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

Abstract

Intercellular communication is essential for the development and maintenance of multicellular organisms. Tunneling nanotubes (TNTs) are a recently recognized means of long and short distance communication between a wide variety of cell types. TNTs are transient filamentous membrane protrusions that connect cytoplasm of neighboring or distant cells. Cytoskeleton fiber-mediated transport of various cargoes occurs through these tubules. These cargoes range from small ions to whole organelles. TNTs have been shown to contribute not only to embryonic development and maintenance of homeostasis, but also to the spread of infectious particles and resistance to therapies. These functions in the development and progression of cancer and infectious disease have sparked increasing scrutiny of TNTs, as their contribution to disease progression lends them a promising therapeutic target. Herein, we summarize the current knowledge of TNT structure and formation as well as the role of TNTs in pathology, focusing on viral, prion, and malignant disease. We then discuss the therapeutic possibilities of TNTs in light of their varied functions. Despite recent progress in the growing field of TNT research, more studies are needed to precisely understand the role of TNTs in pathological conditions and to develop novel therapeutic strategies.

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…However, the significance of intercellular communication by TnTs, first reported in 2004, remains less known . Fortunately, a rapidly increasing body of literature has revealed that TnTs could be formed among different cell types, such as various immune cells, epithelial cells and cancer cells, and further confirmed that TnT is an important pathway for intercellular exchanges of organelles, proteins, signals and pathogens . Depending on the TnTs formed among different cell types, TnTs can play critical roles in viral entry and dissemination, immune response regulation, tumor metastasis and drug resistance .…”

“…24 Fortunately, a rapidly increasing body of literature has revealed that TnTs could be formed among different cell types, such as various immune cells, epithelial cells and cancer cells, and further confirmed that TnT is an important pathway for intercellular exchanges of organelles, proteins, signals and pathogens. 25 Depending on the TnTs formed among different cell types, TnTs can play critical roles in viral entry and dissemination, immune response regulation, tumor metastasis and drug resistance. 26 Regarding cancer, Osswald et al 27 provided the first in vivo evidence of the functions of TnTs in a nude murine tumor-bearing model with patient-derived astrocytoma cells and showed that TnT-connected astrocytoma cells could promote tumor progression and resistance to antitumor therapy.…”

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

“…TNTs are highly dynamic intercellular communication structures consisting of plasma membrane and F-actin, however, the detailed understanding of TNT regulatory mechanisms are still limited. [66][67][68] Since the tyrosine kinase ABL1 and the oncogenic fusion protein BCR-ABL1 include distinct F-and G-actin binding domains with actin bundling activity, 69 we examined various BCR-ABL1 expressing cells with respect to TNT formation. BCR-ABL1 positive CML cells, cell lines, and patient-derived cells, displayed limited numbers or absence of TNT formation compared to acute myeloid leukemia cells, stromal cells and other cancer cells.…”

“…TNTs are proposed as one mechanism of interaction between mesenchymal stromal cells and leukemic cells in the leukemic stem cell niche. 29,68,87,88 Kolba and coworkers showed that stromal cells transferred vesicles through TNTs to K562 cells and that transfer of vesicles correlated with increased resistance toward imatinib treatment. 43 This underscores the importance of interaction between CML cells, mesenchymal stromal cells and the bone marrow niche, a system of cell-to-cell communication that include secreted factors, extracellular matrix interactions and direct cell-to-cell interactions.…”

“…41 Subsequently, TNTs have been proposed to be implicated in disease and to play a role with respect to therapy response recently demonstrated by vesicle exchange from stromal cells to CML cells providing increased resistance to imatinib. 42,43 The BCR-ABL1 protein contains an F-actin binding domain and orchestrates several cellular processes including actin processing, cell attachment to fibronectin and cell migration. 44 Features of CML progenitor cells from patients in the chronic phase include decreased adhesion and low affinity to fibronectin coated surfaces compared to normal counterparts.…”