancers 2019, 11(5), 704; https://doi.org/10.3390/cancers11050704 - 22 May 2019
Cited by 9 | Viewed by 2927
Abstract
This review focuses on connexins and nexus or gap junctions in the genesis, progression, and therapy of carcinomas of the human urinary tract. Some decades ago, the idea was born that gap junctional intercellular communication might prevent both the onset and the progression [...] Read more.
This review focuses on connexins and nexus or gap junctions in the genesis, progression, and therapy of carcinomas of the human urinary tract. Some decades ago, the idea was born that gap junctional intercellular communication might prevent both the onset and the progression of cancer. Later evidence indicated that, on the contrary, synthesis and the presence of connexins as a prerequisite for gap junctional intercellular communication might promote the occurrence of cancer and metastases. The research history of urinary bladder cancer is a good example of the development of scientific perception. So far, the role of gap junctional intercellular communication in carcinogenesis and cancer progression, as well as in therapeutical approaches, remains unclear. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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18 pages, 3180 KiB  
Review
Facets of Communication: Gap Junction Ultrastructure and Function in Cancer Stem Cells and Tumor Cells
by Anja Beckmann, Nadine Hainz, Thomas Tschernig and Carola Meier
Cancers 2019, 11(3), 288; https://doi.org/10.3390/cancers11030288 - 01 Mar 2019
Cited by 19 | Viewed by 5196
Abstract
Gap junction proteins are expressed in cancer stem cells and non-stem cancer cells of many tumors. As the morphology and assembly of gap junction channels are crucial for their function in intercellular communication, one focus of our review is to outline the data [...] Read more.
Gap junction proteins are expressed in cancer stem cells and non-stem cancer cells of many tumors. As the morphology and assembly of gap junction channels are crucial for their function in intercellular communication, one focus of our review is to outline the data on gap junction plaque morphology available for cancer cells. Electron microscopic studies and freeze-fracture analyses on gap junction ultrastructure in cancer are summarized. As the presence of gap junctions is relevant in solid tumors, we exemplarily outline their role in glioblastomas and in breast cancer. These were also shown to contain cancer stem cells, which are an essential cause of tumor onset and of tumor transmission into metastases. For these processes, gap junctional communication was shown to be important and thus we summarize, how the expression of gap junction proteins and the resulting communication between cancer stem cells and their surrounding cells contributes to the dissemination of cancer stem cells via blood or lymphatic vessels. Based on their importance for tumors and metastases, future cancer-specific therapies are expected to address gap junction proteins. In turn, gap junctions also seem to contribute to the unattainability of cancer stem cells by certain treatments and might thus contribute to therapeutic resistance. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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16 pages, 1202 KiB  
Review
The Functional Implications of Endothelial Gap Junctions and Cellular Mechanics in Vascular Angiogenesis
by Takayuki Okamoto, Haruki Usuda, Tetsuya Tanaka, Koichiro Wada and Motomu Shimaoka
Cancers 2019, 11(2), 237; https://doi.org/10.3390/cancers11020237 - 18 Feb 2019
Cited by 34 | Viewed by 7064
Abstract
Angiogenesis—the sprouting and growth of new blood vessels from the existing vasculature—is an important contributor to tumor development, since it facilitates the supply of oxygen and nutrients to cancer cells. Endothelial cells are critically affected during the angiogenic process as their proliferation, motility, [...] Read more.
Angiogenesis—the sprouting and growth of new blood vessels from the existing vasculature—is an important contributor to tumor development, since it facilitates the supply of oxygen and nutrients to cancer cells. Endothelial cells are critically affected during the angiogenic process as their proliferation, motility, and morphology are modulated by pro-angiogenic and environmental factors associated with tumor tissues and cancer cells. Recent in vivo and in vitro studies have revealed that the gap junctions of endothelial cells also participate in the promotion of angiogenesis. Pro-angiogenic factors modulate gap junction function and connexin expression in endothelial cells, whereas endothelial connexins are involved in angiogenic tube formation and in the cell migration of endothelial cells. Several mechanisms, including gap junction function-dependent or -independent pathways, have been proposed. In particular, connexins might have the potential to regulate cell mechanics such as cell morphology, cell migration, and cellular stiffness that are dynamically changed during the angiogenic processes. Here, we review the implication for endothelial gap junctions and cellular mechanics in vascular angiogenesis. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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16 pages, 2440 KiB  
Review
PI3k and Stat3: Oncogenes that are Required for Gap Junctional, Intercellular Communication
by Mulu Geletu, Zaid Taha, Patrick T. Gunning and Leda Raptis
Cancers 2019, 11(2), 167; https://doi.org/10.3390/cancers11020167 - 01 Feb 2019
Cited by 2 | Viewed by 2977
Abstract
Gap junctional, intercellular communication (GJIC) is interrupted in cells transformed by oncogenes such as activated Src. The Src effector, Ras, is required for this effect, so that Ras inhibition restores GJIC in Src-transformed cells. Interestingly, the inhibition of the Src effector phosphatidyl-inositol-3 kinase [...] Read more.
