Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture

IntroductionMetastasis involves the emigration of tumor cells through the vascular endothelium, a process also known as diapedesis. The molecular mechanisms regulating tumor cell diapedesis are poorly understood, but may involve heterocellular gap junctional intercellular communication (GJIC) between tumor cells and endothelial cells.MethodTo test this hypothesis we expressed connexin 43 (Cx43) in GJIC-deficient mammary epithelial tumor cells (HBL100) and examined their ability to form gap junctions, establish heterocellular GJIC and migrate through monolayers of human microvascular endothelial cells (HMVEC) grown on matrigel-coated coverslips.ResultsHBL100 cells expressing Cx43 formed functional heterocellular gap junctions with HMVEC monolayers within 30 minutes. In addition, immunocytochemistry revealed Cx43 localized to contact sites between Cx43 expressing tumor cells and endothelial cells. Quantitative analysis of diapedesis revealed a two-fold increase in diapedesis of Cx43 expressing cells compared to empty vector control cells. The expression of a functionally inactive Cx43 chimeric protein in HBL100 cells failed to increase migration efficiency, suggesting that the observed up-regulation of diapedesis in Cx43 expressing cells required heterocellular GJIC. This finding is further supported by the observation that blocking homocellular and heterocellular GJIC with carbenoxolone in co-cultures also reduced diapedesis of Cx43 expressing HBL100 tumor cells.ConclusionCollectively, our results suggest that heterocellular GJIC between breast tumor cells and endothelial cells may be an important regulatory step during metastasis.

• Publication year

  2005

• Venue

  Breast Cancer Research

• Publication date

  2005-05-13

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/bcr1042PMID 15987459PMCID 1175070
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2004cited by this paper
• Connexin 26 induces growth suppression, apoptosis and increased efficacy of doxorubicin in prostate cancer cells.

  2004cited by this paper
• Endothelial cell intracellular Ca concentration is increased upon breast tumor cell contact and mediates tumor cell transendothelial migration

  2004cited by this paper
• Serum levels of leptin and proinflammatory cytokines in patients with gastrointestinal cancer

  2004cited by this paper
• A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them

  2004cited by this paper
• Tumour-cell invasion and migration: diversity and escape mechanisms

  2003cited by this paper
• Gating and regulation of connexin 43 (Cx43) hemichannels

  2003cited by this paper
• Adhesion and migration of extracellular matrix-stimulated breast cancer.

  2003cited by this paper
• Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer.

  2003cited by this paper
• Tracing the Steps of Metastasis, Cancer's Menacing Ballet

  2003cited by this paper
• Autocrine Regulation of Myocyte Cx43 Expression by VEGF

  2002cited by this paper
• Structural and Functional Diversity of Connexin Genes in the Mouse and Human Genome

  2002cited by this paper
• Connexin 43 Enhances the Adhesivity and Mediates the Invasion of Malignant Glioma Cells

  2002cited by this paper
• Retroviral Delivery of Connexin Genes to Human Breast Tumor Cells Inhibits in Vivo Tumor Growth by a Mechanism That Is Independent of Significant Gap Junctional Intercellular Communication*

  2002cited by this paper
• Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions

  2001cited by this paper
• Breast cancer metastatic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication.

  2001cited by this paper
• Comparative analysis and application of fluorescent protein‐tagged connexins

  2001influential reference
• Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells.

  2001cited by this paper
• RhoA is required for monocyte tail retraction during transendothelial migration

  2001cited by this paper
• The Role of Connexin-Mediated Cell–Cell Communication in Breast Cancer Metastasis

  2001cited by this paper
• Differential regulation of transendothelial migration of THP‐1 cells by ICAM‐1/LFA‐1 and VCAM‐1/VLA‐4

  2001cited by this paper
• Leukocyte transendothelial migration: orchestrating the underlying molecular machinery.

  2001cited by this paper
• Multiple connexin expression in regenerating arterial endothelial gap junctions.

