PL EN


Preferences help
enabled [disable] Abstract
Number of results
2017 | 64 | 3 | 377-389
Article title

Connexin-dependent intercellular stress signaling in tissue homeostasis and tumor development

Content
Title variants
Languages of publication
EN
Abstracts
EN
Cellular stress responses determine tissue development, homeostasis and pathogenesis. Paracrine signaling, exchange of mechanical stimuli and intercellular transfer of small metabolites via connexin-built gap junctional channels are involved in the cellular stress detection and propagation of stress stimuli in multicellular networks. Cellular stress responses are also regulated through the activity of unpaired connexons (hemichannels) and via the intracellular interference of connexins with the cell cycle and pro-apoptotic machinery. Therefore, connexins are considered as multidirectional transmitters of the "outside-in" and "inside-out" stress signaling that are crucial for tissue homeostasis, regeneration and pathology. In particular, the disturbance of connexin function during the multi-stage process of tumor development leads to abnormal reactions of tumor cells to stress stimuli. In this review, we outline the current knowledge on the multidirectional role of connexins in the detection of stress signals. We also discuss the role of connexin-mediated intercellular transmittance of stress signals in tumour promotion, progression and metastatic cascade. Highlights: 1. Connexins and gap junctions protect cells from the microenvironmental stress and are involved in propagation and intracellular processing of stress signals. 2. The quality and quantity of stress stimuli, which may lead to cell adaptation or death by apoptosis, is determined by intrinsic properties of connexins and the cell phenotype. 3. Connexin deficiency increases the resistance of tumor cells to the "outside-in" stress signaling. 4. The connexin-mediated "inside-out" stress signaling participates in tumor cell invasion during the metastatic cascade.
Year
Volume
64
Issue
3
Pages
377-389
Physical description
Dates
published
2017
received
2017-03-18
revised
2017-04-19
accepted
2017-04-19
(unknown)
2017-05-17
References
  • Aasen T (2015) Connexins: junctional and non-junctional modulators of proliferation. Cell Tissue Res 360: 685-699. doi: 10.1007/s00441-014-2078-3.
  • Abercrombie M (1970) Contact inhibition in tissue culture. In Vitro 6: 128-142. doi: 10.1007/BF02616114.
  • Ai XL, Chi Q, Qiu Y, Li HY, Li DJ, Wang JX, Wang ZY (2017) Gap junction protein connexin43 deregulation contributes to bladder carcinogenesis via targeting MAPK pathway. Mol Cell Biochem 428: 109-118. doi: 10.1103/PhysRevLett.118.112001.
  • Andrysik Z, Prochazkova J, Kabatkova M, Umannova L, Simeckova P, Kohoutek J, Kozubik A, Machala M, Vondracek J (2013) Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication. Arch Toxicol 87: 491-503. doi: 10.1007/s00204-012-0963-7.
  • Artesi M, Kroonen J, Bredel M, Nguyen-Khac M, Deprez M, Schoysman L, Poulet C, Chakravarti A, Kim H, Scholtens D, Seute T, Rogister B, Bours V, Robe PA (2015) Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy. Neuro Oncol 17: 392-406. doi: 10.1093/neuonc/nou215.
  • Asamoto M, Hokaiwado N, Murasaki T, Shirai T (2004) Connexin 32 dominant-negative mutant transgenic rats are resistant to hepatic damage by chemicals. Hepatology 40: 205-210. doi: 10.1002/hep.20256.
  • Baines CP (2010) The cardiac mitochondrion: nexus of stress. Annu Rev Physiol 72: 61-80. doi: 10.1146/annurev-physiol-021909-135929.
  • Balla P, Maros ME, Barna G, Antal I, Papp G, Sapi Z, Athanasou NA, Benassi MS, Picci P, Krenacs T (2015) Prognostic impact of reduced connexin43 expression and gap junction coupling of neoplastic stromal cells in giant cell tumor of bone. PLoS One 10: e0125316. doi: 10.1371/journal.pone.0125316.
  • Banerjee D, Gakhar G, Madgwick D, Hurt A, Takemoto D, Nguyen TA (2010) A novel role of gap junction connexin46 protein to protect breast tumors from hypoxia. Int J Cancer 127: 839-848. doi: 10.1002/ijc.25107.
  • Bechyne I, Szpak K, Madeja Z, Czyz J (2011) Functional heterogeneity of non-small lung adenocarcinoma cell sub-populations. Cell Biol Int 36: 99-103. doi: 10.1042/CBI20110151.
  • Benko G, Spajić B, Demirović A, Stimac G, Kru Sbreve Lin B, Tomas D (2011) Prognostic value of connexin43 expression in patients with clinically localized prostate cancer. Prostate Cancer Prostatic Dis 14: 90-95. doi: 10.1038/pcan.2010.51.
  • Berthoud VM, Beyer EC (2009) Oxidative stress, lens gap junctions, and cataracts. Antioxid Redox Signal 11: 339-353. doi: 10.1089/ars.2008.2119.
  • Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP (2007) Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis 24: 587-597. doi: 10.1007/s10585-007-9114-6.
  • Boiko AD, Razorenova OV, van de RM, Swetter SM, Johnson DL, Ly DP, Butler PD, Yang GP, Joshua B, Kaplan MJ, Longaker MT, Weissman IL (2010) Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466: 133-137. doi: 10.3324/haematol.2009.015065.
  • Brabletz T (2012) EMT and MET in metastasis: where are the cancer stem cells? Cancer Cell 22: 699-701. doi: 10.1016/j.ccr.2012.11.009.
  • Brauner T, Hulser DF (1990) Tumor cell invasion and gap junctional communication. II. Normal and malignant cells confronted in multicell spheroids. Invasion metastasis 10: 31-48.
  • Brauner T, Schmid A, Hulser DF (1990) Tumor cell invasion and gap junctional communication. I. Normal and malignant cells confronted in monolayer cultures. Invasion Metastasis 10: 18-30.
