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Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia

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Effectual cell-to-cell communication is essential to the development and differentiation of organisms, the preservation of tissue tasks, and the synchronization of their different physiological actions, but also to the proliferation and metastasis of tumor cells. Tunneling nanotubes (TNTs) are membrane-enclosed tubular connections between cells that carry a multiplicity of cellular loads, such as exosomes, non-coding RNAs, mitochondria, and proteins, and they have been identified as the main participants in healthy and tumoral cell communication. TNTs have been described in numerous tumors in in vitro, ex vivo, and in vivo models favoring the onset and progression of tumors. Tumor cells utilize TNT-like membranous channels to transfer information between themselves or with the tumoral milieu. As a result, tumor cells attain novel capabilities, such as the increased capacity of metastasis, metabolic plasticity, angiogenic aptitude, and chemoresistance, promoting tumor severity. Here, we review the morphological and operational characteristics of TNTs and their influence on hematologic malignancies’ progression and resistance to therapies, focusing on acute and chronic myeloid and acute lymphoid leukemia. Finally, we examine the prospects and challenges for TNTs as a therapeutic approach for hematologic diseases by examining the development of efficient and safe drugs targeting TNTs.
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Citation: Allegra, A.; Di Gioacchino,
M.; Cancemi, G.; Casciaro, M.;
Petrarca, C.; Musolino, C.; Gangemi,
S. Specialized Intercellular
Communications via Tunnelling
Nanotubes in Acute and Chronic
Leukemia. Cancers 2022,14, 659.
https://doi.org/10.3390/
cancers14030659
Academic Editor: Emil Lou
Received: 30 December 2021
Accepted: 27 January 2022
Published: 28 January 2022
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4.0/).
cancers
Review
Specialized Intercellular Communications via Tunnelling
Nanotubes in Acute and Chronic Leukemia
Alessandro Allegra 1, * , Mario Di Gioacchino 2, 3, * , Gabriella Cancemi 1, Marco Casciaro 4,
Claudia Petrarca 2,5 , Caterina Musolino 1and Sebastiano Gangemi 4
1Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Hematology,
University of Messina, 98125 Messina, Italy; gabcan17@gmail.com (G.C.); cmusolino@unime.it (C.M.)
2Center for Advanced Studies and Technology, G.d’Annunzio University, 66100 Chieti, Italy;
claudia.petrarca@unich.it
3Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
4Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine,
University of Messina, 98125 Messina, Italy; marco.casciaro@unime.it (M.C.); gangemis@unime.it (S.G.)
5Department of Medicine and Aging Sciences, G.d’Annunzio University, 66100 Chieti, Italy
*Correspondence: aallegra@unime.it (A.A.); mario.digioacchino@unich.it (M.D.G.)
Simple Summary:
Tunneling nanotubes (TNTs) are cytoplasmic channels which regulate the contacts
between cells and allow the transfer of several elements, including ions, mitochondria, microvesicles,
exosomes, lysosomes, proteins, and microRNAs. Through this transport, TNTs are implicated in
different physiological and pathological phenomena, such as immune response, cell proliferation
and differentiation, embryogenesis, programmed cell death, and angiogenesis. TNTs can promote
cancer progression, transferring substances capable of altering apoptotic dynamics, modifying the
metabolism and energy balance, inducing changes in immunosurveillance, or affecting the response to
chemotherapy. In this review, we evaluated their influence on hematologic malignancies’ progression
and resistance to therapies, focusing on acute and chronic myeloid and acute lymphoid leukemia.
Abstract:
Effectual cell-to-cell communication is essential to the development and differentiation of
organisms, the preservation of tissue tasks, and the synchronization of their different physiological
actions, but also to the proliferation and metastasis of tumor cells. Tunneling nanotubes (TNTs) are
membrane-enclosed tubular connections between cells that carry a multiplicity of cellular loads, such
as exosomes, non-coding RNAs, mitochondria, and proteins, and they have been identified as the
main participants in healthy and tumoral cell communication. TNTs have been described in numerous
tumors in
in vitro
, ex vivo, and
in vivo
models favoring the onset and progression of tumors. Tumor
cells utilize TNT-like membranous channels to transfer information between themselves or with the
tumoral milieu. As a result, tumor cells attain novel capabilities, such as the increased capacity of
metastasis, metabolic plasticity, angiogenic aptitude, and chemoresistance, promoting tumor severity.
Here, we review the morphological and operational characteristics of TNTs and their influence on
hematologic malignancies’ progression and resistance to therapies, focusing on acute and chronic
myeloid and acute lymphoid leukemia. Finally, we examine the prospects and challenges for TNTs as
a therapeutic approach for hematologic diseases by examining the development of efficient and safe
drugs targeting TNTs.
Keywords:
tunneling nanotubes; cell communication; cancer; hematologic malignancies; leukemia;
multiple myeloma; chemoresistance; miRNAs; mitochondrial transfer
1. Introduction
1.1. General Considerations on Tunneling Nanotubes
Intercellular interactions perform an essential action in tissue homeostasis, and are
a critical element for cells and tissues growth. In fact, as biological complexity increases,
Cancers 2022,14, 659. https://doi.org/10.3390/cancers14030659 https://www.mdpi.com/journal/cancers
Cancers 2022,14, 659 2 of 21
cells must elaborate diverse and more advanced systems to transfer temporal and spatial
data. This cell–cell interaction can occur both through the extracellular space, with the
production and release of exosomes, cytokines, and other mediators, and through cell–cell
contacts that facilitate the association between two cytoplasm (Figure 1a). These types of
intercellular interactions are most efficient over brief distances [13].
Tunneling nanotubes (TNTs) are a new form of direct contact interaction among
cells, as they help cells to “talk” directly with each other over lengthier spaces [
4
6
]
(Figure 1a). This breakthrough contested the classical view of cells, the basic unit of
organisms, as separate elements. The detection of TNTs launched the notion of super-
cellularity, which permits the quick stability of metabolic requirements, as well as stress
elements and organelles, via long-distance transfers between cells not closely in contact;
therefore, TNTs make quick reactions between cells possible despite the diversity of type of
cells and tissues [7].
TNTs are cytoplasmic channels, which are members of the group of membrane protru-
sions, such as filopodia, intercellular bridges, and cytonemes. They regulate the contacts
between cells and are independent of soluble factors [
8
,
9
]. These elements permit the transfer
of cellular content between non-adjacent cells [
10
12
]. TNTs have a length oscillating from
50 nm to 1500 nm [
9
] and, given a particularly high length/diameter ratio, a TNT is like a
one-lane road. Different cell types employ TNTs for specific functions, such as forming a
network of cells, causing an intensification of the signal cascade, or to generate a complex
communication system that accelerates the transport of substances. [
13
]. Some TNTs are
open at both ends, and so have membrane continuity [
14
], while other TNTs are close ended,
containing an immune synapse or a junction as a gating system [15,16] (Figure 1b).