  2000cited by this paper
• A role for heterologous gap junctions between melanoma and endothelial cells in metastasis.

  2000influential reference
• Exogenous Expression of N-Cadherin in Breast Cancer Cells Induces Cell Migration, Invasion, and Metastasis

  2000cited by this paper
• Receptor-dependent activation of store-operated calcium entry increases endothelial cell permeability.

  2000cited by this paper
• Interleukin‐1β Increases the Functional Expression of Connexin 43 in Articular Chondrocytes: Evidence for a Ca2+‐Dependent Mechanism

  2000cited by this paper
• Molecular basis of spatio-temporal dynamics in inositol 1,4,5-trisphosphate-mediated Ca2+ signalling.

  2000cited by this paper
• Deficiency of connexin43 gap junctions is an independent marker for breast tumors.

  1999cited by this paper
• Genetic diseases and gene knockouts reveal diverse connexin functions.

  1999cited by this paper
• Suppression of human prostate cancer cell growth by forced expression of connexin genes.

  1999cited by this paper
• N-Cadherin Promotes Motility in Human Breast Cancer Cells Regardless of Their E-Cadherin Expression

  1999cited by this paper
• Connexin transfection induces invasive properties in HeLa cells.

  1998cited by this paper
• Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours

  1998cited by this paper
• Frequent reduction of gap junctional intercellular communication and connexin43 expression in human and mouse lung carcinoma cells.

  1998cited by this paper
• Mechanisms of tumour metastasis.

  1998cited by this paper
• Cell shape changes and cytoskeleton reorganization during transendothelial migration of human melanoma cells

  1998influential reference
• Fibronectin-mediated cell migration promotes glioma cell invasion through chemokinetic activity

  1997cited by this paper
• Gap junctions in human umbilical cord endothelial cells contain multiple connexins.

  1997cited by this paper
• Mechanisms of metastasis.

  1997cited by this paper
• Changes in the distribution of LFA-1, catenins, and F-actin during transendothelial migration of monocytes in culture.

  1997influential reference
• Role of cadherins in the transendothelial migration of melanoma cells in culture.

  1997influential reference
• Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well.

  1996cited by this paper
• Connections with connexins: the molecular basis of direct intercellular signaling.

  1996cited by this paper
• Porcine aortic endothelial gap junctions: identification and permeation by caged InsP3.

  1996cited by this paper
• Integrin expression in breast cancer cytology: a novel predictor of axillary metastasis.

  1996cited by this paper
• Gap junction distribution and connexin expression in human breast.

  1996cited by this paper
• Regulation of endothelial cell gap formation and paracellular permeability.

  1995cited by this paper
• Specific permeability and selective formation of gap junction channels in connexin-transfected HeLa cells

  1995cited by this paper
• Connexin 43 and connexin 40 gap junctional proteins are present in arteriolar smooth muscle and endothelium in vivo.

  1995cited by this paper
• Fate of melanoma cells entering the microcirculation: over 80% survive and extravasate.

  1995cited by this paper
• A pre-loading method of evaluating gap junctional communication by fluorescent dye transfer.

  1995cited by this paper
• Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome.

  1995cited by this paper
• Intercellular communication and carcinogenesis.

  1995cited by this paper
• Aberrant expression of gap junction proteins (connexins) is associated with tumor progression during multistage mouse skin carcinogenesis in vivo.

  1995cited by this paper
• IP3-activated Ca2+ channels in the plasma membrane of cultured vascular endothelial cells.

  1995cited by this paper
• Adhesion-mediated gap junctional communication between lung-metastatatic cancer cells and endothelium.

  1994cited by this paper
• Adhesion-mediated gap junctional communication between lung-metastatatic cancer cells and endothelium.

  1994influential reference
• Cadherins in cancer: implications for invasion and metastasis.

  1993cited by this paper
• Gap-junction protein gene suppresses tumorigenicity.

  1993cited by this paper
• Rapid analysis of leukocyte-endothelial adhesion.

