Trends in Cancer
OpinionImaging Tunneling Membrane Tubes Elucidates Cell Communication in Tumors
Section snippets
Intercellular Communication Is Vital to Cancer Pathobiology
Research in cellular oncology has elucidated the importance of intercellular communication networks in cancer and in other diseases. There is untapped potential for targeting modes of communication as a novel strategic approach to treating cancer. Better understanding of how this communication occurs will provide insight to explain at the cellular level why and how tumors are able to evade and evolve to become resistant to many forms of currently used cancer-directed therapies.
Tumors are highly
Knowns and Unknowns about TNTs in Cancer
TNTs are open-ended cellular extensions that connect distant cells. What is known thus far is that they can act as conduits for direct intercellular transfer of important cell cargo such as mitochondria, exosomes, viruses, and miRNAs 12, 13, 14, 15, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42. The differences between TNTs and other actin-based protrusions have been discussed and summarized extensively elsewhere 21, 43, 44, 45, 46.
Technical Challenges of Imaging TNTs in Tumors
With the publication of numerous seminal studies in the field over the past 5 years, a clearer picture has emerged suggesting that TNTs are a universal phenomenon (not tissue or cell-type specific) and that they are exacerbated and upregulated under conditions that favor disease states 11, 19, 22, 24, 36, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59. TNTs, or at least TNT-like structures, can be imaged in human tumor tissue using widely available confocal imaging techniques and software
Horizontal Cell Transfer and Chemoresistance: TNTs Can (Literally) Bridge the Gap
The cellular mechanisms of cancer resistance to chemotherapy remain unclear. Current paradigms state that chemoresistance emerges as a result of mutations in key regulatory genes, with cells passing these genetic mutations to daughter cells through mitotic division and clonal expansion (vertical transmission). However, horizontal (cell-to-cell) transmission of regulatory factors via channels of cellular communication could also be responsible for the development of chemotherapy resistance. This
Biomarkers to Better Identify TNTs and TMs: An Important Next Step
In the current era of molecular oncology, most if not all tumor-based biomarkers in clinical use are assessed by molecular genomic techniques. However, cancer-specific cellular markers, if identified, also could be of use in stratifying tumors for response to therapies and assessing metastatic potential. Can evaluating a patient’s primary tumor for the presence of TNTs or TMs provide such a valid and novel cellular predictive biomarker of drug resistance? Their role in human tumors in vivo has
Concluding Remarks
The direct form of cell-to-cell communication that occurs via TNT and TM conduits is a fast-emerging concept in cancer cell biology. Over the past decade, the field has steadily graduated from studies solely done in vitro to a next-level examination of human- and animal-derived tumors ex vivo and, most recently, in vivo studies in animal models. The study of this field has made it necessary to adapt existing imaging technologies and also to explore ways to harness emerging ones such as
Acknowledgments
The authors thank Michael Franklin for excellent editorial suggestions and critical review of the manuscript. They also thank Guillermo Marques and Mark Sanders for helpful assistance with confocal microscopy performed at the University Imaging Centers at the University of Minnesota. The authors regret that, due to space limitations, many excellent publications in this field could not be cited. They thank all researchers who have dedicated their efforts to advancing research on this topic. This
Glossary
- Cytonemes
- thin cellular extensions characterized in the wing disc of Drosophila and believed to play a role in morphogen transport. Unlike TNTs/TMs, they do not form tunneled ends to recipient cells.
- Filopodia
- cytoplasmic actin filament-based projections, or protrusions, that are believed to play an important role in cell sensing and migration. Differences from TNTs include the properties of filopodial adherence to the substratum and lack of an open tunnel at the tip.
- Heterotopic
- located at a
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Tunneling nanotubes: The transport highway for astrocyte-neuron communication in the central nervous system
2024, Brain Research BulletinOxygen gradient and tumor heterogeneity: The chronicle of a toxic relationship
2021, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :These conduits that range from 5 to 100 μm in length are thin tube-like structures that are also known to be formed under stress conditions such as hypoxia in primary tumors [171] and multiple forms of cancers [172–175]. Since their discovery in 2004 by Rustom et al., live-cell microscopy and advanced techniques such as stimulated emission depletion (STED) microscopy as well as scanning and transmission electron microscopy have made studying these F-actin-based TNTs easier, which further provides evidence for the exchange of essential cargo such as miRNAs, lipid anchored proteins, mitochondria, and therapeutic drugs between cancer and stromal cell [176,177]. A study led by Wang and Gerde using PC-12 cells has shown mitochondria to be localized within microtubules and transported through the TNTs from healthy cells to cytochrome c-deficient stressed cells to aid better survival of the latter [178].
Mitochondria transfer from tumor-activated stromal cells (TASC) to primary Glioblastoma cells
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :TASC are increasingly studied in many cancers, but there is still very little information about their roles in GBM. However, TASC have been shown to contribute to the increased growth in GBM in vitro by the transfer of materials through TNTs and EVs [24–27]. Regulatory factors released from EV have essential roles, including the support of tumor growth, angiogenesis, metastasis and therapy resistance [28-32].
Keratinocytes Share Gene Expression Fingerprint with Epidermal Langerhans Cells via mRNA Transfer
2019, Journal of Investigative DermatologyCitation Excerpt :We speculate that this biological process might contribute to the maintenance of peripheral tolerance in steady state. It will be important to determine whether melanoma or other skin cancers could exploit this pathway to promote immunological tolerance against cancer antigens and metastasis to LNs (Lou et al., 2012, 2017). The material exchange between eLCs and other epidermal cells is bidirectional.
Characterisation of Tunnelling Nanotubes in Oral Carcinoma Cell Lines
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