Cancers 2022, 14, x FOR PEER REVIEW 2 of 22
Intercellular interactions perform an essential action in tissue homeostasis, and are a
critical element for cells and tissues growth. In fact, as biological complexity increases,
cells must elaborate diverse and more advanced systems to transfer temporal and spatial
data. This cellcell interaction can occur both through the extracellular space, with the
production and release of exosomes, cytokines, and other mediators, and through cell
cell contacts that facilitate the association between two cytoplasm (Figure 1a). These types
of intercellular interactions are most efficient over brief distances [13].
(a)
Figure 1. Cont.
Cancers 2022,14, 659 3 of 21
Cancers 2022, 14, x FOR PEER REVIEW 3 of 22
(b)
Figure 1. (a) Different types of intercellular interaction. Cells can communicate among each other
via the release of exosomes and cytokines, by connecting through junctions and, as described in this
paper, via tunneling nanotubes (TNTs). TNTs belong to the membrane protrusions group. (b) TNT
connections to cells could be of 3 types. Some TNTs are open ended at both ends, and so display
membrane continuity, while other TNTs are close ended, containing an immune synapse or a junc-
tion as gating system.
Tunneling nanotubes (TNTs) are a new form of direct contact interaction among cells,
as they help cells to “talk” directly with each other over lengthier spaces [46] (Figure 1a).
This breakthrough contested the classical view of cells, the basic unit of organisms, as
separate elements. The detection of TNTs launched the notion of super-cellularity, which
permits the quick stability of metabolic requirements, as well as stress elements and orga-
nelles, via long-distance transfers between cells not closely in contact; therefore, TNTs
make quick reactions between cells possible despite the diversity of type of cells and tis-
sues [7].
TNTs are cytoplasmic channels, which are members of the group of membrane pro-
trusions, such as filopodia, intercellular bridges, and cytonemes. They regulate the con-
tacts between cells and are independent of soluble factors [8,9]. These elements permit the
transfer of cellular content between non-adjacent cells [1012]. TNTs have a length oscil-
lating from 50 nm to 1500 nm [9] and, given a particularly high length/diameter ratio, a
TNT is like a one-lane road. Different cell types employ TNTs for specific functions, such
as forming a network of cells, causing an intensification of the signal cascade, or to gener-
ate a complex communication system that accelerates the transport of substances. [13].
Some TNTs are open at both ends, and so have membrane continuity [14], while other
TNTs are close ended, containing an immune synapse or a junction as a gating system
[15,16] (Figure 1b).
The development of TNTs involves the active transformation of actin filaments from
globular actin (G-actin) into double-helical filament actin (F-actin). The main mediator of
the mechanism of actin polymerization is Arp2/3, a protein complex that is stimulated by
Figure 1.
(
a
) Different types of intercellular interaction. Cells can communicate among each other
via the release of exosomes and cytokines, by connecting through junctions and, as described in this
paper, via tunneling nanotubes (TNTs). TNTs belong to the membrane protrusions group. (
b
) TNT
connections to cells could be of 3 types. Some TNTs are open ended at both ends, and so display
membrane continuity, while other TNTs are close ended, containing an immune synapse or a junction
as gating system.
The development of TNTs involves the active transformation of actin filaments from
globular actin (G-actin) into double-helical filament actin (F-actin). The main mediator of
the mechanism of actin polymerization is Arp2/3, a protein complex that is stimulated
by elements of the Wiskott–Aldrich syndrome protein family (e.g., WASP, WAVE), and is
essential for actin nucleation [17].
In addition to F-actin, cytokeratin strings and microtubules are also identified in TNTs
in some types of cells [1820].
F-actin depolymerization substances stop TNT generation, and TNTs are unstable
transient formations that can polymerize and depolymerize rapidly in 30–60 s [
21
,
22
], with
a lifetime oscillating from only some minutes up to numerous hours [2325] (Figure 2).
Different modalities of TNT generation were recognized [
25
]; the first is the de novo
production of TNTs from filopodia-like projections by an actin-directed phenomenon
which happens in several minutes [
26
]. The second is TNT generation during cell–cell
disconnection after a direct contact. This system has been reported in immune cells, such
as natural killer (NK) cells, macrophages, and T cells, and in rat kidney cells [
27
]. During
the contact, cells generate an immune synapse or fuse, while, with the detachment, a TNT
is produced. As mechanical strengths are essential to generating the TNT after membrane
contact, an appropriate membrane interaction is indispensable for the generation of TNTs.
For instance, T cells generate TNTs only after four minutes of uninterrupted contact [
13
].
For the duration of this contact, adhesion proteins make available an adequate connecting
force for retaining the connection at the ends of TNTs [
28
]. Furthermore, the extension of
TNTs necessitates overcoming the resistance of the actomyosin cortex on the inner surface
of the cell membrane, as well as the membrane stiffness.
Cancers 2022,14, 659 4 of 21
Cancers 2022, 14, x FOR PEER REVIEW 4 of 22
elements of the WiskottAldrich syndrome protein family (e.g., WASP, WAVE), and is
essential for actin nucleation [17].
In addition to F-actin, cytokeratin strings and microtubules are also identified in
TNTs in some types of cells [1820].
F-actin depolymerization substances stop TNT generation, and TNTs are unstable
transient formations that can polymerize and depolymerize rapidly in 3060 s [21,22],
with a lifetime oscillating from only some minutes up to numerous hours [2325] (Figure
2).
Figure 2. A magnified nanotube section showing the double-helical filament actin (F-actin). The
main mediator of the procedure of actin polymerization is Arp2/3, a protein complex. TNTs are able
to polymerize and depolymerize quickly in 3060 s.
Different modalities of TNT generation were recognized [25]; the first is the de novo
production of TNTs from filopodia-like projections by an actin-directed phenomenon
which happens in several minutes [26]. The second is TNT generation during cellcell
disconnection after a direct contact. This system has been reported in immune cells, such
as natural killer (NK) cells, macrophages, and T cells, and in rat kidney cells [27]. During
the contact, cells generate an immune synapse or fuse, while, with the detachment, a TNT
is produced. As mechanical strengths are essential to generating the TNT after membrane
contact, an appropriate membrane interaction is indispensable for the generation of TNTs.
Figure 2.
A magnified nanotube section showing the double-helical filament actin (F-actin). The main
mediator of the procedure of actin polymerization is Arp2/3, a protein complex. TNTs are able to
polymerize and depolymerize quickly in 30–60 s.
TNTs operate as intercellular channels for the transfer of elements of diverse dimen-
sions, comprising ions, mitochondria, microvesicles, exosomes, lysosomes, proteins, and
microRNAs [
13
], and via this transport, TNTs are implicated in different physiological and
pathological phenomena, such as the immune response, cell proliferation and differentia-
tion, embryogenesis, programmed cell death, pathogen transport, and angiogenesis [29].