Gap junctional, intercellular communication (GJIC) is interrupted in cells transformed by oncogenes such as activated Src. The Src effector, Ras, is required for this effect, so that Ras inhibition restores GJIC in Src-transformed cells. Interestingly, the inhibition of the Src effector phosphatidyl-inositol-3 kinase (PI3k) or Signal Transducer and Activator of Transcription-3 (Stat3) pathways does not restore GJIC. In the contrary, inhibition of PI3k or Stat3 in non-transformed rodent fibroblasts or epithelial cells or certain human lung carcinoma lines with extensive GJIC inhibits communication, while mutational activation of PI3k or Stat3 increases GJIC. Therefore, it appears that oncogenes such as activated Src have a dual role upon GJIC; acting as inhibitors of communication through the Ras pathway, and as activators through activation of PI3k or Stat3. In the presence of high Src activity the inhibitory functions prevail so that the net effect is gap junction closure. PI3k and Stat3 constitute potent survival signals, so that their inhibition in non-transformed cells triggers apoptosis which, in turn, has been independently demonstrated to suppress GJIC. The interruption of gap junctional communication would confine the apoptotic event to single cells and this might be essential for the maintenance of tissue integrity. We hypothesize that the GJIC activation by PI3k or Stat3 may be linked to their survival function. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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15 pages, 1387 KiB  
Review
Connexins and Integrins in Exosomes
by Motomu Shimaoka, Eiji Kawamoto, Arong Gaowa, Takayuki Okamoto and Eun Jeong Park
Cancers 2019, 11(1), 106; https://doi.org/10.3390/cancers11010106 - 17 Jan 2019
Cited by 58 | Viewed by 6765
Abstract
Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and [...] Read more.
Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and functional coupling via signaling cascades. This connexin-integrin cross-talk exemplifies a biologically important collaboration between channels and adhesion receptors in cells. Exosomes are biological lipid-bilayer nanoparticles secreted from virtually all cells via endosomal pathways into the extracellular space, thereby mediating intercellular communications across a broad range of health and diseases, including cancer progression and metastasis, infection and inflammation, and metabolic deregulation. Connexins and integrins are embedded in the exosomal membranes and have emerged as critical regulators of intercellular communication. This concise review article will explain and discuss recent progress in better understanding the roles of connexins, integrins, and their cross-talk in cells and exosomes. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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Other

14 pages, 2385 KiB  
Perspective
A Barter Economy in Tumors: Exchanging Metabolites through Gap Junctions
by Pawel Swietach and Stefania Monterisi
Cancers 2019, 11(1), 117; https://doi.org/10.3390/cancers11010117 - 20 Jan 2019
Cited by 8 | Viewed by 3863
Abstract
To produce physiological functions, many tissues require their cells to be connected by gap junctions. Such diffusive coupling is important in establishing a cytoplasmic syncytium through which cells can exchange signals, substrates and metabolites. Often the benefits of connectivity become apparent solely at [...] Read more.
To produce physiological functions, many tissues require their cells to be connected by gap junctions. Such diffusive coupling is important in establishing a cytoplasmic syncytium through which cells can exchange signals, substrates and metabolites. Often the benefits of connectivity become apparent solely at the multicellular level, leading to the notion that cells work for a common good rather than exclusively in their self-interest. In some tumors, gap junctional connectivity between cancer cells is reduced or absent, but there are notable cases where it persists or re-emerges in late-stage disease. Diffusive coupling will blur certain phenotypic differences between cells, which may seem to go against the establishment of population heterogeneity, a central pillar of cancer that stems from genetic instability. Here, building on our previous measurements of gap junctional coupling between cancer cells, we use a computational model to simulate the role of connexin-assembled channels in exchanging lactate and bicarbonate ions down their diffusion gradients. Based on the results of these simulations, we propose that an overriding benefit of gap junctional connectivity may relate to lactate/bicarbonate exchange, which would support an elevated metabolic rate in hypoxic tumors. In this example of barter, hypoxic cancer cells provide normoxic neighbors with lactate for mitochondrial oxidation; in exchange, bicarbonate ions, which are more plentiful in normoxic cells, are supplied to hypoxic neighbors to neutralize the H+ ions co-produced glycolytically. Both cells benefit, and so does the tumor. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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17 pages, 847 KiB  
Concept Paper
Cancer Prevention and Therapy of Two Types of Gap Junctional Intercellular Communication–Deficient “Cancer Stem Cell”
by James E. Trosko
Cancers 2019, 11(1), 87; https://doi.org/10.3390/cancers11010087 - 14 Jan 2019
Cited by 15 | Viewed by 3448
Abstract
Early observations showed a lack of growth control and terminal differentiation with a lack of gap junctional intercellular communication (GJIC). Subsequent observations showed that epigenetic tumor promoters and activated oncogenes, which block gap junction function, provide insights into the multi-stage, multi-mechanism carcinogenic process. [...] Read more.
Early observations showed a lack of growth control and terminal differentiation with a lack of gap junctional intercellular communication (GJIC). Subsequent observations showed that epigenetic tumor promoters and activated oncogenes, which block gap junction function, provide insights into the multi-stage, multi-mechanism carcinogenic process. With the isolation of embryonic induced pluri-potent stem cells and organ-specific adult stem cells, gap junctions were linked to early development. While tumors and tumor cell lines are a heterogeneous mixture of “cancer stem cells” and “cancer non-stem cells”, the cancer stem cells seem to be of two types, namely, they express (a) no connexin genes or (b) connexin genes, but do not have functional GJIC. These observations suggest that these “cancer stem cells” originate from normal adult stem cells or from the de-differentiation or re-programming of somatic differentiated cells. This “Concept Paper” provides a hypothesis that “cancer stem cells” either originate from (a) organ-specific adult stem cells before the expression of the connexin genes or (b) organ-specific adult stem cells that just express gap junction genes but that the connexin proteins are rendered dysfunctional by activated oncogenes. Therefore, cancer prevention and therapeutic strategies must account for these two different types of “cancer stem cell”. Full article
(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)
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