Connexins in cancer: bridging the gap to the clinic

Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and -independent functions that are tissue and stage specific. This can elicit both pro- and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential

Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation

Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM

Jonctions communicantes et cancer: implications et perspectives

Les jonctions communicantes (gap junctions) sont des structures membranaires permettant la diffusion intercellulaire de petites molécules (ions, sucres, acides aminés, nucléotides…). La perte de leur fonction, fréquemment induite par des promoteurs de tumeur et associée au phénotype tumorigénique, a fait supposer que les jonctions communicantes étaient impliquées dans le processus de cancérogenèse. Plus récemment, cette hypothèse a été confortée par le fait que le rétablissement de la communication jonctionnelle intercellulaire s’accompagne d’un effet suppresseur de tumeur spécifique. Malgré ces données, plusieurs zones d’ombre subsistent, parmi lesquelles le mode de régulation de l’effet suppresseur et la véritable implication des jonctions communicantes dans la cancérogenèse humaine. Répondre à ces interrogations est d’importance, puisque les jonctions communicantes pourraient être un paramètre à considérer en terme d’efficacité pour certaines thérapies géniques anticancéreuses, voire même pour certaines chimiothérapies.Gap junctions are made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules (< 1 200 Da) such as ions, sugars, aminoacids, nucleotides, second messengers (calcium, inositol triphosphate, etc.). Since their discovery in the early sixties, several groups have described the loss of their function in cancer cells. The accumulation of such data led to the hypothesis that gap junctions are involved in the carcinogenesis process. This assumption has been confirmed by data establishing that gap junctional intercellular communication is inhibited by most of the tumor promoters and that the restoration of such a communication, by transfection of cDNAs encoding gap junction proteins (connexins), inhibits the aberrant growth rates of tumorigenic cells. Despite these important informations, several fundamental questions remain still open. First, we do not know how gap junctions mediate such a tumor suppressor effect and whether it may depend either on the cell type or on the connexin type. Moreover, most of the data concerning a possible involvement of gap junctions in carcinogenesis have been obtained from in vitro and animal models. The very few results which have been currently collected from human tumors are not sufficient to have a clear idea concerning the real involvement of gap junctions in sporadic human cancers. These points as well as other unresolved questions about the role of gap junctional intercellular communication in carcinogenesis are mentionned. To bring some answers, some prospects are proposed with the objective to use gap junctions for increasing the effect of anticancer therapies

Brain Disorders and Chemical Pollutants: A Gap Junction Link?

The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson&rsquo;s disease, Alzheimer&rsquo;s disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain disorders. Taking into account that the brain parenchyma is rich in gap junctions and that most pollutants inhibit their function; brain disorders might be the consequence of gap-junctional alterations due to long-term exposures to pollutants. In this article, this hypothesis is addressed through three complementary aspects: (1) the gap-junctional organization and connexin expression in brain parenchyma and their function; (2) the effect of major pollutants (pesticides, bisphenol A, phthalates, heavy metals, airborne particles, etc.) on gap-junctional and connexin functions; (3) a description of the major brain disorders categorized as neurodevelopmental (autism spectrum disorders, attention deficit hyperactivity disorders, epilepsy), neurobehavioral (migraines, major depressive disorders), neurodegenerative (Parkinson&rsquo;s and Alzheimer&rsquo;s diseases) and cancers (glioma), in which both connexin dysfunction and pollutant involvement have been described. Based on these different aspects, the possible involvement of pollutant-inhibited gap junctions in brain disorders is discussed for prenatal and postnatal exposures

Fractures de l'acétabulum (à propos d'une série de 73 cas au recul médian de 6 ans)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Etude de mécanismes moléculaires associés à l effet suppresseur de tumeur des connexines 30 et 43

Les jonctions communicantes étant connues pour participer au maintien de l homéostasie tissulaire et leur absence étant une caractéristique des cellules cancéreuses, elles ont été suspectées de jouer un rôle important lors de la carcinogénèse. Cette hypothèse a été renforcée par l effet suppresseur de tumeur qui est fréquemment observé après transfection, dans des cellules tumorales, de gènes codant pour les protéines de structure des jonctions communicantes, les connexines (Cx). Le mécanisme moléculaire responsable de l effet suppresseur de tumeur des connexines n est pas encore élucidé. Nous avons tenté de cerner davantage le rôle tenu par les connexines et plus particulièrement de la connexine 43 (Cx43) dans le contrôle de la prolifération cellulaire par l utilisation de divers modèles.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Serotonin and human cancer: A critical view