It has been also demonstrated that TNTs have an essential effect in the transduction of
signals. For instance, Ca
2+
signals can be transmitted via TNTs between distant cells. In
2010, Wang et al. proved that TNTs mediate depolarization coupling in non-neuronal cells,
suggesting that TNTs assist electrical signal transmission [
30
]. Generally, electrical signals
are transported via gap junction or neuronal synapses, which first require a strict contact
for cell communication. Conversely, TNTs may transfer these types of signals over long
distances [
31
]. The rapidity of TNT-dependent transfer is due to the forms of transport. For
active transfer, the speed oscillates from 0.1 to 8 m/s [
32
], which is quicker than passive
transport along the membrane tube. Besides, the transduction of electrical signals through
TNTs occurs in milliseconds [33,34].
Different factors seem able to induce the generation of TNTs, principally, stress situa-
tions, such as infections or inflammations, hypoxia, temperature, x-radiation, and UV and
hydrogen peroxide exposure [
35
43
], which modify cell viability by damaging the DNA or
altering the function of cellular structures. An experiment reported the generation of TNTs
Cancers 2022,14, 659 5 of 21
after an increase in the number of the reactive oxygen species (ROS) in cells. These stressed
cells transmit requests for help to the nearby cells. Therefore, TNTs will be generated by
non-stressed cells to form a communication channel. After the transfer of elements such as
mitochondria, it is possible to avoid cell apoptosis. From this perspective, TNTs might be
considered a tool to increase cell survival during stress [44].
However, other factors seem to contribute to TNT generation. For instance, the
strict control of Rho GTPase activity by Guanine nucleotide exchange factors and GTPase-
activating proteins indicates that these Rho controllers may participate in TNT generation
and clearance [
45
]. Furthermore, several other pathways influence their synthesis, such
as p53-activated pathways, which were stated to be crucial for the generation of TNTs.
Cells generate TNT by stimulating p53, which successively increasing epidermal growth
factor (EGF) expression. EGF stimulates the Akt/PI3k/mTOR system to provoke the actin
polymerization required for TNT synthesis. This procedure is due to the effect of M-sec,
a protein able to modify the cytoskeleton. In fact, the increase in M-sec provokes the
generation of TNTs, while knock-out M-sec models presented a decrease in TNT generation
by as much as one third [
46
,
47
]. However, a study demonstrated that TNTs also form
independently of p53, and the effect of H2O2 on TNT formation is cell-type dependent and
p53 independent [48].
1.2. TNTs and Immune System
A separate discussion needs to be had regarding the formation, structure, and function
of TNTs in the cells of the immune system. In fact, a different cause of TNT generation
might be the Fas ligand receptor in the immune system cells [
49
]. TNTs may regulate
novel controlling systems for immune cell activities, such as chemokine generation, T cell
stimulation, antibody production, or phagocytosis.
Spontaneously, B cells develop a large TNT net that includes not only F-actin, but also
microtubules. B cell receptor- and lipopolysaccharide-originated stimulation signals block
or increase the generation of TNTs. The generation of TNTs may be also controlled by the
amount of RAFT gangliosides, which differ in type and amount in immature and mature
B cells [50].
Matula et al. reported that adipose tissue-derived mesenchymal stem cells (AD-MSCs)
and T cells can transfer cytoplasmic elements via TNTs to induce their immunomodulatory
actions [
51
]. Moreover, the configuration of TNTs is diverse in the different effectors of
the immune system. T cell TNTs contain actin, and no microtubules are identified in
T cells, which is different with respect to the TNTs detected in macrophages. Further-
more, the TNTs developed between T cells are impermeable to calcium ions, and their
configuration is different from the open structures recognized in other cells. T cells can
also receive molecules from antigen-presenting cells (APCs) via TNTs to acquire specific
antigen-presenting abilities [
52
]. Different antigens can be transported through TNTs, and
this transfer in DCs can be stimulated by CD40L+ CD4+ T cells, promoting the onset of
specific T cell responses.
As mentioned above, the TNTs present on the different immune effectors are extremely
heterogeneous from a functional point of view. For instance, the TNTs identified in NK
cells were reported to cooperate with cells over long distances, causing the lysis of remote
target cells. It was also demonstrated that cutting off TNTs can diminish the lysis of target
cells [
16
]. Finally, several cytokines, such as IL-2, IL-12, IL-15, and IL-18, are capable of
generating TNTs in NK cells [16].
Thus, TNTs transmit signals that participate in the activation of effectual immune
responses [
53
]. Moreover, TNTs are the perfect tool for the intracellular transport of antigen
and MHC–antigen complexes (pMHC) between distant immune cells, enhancing T cell
stimulation [
54
]. It has been demonstrated that MHC class I molecules are transported
from one cell to another through TNTs [
55
]. These findings proved that the TNTs regulated
by the HLA-class III-encoded protein LST1 in APCs consent to antigen transport among
the immune cells, which would participate in the antigen cross-presentation [56].
Cancers 2022,14, 659 6 of 21
Finally, TNTs allow the transport of pro-phagocytic factors, and this might also be
relevant for macrophage activity. T cells transport FAS ligands via TNTs, provoking
programmed cell death, after which TNTs can be employed to engage macrophages to
stimulate self-clearance [57].
In consideration of all that has been reported, a rising number of studies have been per-
formed to exploit the features of TNTs to modify the immune response. For instance, Rainy
et al. demonstrated that H-Ras-enriched plasma membrane patches can be transported
from B to T cells by stimulating the generation of TNTs, thus augmenting the function of
T cells [58].
2. TNTs and Cancer
The interaction between tumor cells and neoplastic microenvironments is essential
for tumor progression. Tumor cells may stimulate stromal cells to intensify pathways that
promote cancer cell proliferation, thus facilitating tumor progression. Polak et al. identified
a signal sent from cancer cells to stromal cells via TNTs with the subsequent production of
survival-stimulating factors, such as cytokines [
59
]. Therefore, TNTs might be implicated
in an oncogenic microenvironment framework, and have been identified in numerous
tumor cells, including breast, ovarian bladder cancer, glioblastoma, and neuroblastoma cell
lines [
60
63
]. Furthermore, Ady et al. reported that malignant mesothelioma cells display
20-fold to 80-fold more TNTs with respect to normal mesothelial cells [
64
]. Finally, TNTs are
not only recognized in in vitro tumor cell cultures, but also in in vivo cell cultures [65,66].
In vitro
experiments employing cancer cell lines have clarified several systems through
which TNTs regulate the proliferation and metastasis of tumor cells. TNTs enable homo-
cellular transfer between malignant and normal cells [
40
,
67
]. This material could operate
through various mechanisms, such as the transfer of substances capable of altering the
apoptotic dynamics (pro-growth signals), modifying the metabolism and energy balance,
inducing changes in immunosurveillance, or in the response to chemotherapy. For example,
TNT has recently been reported to propagate the oncogenic information of the K-RAS mu-
tation among colon cancer cells, favoring the spread of the invasive phenotype in recipient
cells. [
68
]. Moreover, numerous experimentations state that TNTs also permit cancer cells
to reset the normal adjacent cells to render them more favorable to the generation of a
tumor niche.