  • Burt JM, Nelson TK, Simon AM, Fang JS (2008) Connexin 37 profoundly slows cell cycle progression in rat insulinoma cells. Am J Physiol Cell Physiol 295: C1103-C1112. doi: 10.1152/ajpcell.299.2008.
  • Carette D, Gilleron J, Chevallier D, Segretain D, Pointis G (2014) Connexin a check-point component of cell apoptosis in normal and physiopathological conditions. Biochimie 101: 1-9. doi: 10.1016/j.biochi.2013.11.015.
  • Caruso RL, Upham BL, Harris C, Trosko JE (2005) Biphasic lindane-induced oxidation of glutathione and inhibition of gap junctions in myometrial cells. Toxicol Sci 86: 417-426. doi: 10.1093/toxsci/kfi208.
  • Castor LN (1970) Flattening, movement and control of division of epithelial-like cells. J Cell Physiol 75: 57-64. doi: 10.1002/jcp.1040750107.
  • Chang WW, Lai CH, Chen MC, Liu CF, Kuan YD, Lin ST, Lee CH (2013) Salmonella enhance chemosensitivity in tumor through connexin 43 upregulation. Int J Cancer 133: 1926-1935. doi: 10.18632/oncotarget.6258.
  • Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A (2011) Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases. Cancer Microenviron 5: 19-28. doi: 10.1007/s12307-011-0085-4.
  • Chipman JK, Mally A, Edwards GO (2003) Disruption of gap junctions in toxicity and carcinogenicity. Toxicol Sci 71: 146-153. doi: 10.1093/toxsci/71.2.146.
  • Choudhary M, Naczki C, Chen W, Barlow KD, Case LD, Metheny-Barlow LJ (2015) Tumor-induced loss of mural Connexin 43 gap junction activity promotes endothelial proliferation. BMC Cancer 15: 427. doi: 10.1186/s12885-015-1420-9.
  • Chovatiya R, Medzhitov R (2014) Stress, inflammation, and defense of homeostasis. Mol Cell 54: 281-288. doi: 10.1016/j.molcel.2014.03.030.
  • Contreras JE, Sanchez HA, Veliz LP, Bukauskas FF, Bennett MV, Saez JC (2004) Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Res Brain Res Rev 47: 290-303. doi: 10.1016/j.brainresrev.2004.08.002.
  • Cotrina ML, Lin JH, Nedergaard M (2008) Adhesive properties of connexin hemichannels. Glia 56: 1791-1798. doi: 10.1002/glia.20728.
  • Cronier L, Crespin S, Strale PO, Defamie N, Mesnil M (2009) Gap junctions and cancer: new functions for an old story. Antioxid Redox Signal 11: 323-338. doi: 10.1089/ars.2008.2153.
  • Czyz J, Madeja Z, Irmer U, Korohoda W, Hulser DF (2005) Flavonoid apigenin inhibits motility and invasiveness of carcinoma cells in vitro. Int J Cancer 114: 12-18. doi: 10.1002/ijc.20620.
  • Czyz J (2008) The stage-specific function of gap junctions during tumourigenesis. Cell Mol Biol Lett 13: 92-102. doi: 10.2478/s11658-007-0039-5.
  • Czyz J, Szpak K, Madeja Z (2012) The role of connexins in prostate cancer promotion and progression. Nat Rev Urol 9: 274-282. doi: 10.1038/nrurol.2012.14.
  • Dbouk HA, Mroue RM, El-Sabban ME, Talhouk RS (2009) Connexins: a myriad of functions extending beyond assembly of gap junction channels. Cell Commun Signal 7: 4. doi: 10.1186/1478-811X-7-4.
  • De Vuyst E, Decrock E, Cabooter L, Dubyak GR, Naus CC, Evans WH, Leybaert L (2006) Intracellular calcium changes trigger connexin 32 hemichannel opening. EMBO J 25: 34-44. doi: 10.1038/sj.emboj.7600908.
  • Decrock E, Vinken M, Bol M, D'Herde K, Rogiers V, Vandenabeele P, Krysko DV, Bultynck G, Leybaert L (2011) Calcium and connexin-based intercellular communication, a deadly catch? Cell Calcium 50: 310-321. doi: 10.1016/j.ceca.2011.05.007.
  • Defamie N, Chepied A, Mesnil M (2014) Connexins, gap junctions and tissue invasion. FEBS Lett 588: 1331-1338. doi: 10.1016/j.febslet.2014.01.012.
  • Doble BW, Dang X, Ping P, Fandrich RR, Nickel BE, Jin Y, Cattini PA, Kardami E (2004) Phosphorylation of serine 262 in the gap junction protein connexin-43 regulates DNA synthesis in cell-cell contact forming cardiomyocytes. J Cell Sci 117: 507-514. doi: 10.1242/jcs.00889.
  • Ek-Vitorin JF, Burt JM (2013) Structural basis for the selective permeability of channels made of communicating junction proteins. Biochim Biophys Acta 1828: 51-68. doi: 10.1016/j.bbamem.2012.02.003.
  • El-Sabban ME, Pauli BU (1991) Cytoplasmic dye transfer between metastatic tumor cells and vascular endothelium. J Cell Biol 115: 1375-1382. doi: 10.1083/jcb.115.5.1375.
  • El-Sabban ME, Pauli BU (1994) Adhesion-mediated gap junctional communication between lung-metastatic cancer cells and endothelium. Invasion Metastasis 14: 164-176.
  • El-Saghir JA, El-Habre ET, El-Sabban ME, Talhouk RS (2011) Connexins: a junctional crossroad to breast cancer. Int J Dev Biol 55: 773-780. doi: 10.1387/ijdb.113372je.
  • Elias LA, Wang DD, Kriegstein AR (2007) Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448: 901-907. doi: 10.1038/nature06063.