  1993cited by this paper
• Decreased E-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors.

  1993cited by this paper
• Connexin40, a component of gap junctions in vascular endothelium, is restricted in its ability to interact with other connexins.

  1993cited by this paper
• Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene

  1993cited by this paper
• Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer.

  1992cited by this paper
• Early steps in hematogenous metastasis of B16F1 melanoma cells in chick embryos studied by high-resolution intravital videomicroscopy.

  1992cited by this paper
• Coupling and connexin 43 expression in microvascular and large vessel endothelial cells.

  1992cited by this paper
• The diversity of connexin genes encoding gap junctional proteins.

  1991cited by this paper
• Expression of gap junction genes in astrocytes and C6 glioma cells.

  1991cited by this paper
• Cytoplasmic dye transfer between metastatic tumor cells and vascular endothelium

  1991influential reference
• A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells.

  1986cited by this paper
• Interactions of tumor cells with vascular endothelial cell monolayers: a model for metastatic invasion.

  1979influential reference
• Mechanisms of metastasis.

  1979cited by this paper

• GJA1-20k, a Short Isoform of Connexin43, from Its Discovery to Its Potential Implication in Cancer Progression

  2025cites this paper
• Endothelial activation during the diapedesis of cancer cells: between the kiss of death and therapeutic breakthrough

  2025influential citation
• The Role of the Bone Marrow Microenvironment in Leukemic Stem Cell Resistance: Pathways of Persistence and Selection.

  2025cites this paper
• Cell-cell junctional proteins in cancer.

  2025cites this paper
• Insights into the role of connexins and specialized intercellular communication pathways in breast cancer: Mechanisms and applications.

  2024cites this paper
• Diversity of Intercellular Communication Modes: A Cancer Biology Perspective

  2024cites this paper
• Inhibitory Effects of Alpha-Connexin Carboxyl-Terminal Peptide on Canine Mammary Epithelial Cells: A Study on Benign and Malignant Phenotypes

  2024cites this paper
• Single-Cell Fluidic Force Spectroscopy Reveals Dynamic Mechanical Fingerprints of Malignancy in Breast Cancer

  2024cites this paper
• Targeting Breast Cancer Stem Cells

  2023cites this paper
• Targeting endothelial permeability in the EPR effect.

  2023cites this paper
• Transcriptional Reprogramming Differentiates Active from Inactive ESR1 Fusions in Endocrine Therapy-Refractory Metastatic Breast Cancer

  2021cites this paper
• Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption

  2021cites this paper
• SARS-CoV-2 Structural Proteins Exposure Alter Thrombotic and Inflammatory Responses in Human Endothelial Cells

  2021cites this paper
• Implication of Connexin 43 as a Tumor Suppressor in Pathogenesis of Breast Cancer

  2021cites this paper
• Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

  2020cites this paper
• Ouabain Promotes Gap Junctional Intercellular Communication in Cancer Cells

  2020cites this paper
• Connexins in Cancer: Jekyll or Hyde?

  2020cites this paper
• Deciphering the Role of the Coagulation Cascade and Autophagy in Cancer-Related Thrombosis and Metastasis

  2020cites this paper
• A Barter Economy in Tumors: Exchanging Metabolites through Gap Junctions

  2019cites this paper
• Differential Regulation of Cx43 Expression and Gap Junction Formation by Progesterone Receptor A and B in Breast Cancer Cells

  2019cites this paper
• Betacellulin enhances ovarian cancer cell migration by up-regulating Connexin43 via MEK-ERK signaling.

  2019cites this paper
• Gap Junction Intercellular Communication in the Carcinogenesis Hallmarks: Is This a Phenomenon or Epiphenomenon?

  2019cites this paper
• Inhibition of Gap Junctions Sensitizes Primary Glioblastoma Cells for Temozolomide

  2019cites this paper
• Passing the Vascular Barrier: Endothelial Signaling Processes Controlling Extravasation.

