Inhibition of Tunneling Nanotubes between Cancer Cell and the Endothelium Alters the Metastatic Phenotype.
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ABSTRACT:
SUBMITTER: Dash C
PROVIDER: S-EPMC8200952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.
| S-EPMC4499808 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-12-01 | GSE209972 | GEO
Project description:Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.
| S-EPMC7601615 | biostudies-literature
Project description:Using tunneling nanotubes (TNTs), various pathological molecules and viruses disseminate to adjacent cells intercellularly. Here, we show that the intracellular invasion of Mycoplasma hyorhinis induces the formation of actin- and tubulin-based TNTs in various mammalian cell lines. M. hyorhinis was found in TNTs generated by M. hyorhinis infection in NIH3T3 cells. Because mycoplasma-free recipient cells received mycoplasmas from M. hyorhinis-infected donor cells in a mixed co-culture system and not a spatially separated co-culture system, direct cell-to-cell contact via TNTs was necessary for the intracellular dissemination of M. hyorhinis. The activity of Rac1, which is a small GTP binding protein, was increased by the intracellular invasion of M. hyorhinis, and its pharmacological and genetic inhibition prevented M. hyorhinis infection-induced TNT generation in NIH3T3 cells. The pharmacological and genetic inhibition of Rac1 also reduced the cell-to-cell dissemination of M. hyorhinis. Based on these data, we conclude that intracellular invasion of M. hyorhinis induces the formation of TNTs, which are used for the cell-to-cell dissemination of M. hyorhinis. [BMB Reports 2019; 52(8): 490-495].
| S-EPMC6726209 | biostudies-literature
Project description:Tunneling nanotubes (TNTs) represent a novel route of intercellular communication. While previous work has shown that TNTs facilitate the exchange of viral or prion proteins from infected to naïve cells, it is not clear whether the viral genome is also transferred via this mechanism and further, whether transfer via this route can result in productive replication of the infectious agents in the recipient cell. Here we present evidence that lung epithelial cells are connected by TNTs, and in spite of the presence of neutralizing antibodies and an antiviral agent, Oseltamivir, influenza virus can exploit these networks to transfer viral proteins and genome from the infected to naïve cell, resulting in productive viral replication in the naïve cells. These observations indicate that influenza viruses can spread using these intercellular networks that connect epithelial cells, evading immune and antiviral defenses and provide an explanation for the incidence of influenza infections even in influenza-immune individuals and vaccine failures.
| S-EPMC5216422 | biostudies-literature
Project description:Intercellular communication is vital to the ecosystem of cancer cell organization and invasion. Identification of key cellular cargo and their varied modes of transport are important considerations in understanding the basic mechanisms of cancer cell growth. Gap junctions, exosomes, and apoptotic bodies play key roles as physical modalities in mediating intercellular transport. Tunneling nanotubes (TNTs)-narrow actin-based cytoplasmic extensions-are unique structures that facilitate direct, long distance cell-to-cell transport of cargo, including microRNAs, mitochondria, and a variety of other sub cellular components. The transport of cargo via TNTs occurs between malignant and stromal cells and can lead to changes in gene regulation that propagate the cancer phenotype. More notably, the transfer of these varied molecules almost invariably plays a critical role in the communication between cancer cells themselves in an effort to resist death by chemotherapy and promote the growth and metastases of the primary oncogenic cell. The more traditional definition of "Systems Biology" is the computational and mathematical modeling of complex biological systems. The concept, however, is now used more widely in biology for a variety of contexts, including interdisciplinary fields of study that focus on complex interactions within biological systems and how these interactions give rise to the function and behavior of such systems. In fact, it is imperative to understand and reconstruct components in their native context rather than examining them separately. The long-term objective of evaluating cancer ecosystems in their proper context is to better diagnose, classify, and more accurately predict the outcome of cancer treatment. Communication is essential for the advancement and evolution of the tumor ecosystem. This interplay results in cancer progression. As key mediators of intercellular communication within the tumor ecosystem, TNTs are the central topic of this article.
| S-EPMC6176212 | biostudies-literature
Project description:Tunneling nanotubes (TNTs) are F-actin-based membrane tubes, and can form between cultured cells and within vital tissues. TNTs mediate intercellular communications that range from electrical signaling to the transfer of organelles. Following peripheral nerve injury, the orchestrated intercellular communications among neural and non-neural cells are required for effective nerve regeneration. It remains unknown whether TNTs exist between neural cells in the peripheral nerve system and how TNTs affect neural regeneration. To address these interesting questions, we investigated the transfer of neurotropic factors, membrane protein, cytoplasmic protein, mitochondria and RNA in functional TNTs formed between cultured Schwann cells (SCs). TNT-like structures were increased not only in cultured SCs after exposure to serum depletion but also in longitudinal sections of proximal sciatic nerve stump harvested after rat peripheral nerve transection. Meanwhile, downregulation of Rab8a or Rab11a in cultured SCs inhibited the formation of functional TNTs and vesicle transfer and led to decrease in cell migration, increase in SCs apoptosis. Likewise, knockdown of Rab8a or Rab11a in primary SCs also suppressed axonal outgrowth from co-cultured dorsal root ganglion (DRG) neurons. Overall, our results suggested that the gene of Rab8a or Rab11a might be involved in the formation of TNTs structures in the peripheral nerve system, while TNTs structures were likely to affect peripheral nerve regeneration through the regulation of neural cell communications.
