The Novel Roles of Connexin Channels and Tunneling Nanotubes in Cancer Pathogenesis

Abstract

Neoplastic growth and cellular differentiation are critical hallmarks of tumor development. It is well established that cell-to-cell communication between tumor cells and “normal” surrounding cells regulates tumor differentiation and proliferation, aggressiveness, and resistance to treatment. Nevertheless, the mechanisms that result in tumor growth and spread as well as the adaptation of healthy surrounding cells to the tumor environment are poorly understood. A major component of these communication systems is composed of connexin (Cx)-containing channels including gap junctions (GJs), tunneling nanotubes (TNTs), and hemichannels (HCs). There are hundreds of reports about the role of Cx-containing channels in the pathogenesis of cancer, and most of them demonstrate a downregulation of these proteins. Nonetheless, new data demonstrate that a localized communication via Cx-containing GJs, HCs, and TNTs plays a key role in tumor growth, differentiation, and resistance to therapies. Moreover, the type and downstream effects of signals communicated between the different populations of tumor cells are still unknown. However, new approaches such as artificial intelligence (AI) and machine learning (ML) could provide new insights into these signals communicated between connected cells. We propose that the identification and characterization of these new communication systems and their associated signaling could provide new targets to prevent or reduce the devastating consequences of cancer.

Investigating Tunneling Nanotubes in Cancer Cells: Guidelines for Structural and Functional Studies through Cell Imaging

“…Interestingly, not only a hostile environment (inflammation, hypoxia, and inadequate pH) enhances TNT formation [4,[8][9][10][11], but also TNTs could contribute to the escape of the cells from the cell death induced by apoptosis [10,[12][13][14]. On the other hand, TNTs convey resistance to chemotherapy by exporting the mitochondria [15,16]. This transfer of mitochondria allows tumor cells to develop one of the hallmarks of tumors, i.e., a metabolic plasticity, in order to acquire migration, proliferation, and resistance properties, particularly to cisplatin and paclitaxel [6,17].…”

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

“…Our laboratory demonstrated that myeloid and glial cells within the CNS are viral reservoirs. These few viral reservoirs, despite the low to undetectable viral replication, are able to amplify toxicity and inflammation to neighboring uninfected cells by a gap junction, hemichannel, and tunneling nanotube mediated mechanism (Eugenin et al, 2009a , b ; Berman et al, 2016 ; Malik and Eugenin, 2016 , 2019 ; Ariazi et al, 2017 ; Okafo et al, 2017 ; Valdebenito et al, 2018 ).…”

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

“…TNTs have also been found in primary human tumors [ 39 , 40 , 41 ]. It is becoming clear that TNTs facilitate a pathway of intercellular conduits in tumors [ 42 ] and may promote numerous malignant features such as invasion, growth, chemo- and radiotherapy resistance, and surgery-induced tumor growth [ 43 , 44 , 45 ].…”

“…Connexins localize to TNTs and regulate intercellular communication [ 44 , 46 , 47 ]. Wang et al [ 46 ] identified TNT-mediated voltage-sensitive electrical coupling that was inhibited by the gap junction inhibitor meclofenamate.…”