  • Elzarrad MK, Haroon A, Willecke K, Dobrowolski R, Gillespie MN, Al-Mehdi AB (2008) Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium. BMC Med 6: 20. doi: 10.1186/1741-7015-6-20.
  • Evans WH, De Vuyst E, Leybaert L (2006) The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem J 397: 1-14. doi: 10.1042/BJ20060175.
  • Foss B, Tronstad KJ, Bruserud O (2010) Connexin-based signaling in acute myelogenous leukemia (AML). Biochim Biophys Acta 1798: 1-8. doi: 10.1016/j.bbamem.2009.10.014.
  • Fredebohm J, Boettcher M, Eisen C, Gaida MM, Heller A, Keleg S, Tost J, Greulich-Bode KM, Hotz-Wagenblatt A, Lathrop M, Giese NA, Hoheisel JD (2012) Establishment and characterization of a highly tumorigenic and cancer stem cell enriched pancreatic cancer cell line as a well defined model system. PLoS One 7: e48503. doi: 10.1371/journal.pone.0048503.
  • Friedl P, Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147: 992-1009. doi: 10.1016/j.cell.2011.11.016.
  • Fujimoto E, Sato H, Negishi E, Ueno K, Nagashima Y, Hagiwara K, Yamasaki H, Yano T (2004) Negative growth control of renal cell carcinoma cell by connexin 32: possible involvement of Her-2. Mol Carcinog 40: 135-142. doi: 10.1002/mc.20025.
  • Fulda S, Gorman AM, Hori O, Samali A (2010) Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010: 214074. doi: 10.1155/2010/214074.
  • Garcia-Rodriguez L, Perez-Torras S, Carrio M, Cascante A, Garcia-Ribas I, Mazo A, Fillat C (2011) Connexin-26 is a key factor mediating gemcitabine bystander effect. Mol Cancer Ther 10: 505-517. doi: 10.1158/1535-7163.MCT-10-0693.
  • Gielen PR, Aftab Q, Ma N, Chen VC, Hong X, Lozinsky S, Naus CC, Sin WC (2013) Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology 75: 539-548. doi: 10.1016/j.neuropharm.2013.05.002.
  • Goldberg GS, Bechberger JF, Tajima Y, Merritt M, Omori Y, Gawinowicz MA, Narayanan R, Tan Y, Sanai Y, Yamasaki H, Naus CC, Tsuda H, Nicholson BJ (2000) Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. Cancer Res 60: 6018-6026.
  • Grek CL, Rhett JM, Bruce JS, Ghatnekar GS, Yeh ES (2016) Connexin 43, breast cancer tumor suppressor: Missed connections? Cancer Lett 374: 117-126. doi: 10.1016/j.canlet.2016.02.008.
  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646-674. doi: 10.1016/j.cell.2011.02.013.
  • Hattori Y, Fukushima M, Maitani Y (2007) Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. Int J Oncol 30: 1427-1439. doi: 10.3892/ijo.30.6.1427.
  • Hattori Y, Maitani Y (2005) Folate-linked nanoparticle-mediated suicide gene therapy in human prostate cancer and nasopharyngeal cancer with herpes simplex virus thymidine kinase. Cancer Gene Ther 12: 796-809. doi: 10.1038/sj.cgt.7700844.
  • Heckman CA (2009) Contact inhibition revisited. J Cell Physiol 220: 574-575. doi: 10.1002/jcp.21775.
  • Hirschi KK, Xu CE, Tsukamoto T, Sager R (1996) Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential. Cell Growth Differ 7: 861-870.
  • Hokaiwado N, Asamoto M, Futakuchi M, Ogawa K, Takahashi S, Shirai T (2007) Both early and late stages of hepatocarcinogenesis are enhanced in Cx32 dominant negative mutant transgenic rats with disrupted gap junctional intercellular communication. J Membr Biol 218: 101-106. doi: 10.1007/s00232-007-9053-9.
  • Huang RP, Hossain MZ, Huang R, Gano J, Fan Y, Boynton AL (2001) Connexin 43 (cx43) enhances chemotherapy-induced apoptosis in human glioblastoma cells. Int J Cancer 92: 130-138. doi: 10.1002/1097-0215(200102)9999:9999<::AID-IJC1165>3.0.CO;2-G.
  • Hutnik CM, Pocrnich CE, Liu H, Laird DW, Shao Q (2008) The protective effect of functional connexin43 channels on a human epithelial cell line exposed to oxidative stress. Invest Ophthalmol Vis Sci 49: 800-806. doi: 10.1167/iovs.07-0717.
  • Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T (2012) Role of connexin-43 in protective PI3K-Akt-GSK-3beta signaling in cardiomyocytes. Am J Physiol Heart Circ Physiol 302: H2536-H2544. doi: 10.1152/ajpheart.00940.2011.
  • Ito A, Katoh F, Kataoka TR, Okada M, Tsubota N, Asada H, Yoshikawa K, Maeda S, Kitamura Y, Yamasaki H, Nojima H (2000) A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J Clin Invest 105: 1189-1197. doi: 10.1172/JCI8257.
  • Iyyathurai J, Decuypere JP, Leybaert L, D'hondt C, Bultynck G (2016) Connexins: substrates and regulators of autophagy. BMC Cell Biol 17 (Suppl 1): 20. doi: 10.1186/s12860-016-0093-9.
  • Jensen K, Patel A, Klubo-Gwiezdzinska J, Bauer A, Vasko V (2011) Inhibition of gap junction transfer sensitizes thyroid cancer cells to anoikis. Endocr Relat Cancer 18: 613-626. doi: 10.1530/ERC-10-0289.
  • Jeyaraman MM, Srisakuldee W, Nickel BE, Kardami E (2012) Connexin43 phosphorylation and cytoprotection in the heart. Biochim Biophys Acta 1818: 2009-2013. doi: 10.1016/j.bbamem.2011.06.023.