Other materials transferred by TNTs could have an effect in neoplastic disease, such
as microRNAs (miRNAs) and elements able of altering apoptotic dynamics. miRNAs are
small, non-coding, single-stranded RNAs, which have been involved in diverse physiologic
and pathologic phenomena, such as the immune response, oxidative stress response,
angiogenesis, neural development, DNA repair, and tumor development [
69
]. It has been
described in ovarian tumors that TNTs ease the transfer of oncogenic miRNAs between
cancer cells and between cancer and nearby stromal cells [63].
Apoptotic and anti-apoptotic inputs can be also transported via TNTs [
16
]. The
participation of TNTs in apoptotic dynamics was demonstrated in T cells, in which apoptotic
signals are transmitted through TNTs, and where immune stimulation induces increased
TNT generation. In fact, it was demonstrated that phagocytosis signals are transported
from apoptotic to normal cells to aid the immune effectors to identify an injured cellular
area [
57
]. An altered number of the functions of TNTs could consequently change the
cellular self-destruction aptitude of the tumoral cells.
Furthermore, angiogenesis is a characteristic of tumors [
70
,
71
]. It was evidenced that
TNTs may stimulate angiogenesis by creating contacts between pericytes and between
pericytes and endothelial cells. For instance, it was reported that pericytes generate TNTs
and promote the proliferation and ramification of vessels in glioblastoma tissues. Longer
TNTs can link far-away vessels, while short TNTs may join adjacent sprouting vessels.
TNTs that link endothelial cells also include lipid drops, which are augmented after VEGF
treatment [
72
,
73
]. Moreover, miRNA transport between endothelial cells and tumor cells via
Cancers 2022,14, 659 7 of 21
TNTs has lately been correlated to cancer progression. It was also reported that metastatic
cancer cells generated TNT-like bridges with endothelial cells [74].
Finally, a crucial role of TNTs in tumors correlates to bioenergetics. The greater part
of human cells employ mitochondria as the principal font of energy. Numerous studies
suggest that some cancers, such as endometrial tumors or pancreatic cancer, depend on
oxidative phosphorylation (OXPHOS) and augmented mitochondrial metabolism [75,76].
Tumor cells can discharge complete mitochondria or their elements, such as mitochon-
drial DNA, to the extracellular area [
77
]. These elements function as damage-associated
molecular patterns (DAMPs) that stimulate the immune effectors [
78
,
79
], inducing in-
flammation and immunosuppression, thus modifying the proliferation ability of the can-
cer [
80
,
81
]. Therefore, the modulation of cancer mitochondria is an essential system that
helps tumor cells to avoid immunosurveillance [
82
,
83
]. Several findings proved that TNTs
are the principal transfer mechanism for mitochondria in both normal and cancer cells [
84
].
Molecular motors are essential for the effective transfer of mitochondria through
TNTs [
37
]. Precisely, myosin Va and myosin X have been identified alongside mitochondria
in TNTs [
85
,
86
], while certain donor cells show a great expression of the small GTPase
Miro1 contained on the external surface of mitochondria [
87
]. When Miro1 was reduced in
MSCs cultured with LA-4 epithelial cells, mitochondrial transport was ineffectual, while
Miro1 increase led to the improved capacity of MSCs to transfer mitochondria [
88
]. Miro1
appears to organize mitochondrial passage along TNTs by supporting the formation of a
molecular motor apparatus [89].
The transport of mitochondria via TNTs was also reported between the cancer milieu
and tumor cells and between cancer cells and the metabolic actions of the accepted mi-
tochondria, which was displayed in several experiments. TNT-mediated mitochondrial
transfer changed the energetic metabolism of the accepting cell, causing increased OXPHOS
and ATP generation [
90
,
91
]. The achievement of mitochondria by tumor cells provoked an
increase in the growth and capacity of progression.
Moreover, resistance to tumor treatment is still a critical problem, causing relapse and
decreased overall survival. Several mechanisms that promote chemoresistance have been
reported [
92
,
93
], and it is recognized that aggressive aptitudes and chemoresistance are
correlated to the augmented communication function in tumor cells, and TNTs could have
an effect in the onset of chemoresistance. Mitochondrial transfer may induce chemore-
sistance through different systems, comprising the inhibition of programmed cell death,
the decreased production of ROS, and the increased salvaging of cells with altered mito-
chondria [
94
]. For instance, mitochondria have been shown to be transported via TNTs
between RT4 (less aggressive) and T24 (extremely aggressive) bladder cancer cells with
the stimulation of mTOR and other pathways to augment the aggressive potential of RT4
cells [
95
]. An analogous system of chemoresistance has been reported in tumor cells that
were isolated from patients and then treated with doxorubicin [
62
]. Doxorubicin causes
TNT generation in a dosage-dependent manner. Tumor cells that are sensitive to chemother-
apy could transfer doxorubicin to resistant cells through TNTs [
62
]. These findings led to
the insertion of antineoplastic drugs to the number of cellular stresses capable of stimu-
lating TNT generation. Moreover, the transport of chemotherapeutic substances not only
decreases the amount of drug that the target cells are receiving, but also endangers adjacent
normal cells to the damaging actions of doxorubicin, while TNTs increase the rate of sur-
vival of cancer cells by reducing the amount of drug in the cellular microenvironment [
62
].
However, the preferential killing of sensitive cancer cells, decreasing the amount of cancer
cells contending for nutrients, improves the ability of resistant cells to proliferate [62].
Lastly, TNTs might mediate other effects, such as the so-called bystander effects [
96
,
97
],
where non-irradiated cells display a radiation response with augmented programmed
cell death and increased DNA damage [
98
]. It is likely that these effects are due to the
TNTs transporting factors which are discharged by irradiated cells to their neighboring
cells [99,100].
Cancers 2022,14, 659 8 of 21
3. TNTs and Hematological Malignancies
The effects of TNT transfer in the tumor microenvironment are critical for the onset,
progression, and drug resistance also in hematological tumors [
101
], as TNTs have an
essential role in the interaction between tumor cells and bone marrow-derived cells [21].
An example of a hematological disease in which TNTs appear to play a role is mul-
tiple myeloma (MM), the second most common hematologic tumor. It remains incurable
for most patients, even though essential progress has been made in the therapy of this
tumor [102106],
Metabolic changes are indispensable for the generation and proliferation of MM
cells, and the MM BM milieu sustains MM growth by stimulating mitochondria-derived
oxidative phosphorylation (Figure 3). Marlein et al. identified mitochondria within the
TNTs connecting BMSCs and myeloma cells [
107
]. TNTs were calculated by analyzing
the amount of TNT anchor points (TAP) that were existent on the membrane of BMSCs.