International audienceBesides its classical functions as a neurotransmitter in the central nervous system, local mediator in the gastrointestinal tract and vasoactive agent in the blood, serotonin has more recently emerged as a growth factor for human tumor cells of different origins (carcinomas, glioma and carcinoids). Several data are also available on serotonin involvement in cancer cell migration, metastatic dissemination and tumor angiogenesis. The serotonin-induced signaling pathways that promote tumor progression are complex and only partly understood in some cancer types. The results of several studies showed that serotonin levels in the tumor played a crucial role in cancer progression. A serotonin production and secretion by neuroendocrine cells have been shown in the progression of several solid tumors and the involvement of a serotoninergic autocrine loop was proposed. Specific receptor subtypes are associated with different fundamental stages of tumor progression and the pattern of receptors expression becomes dysregulated in several human tumors when compared with normal cells or tissues. Serotonin receptors, selective serotonin transporter and serotonin synthesis pathways are potential chemotherapeutic targets for the treatment of several cancers in which therapeutic approaches are limited. Through several asked questions, this critical mini-review discusses the relevance of the involvement of serotonin in human cancer progression

Implications de Cx43 dans les tumeurs gliales humaines (approches in situ et in vitro)

La communication intercellulaire par les jonctions gap (CIJG) a été proposée comme l un des éléments impliqués dans la cancérogenèse très rapidement après sa mise en évidence, dans les années 1960. Ainsi l induction de l expression de connexines, motif structural de base de la CIJG, a été décrite comme étant capable de normaliser le phénotype de cellules cancéreuses. Notre étude de la connexine 43 (Cx43), par tissue micro array, dans des tumeurs gliales humaines (59 échantillons) a montré une délocalisation et une perte de l expression de la protéine. La situation s avère complexe par l hétérogénéité intratumorale; en effet, certaines cellules du tissu tumoral montrent un signal avec une localisation aberrante dans le cytoplasme ou dans le noyau. Certains travaux ayant suggéré que Cx43 pourrait normaliser le phénotype tumoral par une action indépendante de la CIJG, Cx43 ou des formes tronquées de la protéine ont été exprimées par des vecteurs rétroviraux dans des lignées de tumeurs gliales humaines. Les résultats obtenus ont suggéré que l expression de la protéine ne permettait pas de réduire le potentiel prolifératif des cellules tumorales lorsque celles-ci sont maintenues en monocouche. En revanche, la capacité des cellules à proliférer sans ancrage est réduite par l expression de Cx43 mais aussi par des formes tronquées de la protéine ne permettant pas la CIJG. De plus, les cellules exprimant Cx43, entière ou tronquée, apparaissent douées d une plus grande motilité. En conclusion, Cx43 semble jouer un rôle complexe dans la progression des tumeurs gliales humaines, celle-ci apparaissant avec des localisations aberrantes dont l effet demeure inconnu. L expression de la Cx43 ne constituerait pas nécessairement un facteur de bon pronostic, car si les cellules montrent une diminution de leur prolifération dans un environnement défavorable, elles semblent, en revanche, plus aptes à migrer, ce qui permettrait l invasion du tissu environnant.The possible involvement of Gap-Junctional Intercellular Communication (GJIC) in carcinogenesis has been hypothesized in the 1960s. Later, the expression of connexins, the molecular basis of GJIC, has been shown to normalize the phenotype of various tumor cells. Our study, using the tissue micro array approach, was focused on connexin 43 (Cx43) expression in human gliomas (59 tumor samples). We showed that the expression of Cx43 protein was altered and, in several cases, especially in grade-IV gliomas, Cx43 was lost. Nonetheless, due to tumor heterogeneity, a complex pattern of expression was revealed: Cx43 exhibited aberrant staining, that means a translocation into the cytoplasm possibly in the nucleus. Several works suggested that Cx43 could normalize tumor cells by a GJIC-independent mechanism. We investigated the role played by Cx43 and different truncated forms of the protein, unable to restore GJIC, in human glioma cell lines. Our data showed that Cx43 expression did not induce any change on cell proliferation when cell lines were maintained in monolayer cultures. On the contrary, the cells trandusced by Cx43 constructs (full-length or truncated) grew less in soft agar assay. In parallel, it appeared that all the Cx43 constructs increased motility. To conclude, Cx43 seems to play a complex role in human glioma progression. Its expression and localization are altered, but the underlying mechanisms remain unknown. Even if Cx43 seems to be altered in gliomas, a maintained expression of the protein could not be correlated with a good prognosis since their motility is increased by Cx43 expression.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Etude de mécanismes moléculaires associés à l effet suppresseur de tumeur des connexines 30 et 43

Les jonctions communicantes étant connues pour participer au maintien de l homéostasie tissulaire et leur absence étant une caractéristique des cellules cancéreuses, elles ont été suspectées de jouer un rôle important lors de la carcinogénèse. Cette hypothèse a été renforcée par l effet suppresseur de tumeur qui est fréquemment observé après transfection, dans des cellules tumorales, de gènes codant pour les protéines de structure des jonctions communicantes, les connexines (Cx). Le mécanisme moléculaire responsable de l effet suppresseur de tumeur des connexines n est pas encore élucidé. Nous avons tenté de cerner davantage le rôle tenu par les connexines et plus particulièrement de la connexine 43 (Cx43) dans le contrôle de la prolifération cellulaire par l utilisation de divers modèles.POITIERS-BU Sciences (861942102) / SudocSudocFranceF