  • Jin Z, Xu S, Yu H, Yang B, Zhao H, Zhao G (2013) miR-125b inhibits Connexin43 and promotes glioma growth. Cell Mol Neurobiol 33: 1143-1148. doi: 10.1007/s10571-013-9980-1.
  • Jing Y, Guo S, Zhang X, Sun A, Tao F, Ju H, Qian H (2014) Effects of small interfering RNA interference of connexin 37 on subcutaneous gastric tumours in mice. Mol Med Rep 10: 2955-2960. doi: 10.3892/mmr.2014.2609.
  • Johnson LN, Koval M (2009) Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication. Antioxid Redox Signal 11: 355-367. doi: 10.1089/ars.2008.2183.
  • Kanczuga-Koda L, Sulkowska M, Koda M, Rutkowski R, Sulkowski S (2007) Increased expression of gap junction protein - connexin 32 in lymph node metastases of human ductal breast cancer. Folia Histochem Cytobiol 45 (Suppl 1): S175–S180.
  • Kanczuga-Koda L, Sulkowski S, Lenczewski A, Koda M, Wincewicz A, Baltaziak M, Sulkowska M (2006) Increased expression of connexins 26 and 43 in lymph node metastases of breast cancer. J Clin Pathol 59: 429-433. doi: 10.1136/jcp.2005.029272.
  • Kandouz M, Batist G (2010) Gap junctions and connexins as therapeutic targets in cancer. Expert Opin Ther Targets 14: 681-692. doi: 10.1517/14728222.2010.487866.
  • Kar R, Riquelme MA, Werner S, Jiang JX (2013) Connexin 43 channels protect osteocytes against oxidative stress-induced cell death. J Bone Miner Res 28: 1611-1621. doi: 10.1002/jbmr.1917.
  • Kardami E, Dang X, Iacobas DA, Nickel BE, Jeyaraman M, Srisakuldee W, Makazan J, Tanguy S, Spray DC (2007) The role of connexins in controlling cell growth and gene expression. Prog Biophys Mol Biol 94: 245-264. doi: 10.1016/j.pbiomolbio.2007.03.009.
  • Kim JS, Lee WM, Rhee HC, Kim S (2016) Red paprika (Capsicum annuum L.) and its main carotenoids, capsanthin and beta-carotene, prevent hydrogen peroxide-induced inhibition of gap-junction intercellular communication. Chem Biol Interact 254: 146-155. doi: 10.1016/j.cbi.2016.05.004.
  • Knabb MT, Danielsen CA, McShane-Kay K, Mbuy GK, Woodruff RI (2007) Herpes simplex virus-type 2 infectivity and agents that block gap junctional intercellular communication. Virus Res 124: 212-219. doi: 10.1016/j.virusres.2006.11.006.
  • Koffler L, Roshong S, Kyu PI, Cesen-Cummings K, Thompson DC, Dwyer-Nield LD, Rice P, Mamay C, Malkinson AM, Ruch RJ (2000) Growth inhibition in G(1) and altered expression of cyclin D1 and p27(kip-1 )after forced connexin expression in lung and liver carcinoma cells. J Cell Biochem 79: 347-354. doi: 10.1002/1097-4644(20001201)79:3<347::AID-JCB10>3.0.CO;2-2.
  • Koumenis C, Hammond E, Giaccia A (2014) Tumor Microenvironment and Cellular Stress: Signaling, Metabolism, Imaging, and Therapeutic Targets. Springer Science & Business Media Press, New York. ISBN 978-1-4614-5915-6.
  • Krutovskikh VA, Piccoli C, Yamasaki H (2002) Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene 21: 1989-1999. doi: 10.1038/sj/onc/1205187.
  • Krysko DV, Leybaert L, Vandenabeele P, D'Herde K (2005) Gap junctions and the propagation of cell survival and cell death signals. Apoptosis 10: 459-469. doi: 10.1007/s10495-005-1875-2.
  • Kumar S, Weaver VM (2009) Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev 28: 113-127. doi: 10.1007/s10555-008-9173-4.
  • Laird DW (2006) Life cycle of connexins in health and disease. Biochem J 394: 527-543. doi: 10.1042/BJ20051922.
  • Lamiche C, Clarhaut J, Strale PO, Crespin S, Pedretti N, Bernard FX, Naus CC, Chen VC, Foster LJ, Defamie N, Mesnil M, Debiais F, Cronier L (2011) The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells. Clin Exp Metastasis 29: 111-122. doi: 10.1007/s10585-011-9434-4.
  • Lampe PD (1994) Analyzing phorbol ester effects on gap junctional communication: a dramatic inhibition of assembly. J Cell Biol 127: 1895-1905. doi: 10.1083/jcb.127.6.1895.
  • Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited - the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128: 2527–2535. doi: 10.1002/ijc.26031.
  • Langlois S, Cowan KN, Shao Q, Cowan BJ, Laird DW (2010) The tumor-suppressive function of Connexin43 in keratinocytes is mediated in part via interaction with caveolin-1. Cancer Res 70: 4222-4232. doi: 10.1158/0008-5472.CAN-09-3281.
  • Lee SW, Tomasetto C, Sager R (1991) Positive selection of candidate tumor-suppressor genes by subtractive hybridization. Proc Natl Acad Sci U S A 88: 2825-2829. doi: 10.1073/pnas.88.7.2825.
  • Leithe E, Sirnes S, Omori Y, Rivedal E (2006) Downregulation of gap junctions in cancer cells. Crit Rev Oncog 12: 225-256. doi: 10.1615/CritRevOncog.v12.i3-4.30.
  • Leithe E (2016) Regulation of connexins by the ubiquitin system: Implications for intercellular communication and cancer. Biochim Biophys Acta 1865: 133-146. doi: 10.1016/j.bbcan.2016.02.001.
  • Lewalle JM, Cataldo D, Bajou K, Lambert CA, Foidart JM (1998) Endothelial cell intracellular Ca2+ concentration is increased upon breast tumor cell contact and mediates tumor cell transendothelial migration. Clin Exp Metastasis 16: 21-29.
