Correction: Oncogenic extracellular HSP70 disrupts the gap-junctional coupling between capillary cells.

[This corrects the article DOI: 10.18632/oncotarget.3522.

Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease.

The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial, and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in the heart and lungs, and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH.

Pannexin-1 in Human Lymphatic Endothelial Cells Regulates Lymphangiogenesis.

The molecular mechanisms governing the formation of lymphatic vasculature are not yet well understood. Pannexins are transmembrane proteins that form channels which allow for diffusion of ions and small molecules (<1 kDa) between the extracellular space and the cytosol. The expression and function of pannexins in blood vessels have been studied in the last few decades.

Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid.

Several folate-drug conjugates are currently undergoing clinical trials for application in oncology. However, the efficacy of folate-targeted therapy strongly depends on the folate receptor (FR) abundance at the surface of cancer cells. Recently, it has been postulated that up-regulation of FRα by means of chemo-sensitizing agents could enhance the anticancer activity of FR-drug conjugates.

Connexins, important players in the dissemination of prostate cancer cells.

Over the past 50years, increasing experimental evidences have established that connexins (Cxs) and gap junctional intercellular communication (GJIC) ensure an important role in both the onset and development of cancerous processes. In the present review, we focus on the impact of Cxs and GJIC during the development of prostate cancer (PCa), from the primary growth mainly localized in acinar glands and ducts to the distant metastasis mainly concentrated in bone. As observed in several other types of solid tumours, Cxs and especially Cx43 exhibit an ambivalent role with a tumour suppressor effect in the early stages and, conversely, a rather pro-tumoural profile for most of invasion and dissemination steps to secondary sites.

An update on minding the gap in cancer.

This article is a report of the "International Colloquium on Gap junctions: 50Years of Impact on Cancer" that was held 8-9 September 2016, at the Amphitheater "Pôle Biologie Santé" of the University of Poitiers (Poitiers, France). The colloquium was organized by M Mesnil (Université de Poitiers, Poitiers, France) and C Naus (University of British Columbia, Vancouver, Canada) to celebrate the 50th anniversary of the seminal work published in 1966 by Loewenstein and Kanno [Intercellular communication and the control of tissue growth: lack of communication between cancer cells, Nature, 116 (1966) 1248-1249] which initiated studies on the involvement of gap junctions in carcinogenesis. During the colloquium, 15 participants presented reviews or research updates in the field which are summarized below.

Development of a new model of reconstituted mouse epidermis and characterization of its response to proinflammatory cytokines.

The development of three-dimensional models of reconstituted mouse epidermis (RME) has been hampered by the difficulty to maintain murine primary keratinocyte cultures and to achieve a complete epidermal stratification. In this study, a new protocol is proposed for the rapid and convenient generation of RME, which reproduces accurately the architecture of a normal mouse epidermis. During RME morphogenesis, the expression of differentiation markers such as keratins, loricrin, filaggrin, E-cadherin and connexins was followed, showing that RME structure at day 5 was similar to those of a normal mouse epidermis, with the acquisition of the natural barrier function.

Transfer of functional microRNAs between glioblastoma and microvascular endothelial cells through gap junctions.

Extensive invasion and angiogenesis are hallmark features of malignant glioblastomas. Here, we co-cultured U87 human glioblastoma cells and human microvascular endothelial cells (HMEC) to demonstrate the exchange of microRNAs that initially involve the formation of gap junction communications between the two cell types. The functional inhibition of gap junctions by carbenoxolone blocks the transfer of the anti-tumor miR-145-5p from HMEC to U87, and the transfer of the pro-invasive miR-5096 from U87 to HMEC.

Primary tumor- and metastasis-derived colon cancer cells differently modulate connexin expression and function in human capillary endothelial cells.

A gradual loss of functional gap junction between tumor cells has been reported with colorectal cancer (CRC) progression. Here, we explored if colon cancer cells could also affect gap junctions in blood capillary cells. Human microvascular endothelial cells (HMEC) were cultured with two CRC cell lines established from a unique patient.

Oncogenic extracellular HSP70 disrupts the gap-junctional coupling between capillary cells.

High levels of circulating heat shock protein 70 (HSP70) are detected in many cancers. In order to explore the effects of extracellular HSP70 on human microvascular endothelial cells (HMEC), we initially used gap-FRAP technique. Extracellular human HSP70 (rhHSP70), but not rhHSP27, blocks the gap-junction intercellular communication (GJIC) between HMEC, disrupts the structural integrity of HMEC junction plaques, and decreases connexin43 (Cx43) expression, which correlates with the phosphorylation of Cx43 serine residues.

Extracellular HSP27 mediates angiogenesis through Toll-like receptor 3.