TAPs are portions of MM cell membranes that are discovered on the BMSCs after the
TNT link is interrupted. Moreover, it was stated that the CD38 existent on MM cells is
essential for TNT generation, as CD38 was present within the TAPs on the BMSCs (Figure 3).
Moreover, CD38 is greatly present on MM cells, and it is the target of treatments for MM.
The amount of CD38 was recognized to be associated with TNT generation, as an increase
in CD38 facilitates mitochondrial transport from BM stromal cells (BMSCs) to primary
MM cells [
107
]. In an
in vivo
animal study, it has been demonstrated that changing CD38
expression through the shRNA-mediated knockdown of CD38 modifies mitochondrial
transfer; moreover, blocking CD38 inhibited mitochondrial transport, caused a reduction in
the amount of MM, and enhanced animal survival.
Cancers 2022, 14, x FOR PEER REVIEW 9 of 22
Figure 3. The effects of TNT transfer in the tumor microenvironment are critical for cancer onset
and progression. Metabolic changes are indispensable for the beginning and proliferation of MM
cells. RNA, mitochondria, cytokines, exosomes, lysosomes, vesicles, ions, and proteins move from
one cell to another via TNTs. TNT anchor points (TAP) are portions of membranes from the MM
cells that are discovered on the BMSCs after the TNT link is missed. It was stated that CD38 existent
on MM cells is essential for TNT generation, as CD38 was present within TAPs on the BMSCs.
Finally, the transfers mediated by TNTs could also be critical in the onset of organ
alterations by MM, such as the occurrence of lytic lesions. In fact, fast intercellular transfer
via TNTs has been reported during osteoclastogenesis, and TNTs are identified in osteo-
clast precursors. The inhibition of TNT generation by blocking actin assembly or with M-
Sec RNAi considerably reduced osteoclastogenesis, which was associated with the stimu-
lation of the M-Sec gene, whose expression was enhanced by RANKL administration on
an osteoclast precursor cell line [108]. Interfering with this system could be an effective
approach for the prevention or treatment of bone disease in patients with MM.
However, most of the studies on the effects of TNTs in hematological diseases con-
cern acute and chronic myeloid and lymphoid leukemias.
Acute myeloid leukemia (AML) is distinguished by the infiltration of the BM by the
clonal and inadequately differentiated cells of the hematopoietic system [109].
The destiny of hemopoietic stem cells (HSC) is strongly regulated by cell-intrinsic
elements, such as transcriptional and epigenetic controllers, and by cell-extrinsic ele-
ments, such as cytokines, ligands, and adhesion molecules [110]. Numerous data have
demonstrated the existence of cell-to-cell communications between HSC and the niche
cells, such as stromal and endothelial cells, or osteoblasts, which are fundamental for HSC
protection and differentiation [111,112].
Moreover, the bone marrow microenvironment (BMME) defends not only HSCs but
also their cancerous equivalents, the leukemia-initiating cells (LICs). Inside the communi-
cation that happens between HSCs, LICs, and the BMME, the transport of cellular com-
ponents and of mitochondria is the most relevant to intercellular communication
The existence of leukemic TNTs has been described, and AML cells have been re-
ported to generate homotypic and heterotypic TNTs with BM cells [113,114]. The latter
Figure 3.
The effects of TNT transfer in the tumor microenvironment are critical for cancer onset and
progression. Metabolic changes are indispensable for the beginning and proliferation of MM cells.
RNA, mitochondria, cytokines, exosomes, lysosomes, vesicles, ions, and proteins move from one cell
to another via TNTs. TNT anchor points (TAP) are portions of membranes from the MM cells that are
discovered on the BMSCs after the TNT link is missed. It was stated that CD38 existent on MM cells
is essential for TNT generation, as CD38 was present within TAPs on the BMSCs.
Cancers 2022,14, 659 9 of 21
Finally, the transfers mediated by TNTs could also be critical in the onset of organ
alterations by MM, such as the occurrence of lytic lesions. In fact, fast intercellular transfer
via TNTs has been reported during osteoclastogenesis, and TNTs are identified in osteoclast
precursors. The inhibition of TNT generation by blocking actin assembly or with M-Sec
RNAi considerably reduced osteoclastogenesis, which was associated with the stimulation
of the M-Sec gene, whose expression was enhanced by RANKL administration on an
osteoclast precursor cell line [
108
]. Interfering with this system could be an effective
approach for the prevention or treatment of bone disease in patients with MM.
However, most of the studies on the effects of TNTs in hematological diseases concern
acute and chronic myeloid and lymphoid leukemias.
Acute myeloid leukemia (AML) is distinguished by the infiltration of the BM by the
clonal and inadequately differentiated cells of the hematopoietic system [109].
The destiny of hemopoietic stem cells (HSC) is strongly regulated by cell-intrinsic
elements, such as transcriptional and epigenetic controllers, and by cell-extrinsic elements,
such as cytokines, ligands, and adhesion molecules [
110
]. Numerous data have demon-
strated the existence of cell-to-cell communications between HSC and the niche cells, such
as stromal and endothelial cells, or osteoblasts, which are fundamental for HSC protection
and differentiation [111,112].
Moreover, the bone marrow microenvironment (BMME) defends not only HSCs but
also their cancerous equivalents, the leukemia-initiating cells (LICs). Inside the communica-
tion that happens between HSCs, LICs, and the BMME, the transport of cellular components
and of mitochondria is the most relevant to intercellular communication.
The existence of leukemic TNTs has been described, and AML cells have been reported
to generate homotypic and heterotypic TNTs with BM cells [
113
,
114
]. The latter can
transport mitochondria to AML cells, favoring their survival. Generally, as reported
above, tumor cells depend on aerobic glycolysis to produce adenosine triphosphate (ATP),
as theorized by Warburg in 1956 [
115
,
116
], and this is an effect of the stimulation of
the oncogenes that activate glycolysis [
117
]. However, the metabolic activity of AML
blasts differs from most other cancer cells in that AML cells are primarily dependent on
mitochondrial oxidative phosphorylation for their survival. [
118
]. It is also evidenced that
AML cells have greater mitochondria amounts with respect to normal hematopoietic stem
cells [119,120].
Mitochondrial transport was reported in numerous forms of hematological malignan-
cies, where it has a pro-neoplastic meaning [
121
]. Omsland et al. reported that the TNTs
connecting AML cells and stromal cells ease the transport of mitochondria, and AML cells
separated from BM produced more TNTs than cells without stromal elements [
113
]. They
discovered that the NF-
κ
B pathway was involved in TNT production and control, studying
the occurrence of TNTs on AML cell lines and primary AML cells. Moreover, cytarabine,
both alone and with daunorubicin, reduces TNT formation and blocks NF-
κ
B activity,
offering further proof in favor of the participation of the NF-
κ
B system in TNT generation.
Remarkably, daunorubicin was reported to concentrate into lysosomes in TNTs joining
AML cells, supporting the action of TNTs as drug transferring tools [
110
]. Leukemia-stroma
TNTs were reported also to control cytokine secretion, and this might participate in the
onset of leukemia [122].