  • Li G, Gao K, Chi Y, Zhang X, Mitsui T, Yao J, Takeda M (2016) Upregulation of connexin43 contributes to PX-12-induced oxidative cell death. Tumour Biol 37: 7535-7546. doi: 10.1007/s13277-015-4620-7.
  • Li Q, Omori Y, Nishikawa Y, Yoshioka T, Yamamoto Y, Enomoto K (2007) Cytoplasmic accumulation of connexin32 protein enhances motility and metastatic ability of human hepatoma cells in vitro and in vivo. Int J Cancer 121: 536-546. doi: 10.1002/ijc.22696.
  • Li X, Xu YB, Wang Q, Lu Y, Zheng Y, Wang YC, Lubbert M, Zhao KW, Chen GQ (2006) Leukemogenic AML1-ETO fusion protein upregulates expression of connexin 43: the role in AML 1-ETO-induced growth arrest in leukemic cells. J Cell Physiol 208: 594-601. doi: 10.1002/jcp.20695.
  • Li X, Pan JH, Song B, Xiong EQ, Chen ZW, Zhou ZS, Su YP (2012) Suppression of CX43 expression by miR-20a in the progression of human prostate cancer. Cancer Biol Ther 13: 890-898. doi: 10.4161/cbt.20841.
  • Little JB (2006) Cellular radiation effects and the bystander response. Mutat Res 597: 113-118. doi: 10.1016/j.mrfmmm.2005.12.001.
  • Liu CL, Huang YS, Hosokawa M, Miyashita K, Hu ML (2009) Inhibition of proliferation of a hepatoma cell line by fucoxanthin in relation to cell cycle arrest and enhanced gap junctional intercellular communication. Chem Biol Interact 182: 165-172. doi: 10.1016/j.cbi.2009.08.017.
  • Loch-Caruso R, Galvez MM, Brant K, Chung D (2004) Cell and toxicant specific phosphorylation of conexin43: effects of lindane and TPA on rat myometrial and WB-F344 liver cell gap junctions. Cell Biol Toxicol 20: 147-169. doi: 10.1023/B:CBTO.0000029465.74815.62.
  • Loewenstein WR, Kanno Y (1966) Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature 209: 1248-1249. doi: 10.1038/2091248a0.
  • Loewenstein WR, Kanno Y (1967) Intercellular communication and tissue growth. I. Cancerous growth. J Cell Biol 33: 225-234.
  • Loewenstein WR (1979) Junctional intercellular communication and the control of growth. Biochim Biophys Acta 560: 1-65. doi: 10.1016/0304-419X(79)90002-7.
  • Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153: 1194-1217. doi: 10.1016/j.cell.2013.05.039.
  • Lu Z, Qi L, Li GX, Bo XJ, Liu GD, Wang JM (2015) Se-methylselenocysteine suppresses the growth of prostate cancer cell DU145 through connexin 43-induced apoptosis. J Cancer Res Ther 11: 840-845. doi: 10.4103/0973-1482.139265.
  • Maeda S, Tsukihara T (2011) Structure of the gap junction channel and its implications for its biological functions. Cell Mol Life Sci 68: 1115-1129. doi: 10.1007/s00018-010-0551-z.
  • Marusyk A, Polyak K (2013) Cancer. Cancer cell phenotypes, in fifty shades of grey. Science 339: 528-529. doi: 10.1126/science.1234415.
  • Meens MJ, Pfenniger A, Kwak BR, Delmar M (2013) Regulation of cardiovascular connexins by mechanical forces and junctions. Cardiovasc Res 99: 304-314. doi: 10.1093/cvr/cvt095.
  • Mehta PP, Perez-Stable C, Nadji M, Mian M, Asotra K, Roos BA (1999) Suppression of human prostate cancer cell growth by forced expression of connexin genes. Dev Genet 24: 91-110. doi: 10.1002/(SICI)1520-6408(1999)24:1/2<91::AID-DVG10>3.0.CO;2-#.
  • Mol AJ, Geldof AA, Meijer GA, van der Poel HG, van Moorselaar RJ (2007) New experimental markers for early detection of high-risk prostate cancer: role of cell-cell adhesion and cell migration. J Cancer Res Clin Oncol 133: 687-695. doi: 10.1007/s00432-007-0235-8.
  • Momiyama M, Omori Y, Ishizaki Y, Nishikawa Y, Tokairin T, Ogawa J, Enomoto K (2003) Connexin26-mediated gap junctional communication reverses the malignant phenotype of MCF-7 breast cancer cells. Cancer Sci 94: 501-507. doi: 10.1111/j.1349-7006.2003.tb01473.x.
  • Mroue RM, El-Sabban ME, Talhouk RS (2011) Connexins and the gap in context. Integr Biol (Camb) 3: 255-266. doi: 10.1039/C0IB00158A.
  • Naiki-Ito A, Asamoto M, Naiki T, Ogawa K, Takahashi S, Sato S, Shirai T (2010) Gap junction dysfunction reduces acetaminophen hepatotoxicity with impact on apoptotic signaling and connexin 43 protein induction in rat. Toxicol Pathol 38: 280-286. doi: 10.1177/0192623309357951.
  • Nakagawa S, Maeda S, Tsukihara T (2010) Structural and functional studies of gap junction channels. Curr Opin Struct Biol 20: 423-430. doi: 10.1016/j.sbi.2010.05.003.
  • Naoi Y, Miyoshi Y, Taguchi T, Kim SJ, Arai T, Tamaki Y, Noguchi S (2007) Connexin26 expression is associated with lymphatic vessel invasion and poor prognosis in human breast cancer. Breast Cancer Res Treat 106: 11-17. doi: 10.1007/s10549-006-9465-8.
  • Naus CC, Laird DW (2010) Implications and challenges of connexin connections to cancer. Nat Rev Cancer 10: 435-441. doi: 10.1038/nrc2841.