  2019cites this paper
• Pattern of cell‐to‐cell transfer of microRNA by gap junction and its effect on the proliferation of glioma cells

  2019cites this paper
• Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling

  2019cites this paper
• Connexins in cancer: bridging the gap to the clinic

  2019cites this paper
• Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics

  2018cites this paper
• Cancer Connectors: Connexins, Gap Junctions, and Communication

  2018cites this paper
• The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer

  2018cites this paper
• Connexins, important players in the dissemination of prostate cancer cells.

  2018cites this paper
• In vitro inhibited effect of gap junction composed of Cx43 in the invasion and metastasis of testicular cancer resistanced to cisplatin.

  2018cites this paper
• Connexin43high prostate cancer cells induce endothelial connexin43 up-regulation through the activation of intercellular ERK1/2-dependent signaling axis.

  2017cites this paper
• Mind the Gaps in Tumor Immunity: Impact of Connexin-Mediated Intercellular Connections

  2017cites this paper
• Dysregulated connexin 43 in HER2-positive drug resistant breast cancer cells enhances proliferation and migration

  2017cites this paper
• Invasive Cx43high sub-line of human prostate DU145 cells displays increased nanomechanical deformability.

  2017cites this paper
• Collateral Damage Intended—Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy

  2017cites this paper
• Connexin-dependent intercellular stress signaling in tissue homeostasis and tumor development.

  2017cites this paper
• Analysis of gap junctional intercellular communications using a dielectrophoresis-based microchip.

  2017cites this paper
• Enhanced DNA double-strand break repair of microbeam targeted A549 lung carcinoma cells by adjacent WI38 normal lung fibroblast cells via bi-directional signaling.

  2017cites this paper
• Cell–Cell Contacts in Melanoma and the Tumor Microenvironment

  2017cites this paper
• Connexin 43 in the development and progression of breast cancer: What's the connection? (Review)

  2017influential citation
• Regulation of connexins by the ubiquitin system: Implications for intercellular communication and cancer.

  2016cites this paper
• Tumour-Endothelial Cell Communications: Important and Indispensable Mediators of Tumour Angiogenesis.

  2016cites this paper
• Connexin and pannexin channels in cancer

  2016cites this paper
• Cell coupling mediated by connexin 26 selectively contributes to reduced adhesivity and increased migration

  2016cites this paper
• Gap junctions and cancer: communicating for 50 years

  2016cites this paper
• Connexin 43, breast cancer tumor suppressor: Missed connections?

  2016influential citation
• CONNEXIN 26 GAP JUNCTION COUPLING SELECTIVELY CONTRIBUTES TO REDUCED ADHESIVITY AND INCREASED CELL MIGRATION

  2016cites this paper
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  2016cites this paper
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  2016cites this paper
• Gap Junction Coupling Is Required for Tumor Cell Migration Through Lymphatic Endothelium

  2015cites this paper
• Étude de l'implication de la Connexine 43 dans le processus d'invasion des glioblastomes humains

  2015cites this paper
• Beyond the Channel: Role of Connexins in Regulating Normal and Cancerous Processes in the Mammary Gland

  2015cites this paper
• Connexins in colorectal cancer pathogenesis

  2015cites this paper
• Intercellular Communication, the Tumor Microenvironment, and Tumor Progression

  2015cites this paper
• Connexins in migration during development and cancer.

  2015cites this paper
• Fenofibrate enhances barrier function of endothelial continuum within the metastatic niche of prostate cancer cells

  2015cites this paper
• Connexin 43 expression predicts poor progression-free survival in patients with non-muscle invasive urothelial bladder cancer

  2015cites this paper
• Targeting connexin 43 with α–connexin carboxyl-terminal (ACT1) peptide enhances the activity of the targeted inhibitors, tamoxifen and lapatinib, in breast cancer: clinical implication for ACT1

  2015cites this paper
• Correlations of Differentially Expressed Gap Junction Connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with Breast Cancer Progression and Prognosis

  2014influential citation
• Metastasis as a therapeutic target in prostate cancer: a conceptual framework.

