Tunneling Nanotubes: Intercellular Conduits for Direct Cell-to-Cell Communication in Cancer

Intercellular communication among cancer cells and their microenvironment is crucial to disease progression. The mechanisms by which communication occurs between distant cells in a tumor matrix remain poorly understood. In the last two decades, experimental evidence from different groups proved the existence of thin membranous tubes that interconnect cells, named tunneling nanotubes, tumor microtubes, cytonemes or membrane bridges. These highly dynamic membrane protrusions are conduits for direct cell-to-cell communication, particularly for intercellular signaling and transport of cellular cargo over long distances. Tunneling nanotubes and tumor microtubes may play an important role in the pathogenesis of cancer. They may contribute to the resistance of tumor cells against treatments such as surgery, radio- and chemotherapy. In this review, we present the current knowledge about the structure and function of tunneling nanotubes and tumor microtubes in cancer and discuss the therapeutic potential of membrane tubes in cancer treatment.

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Perspectives of cellular communication through tunneling nanotubes in cancer cells and the connection to radiation effects

Radiation Oncology ◽

10.1186/s13014-019-1416-8 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 8

Author(s):

Nicole Matejka ◽

Judith Reindl

Keyword(s):

Cancer Cells ◽

Radiation Effects ◽

Cell Communication ◽

Treatment Resistance ◽

Cell Types ◽

Stress Reaction ◽

Chemotherapy Treatment ◽

Tunneling Nanotubes ◽

Direct Cell ◽

Infected Cells

AbstractDirect cell-to-cell communication is crucial for the survival of cells in stressful situations such as during or after radiation exposure. This communication can lead to non-targeted effects, where non-treated or non-infected cells show effects induced by signal transduction from non-healthy cells or vice versa. In the last 15 years, tunneling nanotubes (TNTs) were identified as membrane connections between cells which facilitate the transfer of several cargoes and signals. TNTs were identified in various cell types and serve as promoter of treatment resistance e.g. in chemotherapy treatment of cancer. Here, we discuss our current understanding of how to differentiate tunneling nanotubes from other direct cellular connections and their role in the stress reaction of cellular networks. We also provide a perspective on how the capability of cells to form such networks is related to the ability to surpass stress and how this can be used to study radioresistance of cancer cells.

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Faculty Opinions recommendation of Lipid-protein cargo transfer: a mode of direct cell-to-cell communication for lipids and their associated proteins.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1051655.503559 ◽

2006 ◽

Author(s):

Barbara Imperiali

Keyword(s):

Cell Communication ◽

Associated Proteins ◽

Direct Cell

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Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications

Journal of Cellular Physiology ◽

10.1002/jcp.27072 ◽

2018 ◽

Vol 234 (2) ◽

pp. 1130-1146 ◽

Cited By ~ 23

Author(s):

Rahul Mittal ◽

Elisa Karhu ◽

Jay-Shing Wang ◽

Stefanie Delgado ◽

Ryan Zukerman ◽

...

Keyword(s):

Cell Communication ◽

Tunneling Nanotubes ◽

Therapeutic Applications

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Cells Connected by Tiny Tunnels

Microscopy Today ◽

10.1017/s1551929500056224 ◽

2004 ◽

Vol 12 (5) ◽

pp. 3-7

Author(s):

Stephen W. Carmichael

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Wheat Germ ◽

Cultured Cells ◽

Cell Communication ◽

Tunneling Nanotubes ◽

Pheochromocytoma Cells ◽

Intracellular Communication ◽

Transmission Electron ◽

Multicellular Organisms

Intracellular communication is imperative for multicellular organisms. Such devices as synapses and gap junctions have been recognized for decades. Now Amin Rustom, Raiser Saffrich, Ivanka Markovic, Paul Walther, and Hans-Hermann Gerdes have described a new model of cell-to-cell communication.While looking at PC12 (rat pheochromocytoma) cells in the presence of fluorescently labeled wheat germ agglutinin, Rustom et al. observed relatively long connections extending between cells. These structures were 50 to 200 nm in diameter and up to several cell diameters in length and were named tunneling nanotubes (TNTs). TNTs were subsequently found connecting cultured cells from other lines. They were consistently positioned along the smallest distance between the cells, did not contact the substrate, and occasionally were branched. TNTs immunostained positive for actin, but did not contain microtubules. Scanning and transmission electron microscopy definitively established that a TNT represented a seamless continuity of the plasma membrane from one cell to another.