The heat-shock protein 27 (HSP27) is up-regulated in tumor cells and released in their microenvironment. Here, we show that extracellular HSP27 has a proangiogenic effect evidenced on chick chorioallantoic membrane. To explore this effect, we test the recombinant human protein (rhHSP27) at physiopathological doses (0.

A galactosidase-responsive doxorubicin-folate conjugate for selective targeting of acute myelogenous leukemia blasts.

Cytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular "Trojan Horse" programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR).

The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells.

For decades, cancer was associated with gap-junction defects. However, more recently it appeared that the gap junction proteins (connexins) could be re-expressed and participate to cancer cell dissemination during the late stages of tumor progression. Since primary tumors of prostate cancer (PCa) are known to be connexin deficient, it was interesting to verify whether their bone-targeted metastatic behaviour could be influenced by the re-expression of the connexin type (connexin43) which is originally present in prostate tissue and highly expressed in bone where it participates to the differentiation of osteoblastic cells.

Down-regulation of Connexin43 expression reveals the involvement of caveolin-1 containing lipid rafts in human U251 glioblastoma cell invasion.

Glioblastoma cells are characterized by high proliferation and invasive capacities. Tumor development has been associated with a decrease of gap-junctional intercellular communication, but the concrete involvement of gap junction proteins, connexins, remains elusive since they are also suspected to promote cell invasion. In order to better understand how connexins control the glioma cell phenotype, we studied the consequences of inhibiting the intrinsic expression of the major astrocytic connexin, Connexin43, in human U251 glioblastoma cells by the shRNA strategy.

ZO-1 is involved in trophoblastic cell differentiation in human placenta.

Trophoblastic cell-cell fusion is an essential event required during human placental development. Several membrane proteins have been described to be directly involved in this process, including connexin 43 (Cx43), syncytin 1 (Herv-W env), and syncytin 2 (Herv-FRD env glycoprotein). Recently, zona occludens (ZO) proteins (peripheral membrane proteins associated with tight junctions, adherens junctions, and gap junctions) were shown to be involved in mouse placental development.

Effect of endothelin-1 on osteoblastic differentiation is modified by the level of connexin43: comparative study on calvarial osteoblastic cells isolated from Cx43+/- and Cx43+/+ mice.

Bone is a dynamic tissue that undergoes a precise remodeling process involving resorptive osteoclastic cells and bone-forming osteoblastic (OB) cells. The functional imbalance of either of these cell types can lead to severe skeletal diseases. The proliferation and differentiation of OB cells play a major role in bone development and turnover.

Gap junctions and cancer: new functions for an old story.

Cancer was one of the first pathologies to be associated with gap-junction defect. Despite the evidence accumulated over the last 40-year period, the molecular involvement of gap junctions and their structural proteins (connexins) in cancer has not been elucidated. The lack of a satisfying explanation may come from the complexity of the disease, evolving through various stages during tumor progression, with cancer cells exhibiting different phenotypes.

Endothelin1-induced Ca(2+) mobilization is altered in calvarial osteoblastic cells of Cx43(+/- ) mice.

During bone remodeling, osteoblastic (OB) cells have a central role leading to the production of extracellular matrix and its subsequent mineralization. As revealed by human physiopathologies, the OB differentiation process is essential for the control of calcium metabolism and normal bone formation. Moreover, accumulating data in the field of bone development suggest that connexin 43 (Cx43)-mediated gap junctional communication plays an important role in OB differentiation and function.

Endothelin-1 inhibits human osteoblastic cell differentiation: influence of connexin-43 expression level.

Gap junctional intercellular communication (GJIC) permits coordinated cellular activities during developmental and differentiation processes. In bone, the involvement of the gap junctional protein, connexin-43 (Cx43), and of GJIC in osteoblastic differentiation and mineralization of the extracellular matrix has been previously demonstrated. Former studies have shown that endothelin-1 (ET-1) was also implicated in the control of osteoblastic proliferation and differentiation.

Involvement of gap junctions in placental functions and development.

Connexin (Cx) expression and gap junctional intercellular communication (GJIC) are involved in development and differentiation processes. Mediating exchanges between mother and fetus, the placenta is formed when fetal membranes are apposed or even fusing or destroying the uterine mucosa. Therefore, an extraordinary variability of placental structures is observed throughout the mammalian species.

Calcium channels activated by endothelin-1 in human trophoblast.

Ca2+ transfer across the syncytiotrophoblast (ST) of the human placenta is essential for normal fetal development. However, the nature of Ca2+ conductance in the ST and the mechanisms by which it is regulated are poorly understood. With the major signal transduction pathway of endothelin-1 (ET1) acting via phospholipase C (PLC) and Ca2+, we used ET1 to analyse the nature of Ca2+ channels on cultured trophoblastic cells by means of cytofluorimetric analysis using the ratiometric Ca2+ indicator Indo-1.