With regards to the systems that control the transit of mitochondria, an essential action
appears to be performed by oxidative stress, which has also been reported to support
tumor growth and progression [
123
125
]. In AML cells, NOX2 produces superoxide,
which pushes bone marrow stromal cells (BMSC) toward AML blasts in the transport
of mitochondria via AML-originated TNTs. Furthermore, blocking NOX2 results in the
inhibition of mitochondrial transport, and an increase in AML programmed cell death.
Adding cytochalasin B to the culture, mitochondria proceed from BMSC to AML blasts
essentially via TNTs. Nevertheless, although mitochondrial transport from BMSC to normal
CD34+ cells occurs in reaction to oxidative stress, the NOX2 block has no effect on normal
CD34+ cell survival. It was suggested that treatment further augments the oxidative stress
Cancers 2022,14, 659 10 of 21
milieu of the BM caused by the AML blast, and so increases mitochondrial transport.
This could be important from the perspective of obtaining minimal residual disease after
treatment. It was observed that the few remaining AML blasts may present an exceptionally
increased number of mitochondria. This condition would support blast survival and may
provoke a relapse [
84
]. Thus, affecting this specific system may be useful in upcoming
approaches designed to decrease the number of relapses from minimal residual disease.
Saito et al. evaluated how the BM milieu modifies the response to OXPHOS reduction
in AML by employing a complex I OXPHOS inhibitor, IACS-010759 [
126
]. Direct com-
munications with BM stromal cells stimulated mitochondrial respiration and increased
the transport of mitochondria that originated from MSCs to AML cells through TNTs.
Moreover, the reduction of OXPHOS also provoked mitochondrial fission and increased
mitophagy in AML cells. As mitochondrial fission is recognized to increase cell migra-
tion [
127
], the authors employed electron microscopy to study mitochondrial transfer from
cells to MSCs, and stated that cytarabine augmented the mitochondrial transport stimu-
lated by OXPHOS inhibition. Thus, affecting mitochondrial respiratory activity is a new
possibility to proficiently destroy leukemic cells [120,128].
In was also reported that the portion of LICs that have acquired mitochondria during
cytarabine administration are more resilient to cell death and possess a greater proliferation
capacity [
114
]. Thus, pharmacological methods modifying leukemic metabolism to an
inferior OXPHOS significantly enhance the therapeutic effects of cytarabine [129].
3.1. TNTs and Acute Lymphoblastic Leukemia (ALL)
B ALL cells are located in the BM and are able to alter normal hematopoietic stem cell
niches [130].
Several studies have recognized TNT generation as a new controller of communica-
tion between B cell precursor (BCP)-ALL cells and their BM niche, which facilitates the
signaling from ALL cells to MSCs, and modifies the production of chemokines in the BM
milieu. A study demonstrated that ALL cells utilize TNTs to transfer communications
to MSCs [
59
]. This event causes the production of pro-survival cytokines, such as inter-
leukin 8, interferon-gamma-inducible protein 10/CXC chemokine ligand 10, and monocyte
chemotactic protein-1/CC chemokine ligand 2 [
59
]. These data suggest that TNTs are
essential for the survival of ALL cells, while the interference of TNTs remarkably reduces
the leukemogenic processes [130].
Burt et al. studied the MSC niche in adult ALL patients [
131
]. Primary MSC and MSC
cell lines became activated after the administration of cytarabine (AraC) and daunorubicin
(DNR), drugs that are able to induce ROS formation. This activation was reduced by admin-
istering the antioxidant N-acetyl cysteine. Chemotherapy-stimulated MSC cell lines were
studied in a co-culture experimental model with ALL targets. Stimulated MSC blocked
treatment-provoked programmed cell death in ALL targets, with mitochondrial trans-
port occurring via TNTs. The decrease in mitochondrial transport through mitochondrial
diminution or by interfering with TNT generation and employing microtubule inhibitors,
such as vincristine (VCR), avoided the antiapoptotic activity of the stimulated MSC. Steroids
also stopped the stimulation of MSC. It was also reported that AraC-induced the stimula-
tion of MSC, mitochondrial transport, and mitochondrial amount increased in an animal
model of ALL [
131
]. These findings suggest a therapeutic strategy for successful therapy
with ALL.
A recent study by Manshouri et al. demonstrated the generation of chemoresis-
tance against Janus kinase 2 (JAK2) inhibitors by BM-MSC-produced chemokines in JAK2-
mutated cells [
132
]. BCP-ALL cells employ TNTs to provoke an inflammatory cytokine en-
vironment within the BM milieu [
133
]. Several of these cytokines are involved in leukemia
persistence [
134
]. This inflammatory condition was partially overturned, and ALL cell sur-
vival was reduced when TNTs were blocked [
135
] (Figure 4). Furthermore, it was reported
that TNT signaling from MSCs to ALL cells might also provoke the chemoresistance of
Cancers 2022,14, 659 11 of 21
leukemic cells (Figure 4). For example, TNTs have been reported to transfer drug efflux
pumps, such as P-glycoproteins, toward tumor cells [92].
Cancers 2022, 14, x FOR PEER REVIEW 12 of 22
Figure 4. BCP-ALL cells employ TNTs to provoke an inflammatory microenvironmental condition
within BM cells. The transfer of pro-inflammatory substances, such as specific microRNAs, alarm-
ins, and cytokines, was involved in tumor development and progression in several tumors. Several
cytokines were demonstrated to be involved in leukemia persistence. TNTs were blockaded, reduc-
ing this inflammatory condition and reducing ALL cell survival.
A unique sort of transfer of mitochondria due to TNTs is that correlated to autoph-
agy, a condition that decomposes and reutilizes harmed cellular elements, such as pro-
teins and organelles. This procedure has been involved in tumor onset and inhibition.
Autophagy is operated by vesicles called autophagosomes, which are formed by an actin
cytoskeleton, and TNT generation is also due to actin. Remarkably, autophagy stimulation
via the starvation of cells has been recognized to increase the generation of TNTs, propos-
ing a connection between these two events. Moreover, TNT transfer causes the production
of pro-survival cytokines, and autophagy is also a controller of cytokine production, and
this signaling is regulated by mitochondrial ROS and DNA [136138]. The transport of
autophagosomes and mitochondria from leukemic cells to MSCs might consequently jus-
tify the liberation of helpful elements by the tumor milieu. Remarkably, the production of
the adhesion molecule ICAM1 is recognized to be increased by cytokines and ROS [139],
Figure 4.
BCP-ALL cells employ TNTs to provoke an inflammatory microenvironmental condition
within BM cells. The transfer of pro-inflammatory substances, such as specific microRNAs, alarmins,
and cytokines, was involved in tumor development and progression in several tumors. Several
cytokines were demonstrated to be involved in leukemia persistence. TNTs were blockaded, reducing
this inflammatory condition and reducing ALL cell survival.