| S-EPMC5260982 | biostudies-literature
Project description:Tunneling nanotubes (TNTs) are actin-based membranous structures bridging distant cells for intercellular communication. We define roles for TNTs in stress adaptation and treatment resistance in prostate cancer (PCa). Androgen receptor (AR) blockade and metabolic stress induce TNTs, but not in normal prostatic epithelial or osteoblast cells. Co-culture assays reveal enhanced TNT formation between stressed and unstressed PCa cells as well as from stressed PCa to osteoblasts. Stress-induced chaperones clusterin and YB-1 localize within TNTs, are transported bi-directionally via TNTs and facilitate TNT formation in PI3K/AKT and Eps8-dependent manner. AR variants, induced by AR antagonism to mediate resistance to AR pathway inhibition, also enhance TNT production and rescue loss of clusterin- or YB-1-repressed TNT formation. TNT disruption sensitizes PCa to treatment-induced cell death. These data define a mechanistic network involving stress induction of chaperone and AR variants, PI3K/AKT signaling, actin remodeling and TNT-mediated intercellular communication that confer stress adaptative cell survival.
| S-EPMC6534589 | biostudies-literature
Project description:By allowing insured communication between cancer cells themselves and with the neighboring stromal cells, tunneling nanotubes (TNTs) are involved in the multistep process of cancer development from tumorigenesis to the treatment resistance. However, despite their critical role in the biology of cancer, the study of the TNTs has been announced challenging due to not only the absence of a specific biomarker but also the fragile and transitory nature of their structure and the fact that they are hovering freely above the substratum. Here, we proposed to review guidelines to follow for studying the structure and functionality of TNTs in tumoral neuroendocrine cells (PC12) and nontumorigenic human bronchial epithelial cells (HBEC-3, H28). In particular, we reported how crucial is it (i) to consider the culture conditions (culture surface, cell density), (ii) to visualize the formation of TNTs in living cells (mechanisms of formation, 3D representation), and (iii) to identify the cytoskeleton components and the associated elements (categories, origin, tip, and formation/transport) in the TNTs. We also focused on the input of high-resolution cell imaging approaches including Stimulated Emission Depletion (STED) nanoscopy, Transmitted and Scanning Electron Microscopies (TEM and SEM). In addition, we underlined the important role of the organelles in the mechanisms of TNT formation and transfer between the cancer cells. Finally, new biological models for the identification of the TNTs between cancer cells and stromal cells (liquid air interface, ex vivo, in vivo) and the clinical considerations will also be discussed.
| S-EPMC7174938 | biostudies-literature
Project description:BackgroundMetastasis is the cause of most cancer-related deaths. It is known that breast cancer cells in proximity to macrophages become more invasive in an Epidermal Growth Factor (EGF) dependent manner. Tunneling nanotubes (TNTs) are thin, F-actin containing, cellular protrusions that mediate intercellular communication and have been identified in many tumors. The mechanism of TNT formation varies between different cell types. M-Sec (TNFAIP2) has been demonstrated to be involved in TNT formation in some cell types including macrophages. Yet, the requirement of M-Sec in tumor cell TNT formation in response to macrophages has not been explored.AimThe aim of this study was to determine whether EGF was required for macrophage induced tumor cell TNTs in an M-Sec dependent manner and what possible roles tumor cell TNTs play in tumor cell migration and invasion.Methods and resultsMacrophage Conditioned Media (CM) was used to induce an increase in TNTs in a number of breast cancer cell lines as measured by live cell microscopy. Tumor cell TNT formation by CM was dependent on the presence of EGF which was sufficient to induce TNT formation. CM treatment enhanced the level of M-Sec identified using western blot analysis. Reduction of endogenous M-Sec levels via shRNA in MTLn3 mammary adenocarcinoma cells inhibited the formation of TNTs. The role of tumor cell TNTs in cell behavior was tested using in vitro transwell and 3D invasion assays. No effect on chemotaxis was detected but 3D invasion was reduced following the knockdown of M-Sec in tumor cell TNTs.ConclusionsOur results show that EGF was necessary and sufficient for tumor cell TNT formation which was dependent on cellular M-Sec levels. While tumor cell TNTs may not play a role in individual cell behaviors like chemotaxis, they may be important in more complex tumor cell behaviors such as 3D invasion.
| S-EPMC7254960 | biostudies-literature