  • Nelson CM, Bissell MJ (2006) Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 22: 287-309. doi: 10.1146/annurev.cellbio.22.010305.104315.
  • Nielsen MS, Axelsen LN, Sorgen PL, Verma V, Delmar M, Holstein-Rathlou NH (2012) Gap junctions. Compr Physiol 2: 1981-2035. doi: 10.1002/cphy.c110051.
  • Omori Y, Li Q, Nishikawa Y, Yoshioka T, Yoshida M, Nishimura T, Enomoto K (2007) Pathological significance of intracytoplasmic connexin proteins: implication in tumor progression. J Membr Biol 218: 73-77. doi: 10.1007/s00232-007-9048-6.
  • Orellana JA, Sanchez HA, Schalper KA, Figueroa V, Saez JC (2012) Regulation of intercellular calcium signaling through calcium interactions with connexin-based channels. Adv Exp Med Biol 740: 777-794. doi: 10.1007/978-94-007-2888-2_34.
  • Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4: 552-565. doi: 10.1038/nrm1150.
  • Oshima A (2014) Structure and closure of connexin gap junction channels. FEBS Lett 588: 1230-1237. doi: 10.1016/j.febslet.2014.01.042.
  • Oviedo-Orta E, Evans WH (2002) Gap junctions and connexins: potential contributors to the immunological synapse. J Leukoc Biol 72: 636-642.
  • Piwowarczyk K, Paw M, Ryszawy D, Rutkowska-Zapała M, Madeja Z, Siedlar M, Czyz J (2017) Connexin43high prostate cancer cells induce endothelial connexin43 up-regulation through the activation of intercellular ERK1/2-dependent signaling axis. Eur J Cell Biol. doi: 10.1016/j.ejcb.2017.03.012.
  • Piwowarczyk K, Wybieralska E, Baran J, Borowczyk J, Rybak P, Kosinska M, Wlodarczyk AJ, Michalik M, Siedlar M, Madeja Z, Dobrucki J, Reiss K, Czyz J (2015) Fenofibrate enhances barrier function of endothelial continuum within the metastatic niche of prostate cancer cells. Expert Opin Ther Targets 19: 163-176. doi: 10.1517/14728222.2014.981153.
  • Plotkin LI, Stains JP (2015) Connexins and pannexins in the skeleton: gap junctions, hemichannels and more. Cell Mol Life Sci 72: 2853-2867. doi: 10.1007/s00018-015-1963-6.
  • Pogoda K, Kameritsch P, Retamal MA, Vega JL (2016) Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: a revision. BMC Cell Biol 17 (Suppl 1): 11. doi: 10.1186/s12860-016-0099-3.
  • Pollmann MA, Shao Q, Laird DW, Sandig M (2005) Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture. Breast Cancer Res 7: R522-R534. doi: 10.1186/bcr1042.
  • Puliafito A, Hufnagel L, Neveu P, Streichan S, Sigal A, Fygenson DK, Shraiman BI (2012) Collective and single cell behavior in epithelial contact inhibition. Proc Natl Acad Sci U S A 109: 739-744. doi: 10.1073/pnas.1007809109.
  • Qin H, Shao Q, Thomas T, Kalra J, Alaoui-Jamali MA, Laird DW (2003) Connexin26 regulates the expression of angiogenesis-related genes in human breast tumor cells by both GJIC-dependent and -independent mechanisms. Cell Commun Adhes 10: 387-393.
  • Quintanilla RA, Orellana JA, von Bernhardi R (2012) Understanding risk factors for Alzheimer's disease: interplay of neuroinflammation, connexin-based communication and oxidative stress. Arch Med Res 43: 632-644. doi: 10.1016/j.arcmed.2012.10.016.
  • Ramachandran S, Xie LH, John SA, Subramaniam S, Lal R (2007) A novel role for connexin hemichannel in oxidative stress and smoking-induced cell injury. PLoS One 2: e712. doi: 10.1371/journal.pone.0000712.
  • Ren P, Mehta PP, Ruch RJ (1998) Inhibition of gap junctional intercellular communication by tumor promoters in connexin43 and connexin32-expressing liver cells: cell specificity and role of protein kinase C. Carcinogenesis 19: 169-175. doi: doi: 10.1093/carcin/19.1.169.
  • Retamal MA, Reyes EP, Garcia IE, Pinto B, Martinez AD, Gonzalez C (2015) Diseases associated with leaky hemichannels. Front Cell Neurosci 9: 267. doi: 10.3389/fncel.2015.00267.
  • Rodriguez-Sinovas A, Cabestrero A, Lopez D, Torre I, Morente M, Abellan A, Miro E, Ruiz-Meana M, Garcia-Dorado D (2007) The modulatory effects of connexin 43 on cell death/survival beyond cell coupling. Prog Biophys Mol Biol 94: 219-232. doi: 10.1016/j.pbiomolbio.2007.03.003.
  • Ryszawy D, Sarna M, Rak M, Szpak K, Kedracka-Krok S, Michalik M, Siedlar M, Zuba-Surma E, Burda K, Korohoda W, Madeja Z, Czyz J (2014) Functional links between Snail-1 and Cx43 account for the recruitment of Cx43-positive cells into the invasive front of prostate cancer. Carcinogenesis 35: 1920-1930. doi: 10.1093/carcin/bgu033.
  • Saez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MV (2005) Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta 1711: 215-224. doi: 10.1016/j.bbamem.2005.01.014.
  • Saez JC, Schalper KA, Retamal MA, Orellana JA, Shoji KF, Bennett MV (2010) Cell membrane permeabilization via connexin hemichannels in living and dying cells. Exp Cell Res 316: 2377-2389. doi: 10.1016/j.yexcr.2010.05.026.
  • Samali A, Fulda S, Gorman AM, Hori O, Srinivasula SM (2010) Cell stress and cell death. Int J Cell Biol Article ID 245803. doi: 10.1155/2010/245803.