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Myocardial gap junctions: targets for novel approaches in the prevention of life-threatening cardiac arrhythmias

Physiological Research ◽

10.33549/physiolres.931546 ◽

2008 ◽

pp. S1-S13

Author(s):

N Tribulová ◽

V Knezl ◽

Ľ Okruhlicová ◽

J Slezák

Keyword(s):

Gap Junctions ◽

Heart Function ◽

Cell Communication ◽

Persistent Atrial Fibrillation ◽

Gap Junctional Communication ◽

Novel Treatments ◽

Junctional Communication ◽

Life Threatening ◽

Direct Cell ◽

Gap Junctional

Direct cell-to-cell communication in the heart is maintained via gap junction channels composed of proteins termed connexins. Connexin channels ensure molecular and electrical signals propagation and hence are crucial in myocardial synchronization and heart function. Disease-induced gap junctions remodeling and/or an impairment or even block of intercellular communication due to acute pathological conditions results in derangements of myocardial conduction and synchronization. This is critical in the development of both ventricular fibrillation, which is a major cause of sudden cardiac death and persistent atrial fibrillation, most common arrhythmia in clinical practice often resulting in stroke. Many studies suggest that alterations in topology (remodeling), expression, phosphorylation and particularly function of connexin channels due to age or disease are implicated in the development of these life-threatening arrhythmias. It seems therefore challenging to examine whether compounds that could prevent or attenuate gap junctions remodeling and connexin channels dysfunction can protect the heart against arrhythmias that cause sudden death in humans. This assumption is supported by very recent findings showing that an increase of gap junctional conductance by specific peptides can prevents atrial conduction slowing or re-entrant ventricular tachycardia in ischemic heart. Suppression of ischemia-induced dephosphorylation of connexin seems to be one of the mechanisms involved. Another approach for identifying novel treatments is based on the hypothesis that even non-antiarrhythmic drugs with antiarrhythmic ability can modulate gap junctional communication and hence attenuate arrhythmogenic substrates.

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Gap Junction Channelopathies and Calmodulinopathies. Do Disease-Causing Calmodulin Mutants Affect Direct Cell–Cell Communication?

International Journal of Molecular Sciences ◽

10.3390/ijms22179169 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9169

Author(s):

Camillo Peracchia

Keyword(s):

Gap Junction ◽

Genetic Diseases ◽

Channel Gating ◽

Cell Communication ◽

Potential Effect ◽

Gap Junction Channel ◽

Direct Cell ◽

Connexin Genes ◽

Cell Cell

The cloning of connexins cDNA opened the way to the field of gap junction channelopathies. Thus far, at least 35 genetic diseases, resulting from mutations of 11 different connexin genes, are known to cause numerous structural and functional defects in the central and peripheral nervous system as well as in the heart, skin, eyes, teeth, ears, bone, hair, nails and lymphatic system. While all of these diseases are due to connexin mutations, minimal attention has been paid to the potential diseases of cell–cell communication caused by mutations of Cx-associated molecules. An important Cx accessory protein is calmodulin (CaM), which is the major regulator of gap junction channel gating and a molecule relevant to gap junction formation. Recently, diseases caused by CaM mutations (calmodulinopathies) have been identified, but thus far calmodulinopathy studies have not considered the potential effect of CaM mutations on gap junction function. The major goal of this review is to raise awareness on the likely role of CaM mutations in defects of gap junction mediated cell communication. Our studies have demonstrated that certain CaM mutants affect gap junction channel gating or expression, so it would not be surprising to learn that CaM mutations known to cause diseases also affect cell communication mediated by gap junction channels.