  2014cites this paper
• Functional links between Snail-1 and Cx43 account for the recruitment of Cx43-positive cells into the invasive front of prostate cancer.

  2014cites this paper
• Connexin43 Reduces Melanoma Growth within a Keratinocyte Microenvironment and during Tumorigenesis in Vivo*

  2013cites this paper
• Gap Junctions and Connexins in the Immune Defense Against Tumors

  2013cites this paper
• Melanoma's connections to the tumour microenvironment.

  2013cites this paper
• Aberrant Expression of Cx43 Is Associated with the Peritoneal Metastasis of Gastric Cancer and Cx43-Mediated Gap Junction Enhances Gastric Cancer Cell Diapedesis from Peritoneal Mesothelium

  2013cites this paper
• Functional heterogeneity of non‐small lung adenocarcinoma cell sub‐populations

  2012cites this paper
• Driving transcriptional regulators in melanoma metastasis

  2012cites this paper
• The role of connexins in prostate cancer promotion and progression

  2012cites this paper
• Connexin43 Expression Increases in the Epithelium and Stroma along the Colonic Neoplastic Progression Pathway: Implications for Its Oncogenic Role

  2011cites this paper
• Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment.

  2011cites this paper
• Expression of connexin 43 and E-cadherin in choroidal melanoma.

  2011cites this paper
• Involvement of epithelial-mesenchymal transition in adenoid cystic carcinoma metastasis.

  2011cites this paper
• Influence de la connexine 43 sur le phénotype des cellules cancéreuses prostatiques et sur le développement de métastases osseuses

  2011cites this paper
• The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells

  2011cites this paper
• microRNAs, Gap Junctional Intercellular Communication and Mesenchymal Stem Cells in Breast Cancer Metastasis.

  2011cites this paper
• Expression and significance of Cx43 and E-cadherin in gastric cancer and metastatic lymph nodes

  2011cites this paper
• The Emerging Role of the Thrombin Receptor (PAR-1) in Melanoma Metastasis - a Possible Therapeutic Target

  2011cites this paper
• Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations.

  2011cites this paper
• Cell-cell and cell-matrix contacts in melanoma and the tumor microenvironment

  2011cites this paper
• Connexin43 Modulates Cell Polarity and Directional Cell Migration by Regulating Microtubule Dynamics

  2011cites this paper
• Connexins: a junctional crossroad to breast cancer.

  2011cites this paper
• DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

  2011cites this paper
• Implications and challenges of connexin connections to cancer

  2010cites this paper
• Clinical significance of vascular endothelial growth factor and connexin43 for predicting pancreatic cancer clinicopathologic parameters

  2010cites this paper
• Cell line misidentification: the beginning of the end

  2010cites this paper
• Establishing the Tumor Microenvironment

  2010cites this paper
• Functional microRNA is transferred between glioma cells.

  2010cites this paper
• Commentaryjunctions remain dynamic

  2010cites this paper
• Adherens junctions remain dynamic

  2010cites this paper
• Determinants of leader cells in collective cell migration.

  2010cites this paper
• Cancer esearch or and Stem Cell Biology R ctional MicroRNA Is Transferred between Glioma Cells

  2010cites this paper
• Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old

  2010influential citation
• The role of gap junctions in cellular migration

  2009influential citation
• Connexins and Carcinogenesis

  2009cites this paper
• An In Vitro Model System For Cardiac Cell Therapy

  2009cites this paper
• THE ACTIONS OF CARBENOXOLONE ON GLYCOGEN CATABOLISM AND OXYGEN CONSUMPTION IN LIVERS OF FED RATS

  2009cites this paper
• Gap Junctions and Cancer: New Functions for an Old Story

  2009influential citation
• Reciprocal influence of connexins and apical junction proteins on their expressions and functions.

  2009cites this paper