  • Sato H, Fukumoto K, Hada S, Hagiwara H, Fujimoto E, Negishi E, Ueno K, Yano T (2007a) Enhancing effect of connexin 32 gene on vinorelbine-induced cytotoxicity in A549 lung adenocarcinoma cells. Cancer Chemother Pharmacol 60: 449-457. doi: 10.1007/s00280-006-0406-3.
  • Sato H, Senba H, Virgona N, Fukumoto K, Ishida T, Hagiwara H, Negishi E, Ueno K, Yamasaki H, Yano T (2007b) Connexin 32 potentiates vinblastine-induced cytotoxicity in renal cell carcinoma cells. Mol Carcinog 46: 215-224. doi: 10.1002/mc.20267.
  • Sato H, Iwata H, Takano Y, Yamada R, Okuzawa H, Nagashima Y, Yamaura K, Ueno K, Yano T (2009) Enhanced effect of connexin 43 on cisplatin-induced cytotoxicity in mesothelioma cells. J Pharmacol Sci 110: 466-475. doi.org/10.1254/jphs.08327FP.
  • Savagner P (2010) The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol 21 (Suppl 7): vii89-vii92. doi: 10.1093/annonc/mdq292.
  • Schalper KA, Riquelme MA, Branes MC, Martinez AD, Vega JL, Berthoud VM, Bennett MV, Saez JC (2012) Modulation of gap junction channels and hemichannels by growth factors. Mol Biosyst 8: 685-698. doi: 10.1039/c1mb05294b.
  • Shibata M, Shen MM (2013) The roots of cancer: Stem cells and the basis for tumor heterogeneity. Bioessays 35: 253-260. doi: 10.1002/bies.201200101.
  • Shishido SN, Nguyen TA (2016) Induction of apoptosis by PQ1, a gap junction enhancer that upregulates connexin 43 and activates the MAPK signaling pathway in mammary carcinoma cells. Int J Mol Sci 17: E178. doi: 10.3390/ijms17020178.
  • Sin WC, Crespin S, Mesnil M (2012) Opposing roles of connexin43 in glioma progression. Biochim Biophys Acta 1818: 2058-2067. doi: 10.1016/j.bbamem.2011.10.022.
  • Sinyuk M, Alvarado AG, Nesmiyanov P, Shaw J, Mulkearns-Hubert EE, Eurich JT, Hale JS, Bogdanova A, Hitomi M, Maciejewski J, Huang AY, Saunthararajah Y, Lathia JD (2015) Cx25 contributes to leukemia cell communication and chemosensitivity. Oncotarget 6: 31508-31521. doi: 10.18632/oncotarget.5226.
  • Sirnes S, Lind GE, Bruun J, Fykerud TA, Mesnil M, Lothe RA, Rivedal E, Kolberg M, Leithe E (2015) Connexins in colorectal cancer pathogenesis. Int J Cancer 137: 1-11. doi: 10.1002/ijc.28911.
  • Sohl G, Willecke K (2004) Gap junctions and the connexin protein family. Cardiovasc Res 62: 228-232. doi: 10.1016/j.cardiores.2003.11.013.
  • Sovari AA (2016) Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress. Cardiol Res Pract Article ID 9656078. doi: 10.1155/2016/9656078.
  • Sroka J, Czyz J, Wojewoda M, Madeja Z (2008) The inhibitory effect of diphenyltin on gap junctional intercellular communication in HEK-293 cells is reduced by thioredoxin reductase 1. Toxicol Lett 183: 45-51. doi: 10.1016/j.toxlet.2008.09.012.
  • Stoletov K, Strnadel J, Zardouzian E, Momiyama M, Park FD, Kelber JA, Pizzo DP, Hoffman R, VandenBerg SR, Klemke RL (2013) Role of connexins in metastatic breast cancer and melanoma brain colonization. J Cell Sci 126: 904-913. doi: 10.1242/jcs.112748.
  • Su V, Lau AF (2014) Connexins: mechanisms regulating protein levels and intercellular communication. FEBS Lett 588: 1212-1220. doi: 10.1016/j.febslet.2014.01.013.
  • Su YA, Bittner ML, Chen Y, Tao L, Jiang Y, Zhang Y, Stephan DA, Trent JM (2000) Identification of tumor-suppressor genes using human melanoma cell lines UACC903, UACC903(+6), and SRS3 by comparison of expression profiles. Mol Carcinog 28: 119-127. doi: 10.1002/1098-2744(200006)28:2<119::AID-MC8>3.0.CO;2-N.
  • Sun P, Liu Y, Ying H, Li S (2012a) Action of db-cAMP on the bystander effect and chemosensitivity through connexin 43 and Bcl-2-mediated pathways in medulloblastoma cells. Oncol Rep 28: 969-976. doi: 10.3892/or.2012.1900.
  • Sun Y, Zhao X, Yao Y, Qi X, Yuan Y, Hu Y (2012b) Connexin 43 interacts with Bax to regulate apoptosis of pancreatic cancer through a gap junction-independent pathway. Int J Oncol 41: 941-948. doi: 10.3892/ijo.2012.1524.
  • Szpak K, Wybieralska E, Niedzialkowska E, Rak M, Bechyne I, Michalik M, Madeja Z, Czyz J (2011) DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of CX43. Cell Mol Biol Lett 16: 625. doi: 10.2478/s11658-011-0027-7.
  • Tanaka M, Grossman HB (2001) Connexin 26 gene therapy of human bladder cancer: induction of growth suppression, apoptosis, and synergy with Cisplatin. Hum Gene Ther 12: 2225-2236. doi: 10.1089/10430340152710568.
  • Tanaka M, Grossman HB (2004) Connexin 26 induces growth suppression, apoptosis and increased efficacy of doxorubicin in prostate cancer cells. Oncol Rep 11: 537-541. doi: 10.3892/or.11.2.537.