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Cell to cell hijacking: Role of membrane nanotubes

Asian Journal of Medical Sciences ◽

10.3126/ajms.v13i1.41174 ◽

2022 ◽

Vol 13 (1) ◽

pp. 1-2

Author(s):

Karthikeyan Pethusamy ◽

Ruby Dhar ◽

Arun Kumar ◽

Subhradip Karmakar

Keyword(s):

Cancer Cells ◽

Physiological Function ◽

Cell Communication ◽

Treatment Resistance ◽

Cell Types ◽

Chemotherapy Treatment ◽

Tunneling Nanotubes ◽

Membrane Nanotubes ◽

Membrane Protrusions

Cell to Cell communications is the pivot for life processes. Any event that disrupts this leads to the loss of physiological function, eventually leading to cell death. Evolutionarily, cells developed an elaborate mechanism to undertake this paramount responsibility through cell surface glycocalyx, receptors, integrins, and other recognition molecules. Cells also exchange through local acting soluble mediators as well as through vesicles and exosomes. Recent development in this field led to the identification of a spectacular network of membrane process that seems to be the supremo of all that was known about cellular communications. These are called membrane nanotubes or tunneling nanotubes (TNT). Cellular communication can be subdivided into contact and contactless. The former provides more rapid and molecule transfer as compared to the latter. Tunneling nanotubes (TNTs) are a novel type of contact-based communication. TNTs are straight, thin membrane extensions connecting cells over long distances first reported in PC12 cells in 2004. TNT is believed to form from actin-based membrane protrusion. There are three different models of TNT formation. a>Protrusions from one cell grow and extend until it reaches the other cell, followed by a membrane fusion. b> Membrane protrusions grow from both cells until they meet and establish a connection c> TNT formation by cell dislodgement when cells migrate further apart from each other, and during this movement, TNT is formed. It is possible that all these three models may be operational depending on cell types and context. Tunneling nanotubes (TNT) are dynamic connections between cells, representing a novel route for cell-to-cell communication. TNT was reported in various cell types, like epithelial cells, neuronal cells, mesenchyma cells, and immune cells engaged in intercellular exchanges of molecules, subcellular organelles, and pathogen and viruses transport routes. TNT can extend up to 200 µm in length and about 50 nm to 1500 nm in diameter in macrophages. TNT can be established between similar cell types (homo-TNT) or between one cell type and another ( hetro TNT) and thus may be involved in the initiation and growth of cancer as well as dissemination of cancer cells. TNTs are also assumed to play a role in treatment resistance, e.g., in chemotherapy treatment of cancer. Recently, TNT has been used to hijack mitochondria from healthy cells by the cancer cells as a source of energy. TNT was also reported to transport miRNA and other RNA to the surrounding stroma creating an environment suitable for cancer growth. More research in this discipline is needed to understand the full function of these wonderful nanostructures.

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The role of gap junctions in amphibian development

Development ◽

10.1242/dev.89.supplement.365 ◽

1985 ◽

Vol 89 (Supplement) ◽

pp. 365-380

Author(s):

Anne E. Warner

Keyword(s):

Gap Junctions ◽

Protein Pattern ◽

Cell Communication ◽

Embryonic Cells ◽

Amphibian Embryo ◽

Junctional Communication ◽

Direct Cell ◽

Insect Epidermis ◽

Gap Junctional ◽

Communication Pathway

The possibility that communication through gap junctions may be important during embryonic development has often been raised since gap junctions were first described between early embryonic cells. It is now known that this direct cell-to-cell communication pathway disappears between groups of embryonic cells with different developmental fates as the embryo progresses through development, suggesting that transfer through the gap junctional pathway may play some part in controlling events during development. Supportive evidence for a role for gap junctions comes from experiments demonstrating that the properties of gap junctions differ at the border separating each segment in insect epidermis. Recently it has been shown that the ability to exchange small dyes between cells in the amphibian embryo depends on the position of each cell with respect to the grey crescent. When communication through gap junctions is prevented, by injecting antibodies to gap junctions protein, pattern formation is severely disturbed in the non-communicating region. The paper describes experiments on the pattern of junctional communication at early stages of development of the amphibian embryo and illustrates how anti-gap junction antibodies are being used to determine when and where communication through gap junctions may play an important role during development.

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