A unique sort of transfer of mitochondria due to TNTs is that correlated to autophagy,
a condition that decomposes and reutilizes harmed cellular elements, such as proteins and
organelles. This procedure has been involved in tumor onset and inhibition. Autophagy is
operated by vesicles called autophagosomes, which are formed by an actin cytoskeleton,
and TNT generation is also due to actin. Remarkably, autophagy stimulation via the
starvation of cells has been recognized to increase the generation of TNTs, proposing a
connection between these two events. Moreover, TNT transfer causes the production of
pro-survival cytokines, and autophagy is also a controller of cytokine production, and
this signaling is regulated by mitochondrial ROS and DNA [
136
138
]. The transport of
autophagosomes and mitochondria from leukemic cells to MSCs might consequently justify
the liberation of helpful elements by the tumor milieu. Remarkably, the production of the
adhesion molecule ICAM1 is recognized to be increased by cytokines and ROS [
139
], and
its transfer to MSCs may facilitate TNT action. A study demonstrated that autophagosomes
are transferred via TNTs, and the transport of autophagosomes and mitochondria from
Cancers 2022,14, 659 12 of 21
ALL cells to MSCs might be an essential system that leukemic cells employ to modify the
BM milieu. This study confirms that leukemic cells transport autophagosomes to MSCs to
increase autophagy-provoked cytokine production, and are able to modify the progression
of ALL [140].
3.2. TNTs and T Cell Acute Lymphoblastic Leukaemia (T-ALL)
T cell acute lymphoblastic leukemia is an aggressive hematological malignancy. De-
spite the high cure rate of T-ALL, chemoresistance remains a critical clinical barrier.
T-ALL BM-MSCs defend leukemic cells from treatment, although the causal mech-
anism is unknown. In a study on Jurkat cells, chemotherapy resulted in intracellular
oxidative stress. Jurkat cells transferred large numbers of mitochondria to MSCs, but
withdrew a small number of mitochondria from MSCs, thus causing chemoresistance.
This mitochondrial transfer procedure was performed via TNT. Furthermore, Jurkat cells
adhered to MSCs in the culture medium, and this process was due to ICAM-1. The use of
an antibody against ICAM-1 reduced the amount of adhering Jurkat cells, and increased
chemotherapy-caused cell death. Inhibiting mitochondria transport with cytochalasin D
reduced the ability of MSCs to defend T-ALL cells. Therefore, the reduction of T-ALL
cell/MSC adhesion-originated mitochondria transfer may be a new method for T-ALL
therapy, and increasing mitochondrial ROS represents a possible means of destroying
T-ALL cells [141].
A role of TNTs has been demonstrated in other forms of hematological malignancies
involving T lymphocytes. Adult T cell leukemia/lymphoma (ATL) is a malignancy of
peripheral T lymphocytes provoked by human T cell leukemia virus type 1 infection
(HTLV-1). This leukemia is extremely resistant to treatment, and it is estimated that at
least 5–10 million patients are infected with HTLV-1, the first human oncogenic retrovirus
detected [142].
In contrast to HIV-1, cell-free HTLV-1 in the blood of HTLV-1 infected patients is
poorly infectious [
143
]. Thus, cell-to-cell communication is the principal modality of HTLV-
1 transmission and diffusion [
144
,
145
]. Therefore, systems able to decrease cell-to-cell virus
transmission have the possibility to diminish the viral burden and the onset of leukemia.
Two diverse modalities of cell-to-cell connections have been reported in HTLV-1 diffusion.
The virological synapse is a virus caused by strong cell-to-cell connection, generating a
synaptic intercellular fissure permitting viral transmission. This provokes a polarization
of the microtubule-organizing center in the giver cell to the virological synapse [
146
]. For
longer distances, cellular channels have been described, and the diffusion of HTLV-1 via
these forms of cell-to-cell contacts could offer a defense from identification by the immune
system [147].
Omsland et al. stated that HTLV-1-bearing cells are connected by TNTs [
145
]. More-
over, TNTs connect infected and uninfected T cells, and the viral proteins Tax and Gag are
present in these TNTs. TNT generation is stimulated by HTLV-1 protein p8. The admin-
istration of cytarabine to MT-2 cells decreases the number of TNTs and TNT generation
stimulated by the p8 protein. Thus, cytarabine could be a new anti-HTLV-1 treatment able
to interfere with viral diffusion [148].
3.3. TNTs and Chronic Myeloid Leukemia (CML)
The communications between cells due to TNTs are also relevant in chronic myeloid
leukemia (CML), a myeloid stem cell malignancy due to the tyrosine kinase BCR-ABL1
fusion protein originated from the chromosomal translocation t(9;22) [149].
Numerous reports demonstrated that stromal and leukemic cells interrelate bidirec-
tionally, to sustain leukemogenesis [
150
152
]. Furthermore, cellular interconnections are
essential in the onset in the stroma-originated chemoresistance of CML.
TNTs have been suggested to be involved in CML onset and in the treatment re-
sponse [
153
]. Kolba et al. described a direct transport of vesicles through TNTs from
stromal to CML cells, providing a defense against imatinib-induced programmed cell
Cancers 2022,14, 659 13 of 21
death. Several specific proteins with effects in cell survival are transported with these
vesicles [154].
A different study evaluated TNTs in CML cells after the administration of tyrosine
kinase inhibitors (TKIs) and interferon-
α
(IFN
α
) [
155
]. It was demonstrated that CML
cells from patients in chronic phase or from blast crisis phase cell lines, Kcl-22 and K562,
generated scarce or no TNTs. The administration of imatinib increased TNT generation in
both Kcl-22 and K562 cells, while IFN
α
or nilotinib worked in Kcl-22 cells only. Ex vivo
treated cells from CML subjects demonstrated limited modifications in TNT generation
analogously to BM cells from normal subjects. Remarkably,
in vivo
nilotinib administration
in a Kcl-22 experimental animal model caused morphological variations and the occurrence
of TNT-like formations in the Kcl-22 cells. These findings reveal that CML cells present
small amounts of TNTs, but chemotherapeutic agents increase TNT generation. To confirm
the participation of BCR-ABL1 in TNT generation, a doxycycline-inducible BCR-ABL1
Ba/F3 cell system was used. The fact that the administration of imatinib did not cause an
increase in TNT formation in BCR-ABL1 cells presenting Ba/F3, but rather in Ba/F3 cells
alone, indicates that the increase in TNT most likely involves other elements besides the
inhibition of BCR-ABL1. This was also demonstrated by the evaluation of intracellular
signaling through mass cytometry, in which known BCR-ABL1 targets, such as phospho-
STAT-5, were reduced by TKI administration, regardless of the reported differences in TNT
response [155].
The therapeutic effects of TKIs and IFN
α
in CML may thus be more dependent on
leukemia–stroma and cell–cell communications than before estimated.