  • Tang B, Peng ZH, Yu PW, Yu G, Qian F, Zeng DZ, Zhao YL, Shi Y, Hao YX, Luo HX (2013) 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. PLoS One 8: e74527. doi: 10.1371/journal.pone.0074527.
  • Tate AW, Lung T, Radhakrishnan A, Lim SD, Lin X, Edlund M (2006) Changes in gap junctional connexin isoforms during prostate cancer progression. Prostate 66: 19-31. doi: 10.1002/pros.20317.
  • Teleki I, Szasz AM, Maros ME, Gyorffy B, Kulka J, Meggyeshazi N, Kiszner G, Balla P, Samu A, Krenacs T (2014) Correlations of differentially expressed gap junction connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with breast cancer progression and prognosis: PLoS One 9: e112541. doi: 10.1371/journal.pone.0112541.
  • Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139: 871-890. doi: 10.1016/j.cell.2009.11.007.
  • Tinkle CL, Pasolli HA, Stokes N, Fuchs E (2008) New insights into cadherin function in epidermal sheet formation and maintenance of tissue integrity. Proc Natl Acad Sci U S A 105: 15405-15410. doi: 10.1073/pnas.0807374105.
  • Tittarelli A, Guerrero I, Tempio F, Gleisner MA, Avalos I, Sabanegh S, Ortiz C, Michea L, Lopez MN, Mendoza-Naranjo A, Salazar-Onfray F (2015) Overexpression of connexin 43 reduces melanoma proliferative and metastatic capacity. Br J Cancer 113: 259-267. doi: 10.1038/bjc.2015.162.
  • Tsujino T, Nagata T, Katoh F, Yamasaki H (2007) Inhibition of Balb/c 3T3 cell transformation by synthetic acyclic retinoid NIK-333; possible involvement of enhanced gap junctional intercellular communication. Cancer Detect Prev 31: 332-338. doi: 10.1016/j.cdp.2007.06.001.
  • VanSlyke JK, Musil LS (2005) Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol Biol Cell 16: 5247-5257. doi: 10.1091/mbc.E05-05-0415.
  • Vanslyke JK, Naus CC, Musil LS (2009) Conformational maturation and post-ER multisubunit assembly of gap junction proteins. Mol Biol Cell 20: 2451-2463. doi: 10.1091/mbc.E09-01-0062.
  • Vinken M, Decrock E, De Vuyst E, Ponsaerts R, D'hondt C, Bultynck G, Ceelen L, Vanhaecke T, Leybaert L, Rogiers V (2011) Connexins: sensors and regulators of cell cycling. Biochim Biophys Acta 1815: 13-25. doi: 10.1016/j.bbcan.2010.08.004.
  • Vinken M, Decrock E, Leybaert L, Bultynck G, Himpens B, Vanhaecke T, Rogiers V (2012) Non-channel functions of connexins in cell growth and cell death. Biochim Biophys Acta 1818: 2002-2008. doi.org/10.1016/j.bbamem.2011.06.011.
  • Visvader JE (2011) Cells of origin in cancer. Nature 469: 314-322. doi: 10.1038/nature09781.
  • Wang M, Berthoud VM, Beyer EC (2007) Connexin43 increases the sensitivity of prostate cancer cells to TNFalpha-induced apoptosis. J Cell Sci 120: 320-329. doi: 10.1242/jcs.03343.
  • Wong P, Tan T, Chan C, Laxton V, Chan YW, Liu T, Wong WT, Tse G (2016) The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches. Front Physiol 7: 596. doi: 10.3389/fphys.2016.00596.
  • Wong P, Laxton V, Srivastava S, Chan YW, Tse G (2017) The role of gap junctions in inflammatory and neoplastic disorders (Review). Int J Mol Med 39: 498-506. doi: 10.3892/ijmm.2017.2859.
  • Wu L, Zhou WB, Shen F, Liu W, Wu HW, Zhou SJ, Li SW (2016) Connexin32‑mediated antitumor effects of suicide gene therapy against hepatocellular carcinoma: In vitro and in vivo anticancer activity. Mol Med Rep 13: 3213-3219. doi: 10.3892/mmr.2016.4895.
  • Wysoczynski M, Miekus K, Jankowski K, Wanzeck J, Bertolone S, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (2007) Leukemia inhibitory factor: a newly identified metastatic factor in rhabdomyosarcomas. Cancer Res 67: 2131-2140. doi: 10.1158/0008-5472.CAN-06-1021.
  • Yamasaki H, Krutovskikh V, Mesnil M, Tanaka T, Zaidan-Dagli ML, Omori Y (1999) Role of connexin (gap junction) genes in cell growth control and carcinogenesis. C R Acad Sci III 322: 151-159. doi.org/10.1016/S0764-4469(99)80038-9.
  • Zhang W, DeMattia JA, Song H, Couldwell WT (2003a) Communication between malignant glioma cells and vascular endothelial cells through gap junctions. J Neurosurg 98: 846-853. doi: 10.3171/jns.2003.98.4.0846.
  • Zhang YW, Kaneda M, Morita I (2003b) The gap junction-independent tumor-suppressing effect of connexin 43. J Biol Chem 278: 44852-44856. doi: 10.1074/jbc.M305072200.
  • Zhang YW, Nakayama K, Nakayama K, Morita I (2003c) A novel route for connexin 43 to inhibit cell proliferation: negative regulation of S-phase kinase-associated protein (Skp 2). Cancer Res 63: 1623-1630.
  • Zucker SN, Bancroft TA, Place DE, Des SB, Bagati A, Berezney R (2013) A dominant negative Cx43 mutant differentially affects tumorigenic and invasive properties in human metastatic melanoma cells. J Cell Physiol 228: 853-859. doi: 10.1002/jcp.24235.
Document Type
Publication order reference
YADDA identifier
bwmeta1.element.bwnjournal-article-abpv64p377kz
Identifiers
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.