Connexins in cancer: bridging the gap to the clinic

Aasen, Trond; Leithe, Edward; Graham, Sheila V.; Kameritsch, Petra; Mayán, M.D.; Mesnil, Marc; Pogoda, Kristin; Tabernero, Arantxa

doi:10.1038/s41388-019-0741-6

Cited by 156 publications

(169 citation statements)

References 213 publications

(240 reference statements)

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“…Interference with Cx43 expression or channel function inhibits cancer cell migration in vitro (Ogawa et al, 2012) and reduces metastatic seeding by reducing binding of circulating tumor cells to vascular endothelial cells (el-Sabban and Pauli, 1991;Elzarrad et al, 2008;Stoletov et al, 2013). Because connexins exert a range of functions, and these may vary between tumor types and experimental conditions, an integrating concept on how connexins either suppress or enhance neoplastic progression is lacking (Aasen et al, 2019;Naus and Laird, 2010).…”

Section: Introductionmentioning

confidence: 99%

Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

Khalil

Ilina

Vasaturo

et al. 2019

Preprint

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Progression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell-cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells co-express adherens junctions and connexin-43 (Cx43) gap junctions in vitro and in patient samples, yet whether gap junctions contribute to collective invasion remains unclear. We here show that Cx43 is required for chemical coupling between collectively invading breast cancer cells and, by its hemichannel function, adenosine nucleotide release into the extracellular space. Using molecular interference and rescue strategies in vitro and in orthotopic mammary tumors in vivo, Cx43-dependent adenosine nucleotide release was identified as essential mediator engaging the nucleoside receptor ADORA1, to induce leader cell activity and collective migration. In clinical samples joint-upregulation of Cx43 and ADORA1 predicts decreased relapse-free survival. This identifies autocrine nucleotide signaling, through a Cx43/ADORA1 axis, as critical pathway in leader cell function and collective cancer cell invasion.

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Section: Introductionmentioning

confidence: 99%

Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

Khalil

Ilina

Vasaturo

et al. 2019

Preprint

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“…Connexins are widely expressed in the normal mammary glands, where gap junctions have distinct functions in development and homeostasis, such as modulation of cell proliferation and lactation (99). In advanced breast neoplasms, they are believed to increase the capacity of tumor cells to metastasize through enhancing their invasion and adhesion ability as well as by protecting tumor cells from hypoxia-induced death (100)(101)(102). Furthermore, some subtypes of connexins, namely Cx26, Cx32, and Cx43 are overexpressed in metastatic lymph nodes of ductal carcinomas (103,104).…”

Section: Biological Characteristics Of the Primary Tumorsmentioning

confidence: 99%

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

et al. 2020

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Breast cancer-related lymphedema (BCRL) occurs in a significant number of breast cancer survivors as a consequence of the axillary lymphatics' impairment after therapy (mainly axillary surgery and irradiation). Despite the recent achievements in the clinical management of these patients, BCRL is often diagnosed at its occurrence. In most cases, it remains a progressive and irreversible condition, with dramatic consequences in terms of quality of life and on sanitary costs. There are still no validated pre-surgical strategies to identify individuals that harbor an increased risk of BCRL. However, clinical, therapeutic, and tumor-specific traits are recurrent in these patients. Over the past few years, many studies have unraveled the complexity of the molecular and transcriptional events leading to the lymphatic system ontogenesis. Additionally, molecular insights are coming from the study of the germline alterations involved at variable levels in BCRL models. Regrettably, there is a substantial lack of predictive biomarkers for BCRL, given that our knowledge of its molecular milieu remains extremely puzzled. The purposes of this review were (i) to outline the biology underpinning the ontogenesis of the lymphatic system; (ii) to assess the current state of knowledge of the molecular alterations that can be involved in BCRL pathogenesis and progression; (iii) to discuss the present and shortterm future perspectives in biomarker-based patients' risk stratification; and (iv) to provide practical information that can be employed to improve the quality of life of these patients.

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“…Autoand paracrine communication Plasma-generated ROS and intracellular ROS produced upon plasma treatment triggered bystander effect and damaged GJs [197] Bystander effect: GJs can transmit ROS and cell death signals to neighbouring cells [196,221] Connexins Form gap junctions, transfer ions, small messengers, and metabolites. Forms hemichannels that communicate intra-and extracellular spaces [222] Destroyed structure of connexins' N-terminal tail [197]. Temporary loss of cell-cell contact [223].…”

Section: Unknownmentioning

confidence: 99%

Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

Privat-Maldonado

Bengtson

Razzokov

et al. 2019

Cancers

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Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and to determine the treatment outcome. Cold plasma (here referred as ‘plasma’) is an emerging anticancer technology that generates a unique cocktail of reactive oxygen and nitrogen species to eliminate cancerous cells via multiple mechanisms of action. While plasma is currently regarded as a local therapy, it can also modulate the mechanisms of cell-to-cell and cell-to-ECM communication, which could facilitate the propagation of its effect in tissue and distant sites. However, it is still largely unknown how the physical interactions occurring between cells and/or the ECM in the tumour microenvironment affect the plasma therapy outcome. In this review, we discuss the effect of plasma on cell-to-cell and cell-to-ECM communication in the context of the tumour microenvironment and suggest new avenues of research to advance our knowledge in the field. Furthermore, we revise the relevant state-of-the-art in three-dimensional in vitro models that could be used to analyse cell-to-cell and cell-to-ECM communication and further strengthen our understanding of the effect of plasma in solid tumours.

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Connexins in cancer: bridging the gap to the clinic

Cited by 156 publications

References 213 publications

Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

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