4. Conclusions
The participation of TNTs in various pathological conditions makes them an essential
target for treating diseases such as leukemia [
156
]. Recognizing the molecular bases for TNT
generation and the type of molecular information transferred between leukemic and BM
cells through TNTs
in vivo
represents a crucial field for pharmacological experimentations.
Our ability to influence TNTs
in vivo
will be helpful to attain an efficient management of
hematologic malignancies.
Numerous substances affecting different pathways, such as NF-KB and mTOR, or
blocking actin polymerization, thus causing the reduction of TNTs formation, have been
identified, including cytochalasin D, cytarabine, latrunculin A and B, daunorubicin,
everolimus, metformin, nocodazole CK-666, ML-141, 6-thio-GTP, BAY-117082, and oc-
tanol [
153
]. The administration of these molecules seems appropriate for antileukemic
treatment, reducing the transport of biological substances between leukemic cells and
between leukemic and microenvironment cells.
Moreover, TNTs can also offer an efficient instrument for long-range cellular drug
delivery [64].
In the context of studies on the use TNTs as tools for drug transport and delivery
to leukemic cells, it has been reported that polymeric nanoparticles can be transported
through TNTs. This strategy, combining polymeric nanoparticles as a transmitter and TNTs
as a transferer for antileukemic treatment, would make the delivery of the drug to all the
cellular elements of the BM uniform, especially in a hypoxic context [157].
However, the modification of TNT functions can be used to achieve goals diametrically
opposite to those reported above. It could be useful to use the ability of TNTs to support
cell viability as part of leukemic treatment: this strategy could be used in hematological
patients undergoing stem cell transplantation, whose main constraint is the senescence
reached by the transplanted cells, reducing their effectiveness over time [158].
Nowadays, only a limited number of substances, such as arachidonic acid and doxoru-
bicin, have been demonstrated ta to increase TNT generation in tumor cells [
70
]. Identifying
TNT inhibitors seems more feasible than finding drugs capable of stimulating TNT genera-
tion. Actin inhibitors have been extensively employed in
in vitro
experiments. Neverthe-
less, these substances are difficult to use as drugs due to their cytotoxic properties [
159
161
].
Cancers 2022,14, 659 14 of 21
In fact, there can be many possible negative effects with the clinical use of molecules capable
of modifying TNT-mediated transfer. In fact, TNTs are principally constituted by actin,
which is crucial for different cellular functions and for the preservation of the cytoskeleton:
we must target only pathological systems, while protecting normal elements and functions.
Molecules exclusively affecting the proteins that control TNT generation may be those
with less toxicity. In some reports, the number and function of TNTs could be decreased
by the short hairpin RNA (shRNA)-derived knockdown of CD38 in MM cells [
107
], by
altering the IL-10/STAT3 pathway in macrophages [
162
], or by inhibiting Ca
2+
/calmodulin-
dependent protein kinases II in neuronal cell lines [
163
]. In any case, it is challenging to
identify wide-spectrum inhibitors for the various TNT-generating mechanisms. A different
approach is to destroy TNT links by altering the generation or the activity of some cell
adhesion proteins, such as cadherin [
28
]. Moreover, M-sec, a controller of TNT generation,
has also been suggested as a possible target to influence mitochondrial transport; TNF-
alpha inhibitors, such as those employed for the treatment of autoimmune diseases, may
decrease TNT generation, as M-sec is TNF-alpha inducible [164].
Other experiments have demonstrated that metformin or the mTOR inhibitor,
everolimus, reduce TNT generation
in vitro
[
36
], while cytochalasin B and D block the actin
polymerization that inhibits TNT generation [
165
]. Nevertheless, as reported above, as
inhibitors, they are too unspecific, lacking the essential specificity for successful therapeutic
applications. Cytarabine was also described to block TNT generation, and it is presently
used to treat different forms of leukemia.
In any case, numerous investigations have been launched to evaluate the inhibition of
TNT generation as a possible oncological treatment. The initial findings have displayed
that the reduction of the TNT-derived transport of the mitochondria causes an increase in
chemotherapy-caused cell death and in a more prolonged animal survival [
141
]. Thus, it
seems that inhibiting TNT connections could be a useful approach for cancer treatment.
On the contrary, as mentioned above, we must stimulate the generation of TNT if the
contact derived from TNT allows the transfer of molecules capable of repairing damaged
healthy cells [
166
]. The capacity of cells to utilize TNTs as a channel to help distressed cells
might be a biological mechanism for cell or tissue self-repairing.
The manipulation of TNTs could also be useful to improve the spread of antineoplastic
drugs. In fact, the distribution of macromolecular drugs in tumor tissues generally is slow,
and scarcely reaches all target cells [
167
]. The use of antineoplastic delivery via TNT could
be a new method for administering drugs in a highly specific way, and could be an effective
modality for the circulation of anticancer substances among related tumor cells [167].
Notwithstanding these encouraging possibilities, other problems for therapeutic use
of TNTs remain. One such challenge depends on the instability of these formations, as they
are susceptible to several types of stress, such as light, trypsinization, mechanical stress,
chemicals, and transfection, all of which can provoke the break of these formations. These
problems are evident in
in vitro
models. Moreover, when attempting to reproduce the
in vivo
tumor milieu, several signaling components, such as exosomes and microvesicles,
can have a mystifying effect on results [153].
To lock the break between our present comprehension and future clinical treatments,
we need better knowledge of TNT-dependent communication, and new perspectives for
detecting other TNT generation pathways would permit us to target them in treating an
increasing number of TNT-involved malignancies [
168
]. Nonetheless, the recent advances
in screening TNT inhibitors may accelerate the advent of a new epoch for TNT research
and translational medicine in the treatment of hematologic diseases.
Author Contributions:
Conceptualization, A.A., M.D.G. and S.G.; methodology, G.C. and C.M.;
software, G.C.; data curation, G.C. and C.P.; writing—original draft preparation, A.A.; writing—
review and editing, A.A., M.D.G., C.M., C.P., M.C. and S.G. Figure conceptualization and design,
M.C. and G.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Cancers 2022,14, 659 15 of 21
Conflicts of Interest: The authors declare no conflict of interest.
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... Structure and formation of TNTs TNTs were first described as several micrometers long actincontaining membrane connections formed between PC12 cells Frontiers in Cell and Developmental Biology frontiersin.org in vitro, mediating transfer of vesicles and organelle (Rustom et al., 2004). Since this initial observation, TNTs have been observed in a number of both cancer and non-cancerous cell types, both in vitro and in vivo (Islam et al., 2012;Jiang et al., 2016;Berridge and Neuzil, 2017;Hekmatshoar et al., 2018;Mittal et al., 2019;Pinto et al., 2020;Sahinbegovic et al., 2020;Tiwari et al., 2021;Allegra et al., 2022;Khattar et al., 2022). Although capable to move many different cargos (miRNA, lysosomes, liposomes, Golgi vesicles, calcium, etc.) across connections lasting for minutes to hours, most common cargo transferred via TNTs are mitochondria. ...
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