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Oncol."],"abstract":"<jats:p>It is well established that the role of the tumor microenvironment (TME) in cancer progression and therapeutic resistance is crucial, but many of the underlying mechanisms are still being elucidated. Even with better understanding of molecular oncology and identification of genomic drivers of these processes, there has been a relative lag in identifying and appreciating the cellular drivers of both invasion and resistance. Intercellular communication is a vital process that unifies and synchronizes the diverse components of the tumoral infrastructure. Elucidation of the role of extracellular vesicles (EVs) over the past decade has cast a brighter light on this field. And yet even with this advance, in addition to diffusible soluble factor-mediated paracrine and endocrine cell communication as well as EVs, additional niches of intratumoral communication are filled by other modes of intercellular transfer. Tunneling nanotubes (TNTs), tumor microtubes (TMs), and other similar intercellular channels are long filamentous actin-based cellular conduits (in most epithelial cancer cell types, ~15-500 \u00b5m in length; 50\u20131000+ nm in width). They extend and form direct connections between distant cells, serving as conduits for direct intercellular transfer of cell cargo, such as mitochondria, exosomes, and microRNAs; however, many of their functional roles in mediating tumor growth remain unknown. These conduits literally create a physical bridge to create a syncytial network of dispersed cells amidst the intercellular stroma-rich matrix. Emerging evidence suggests that they provide a cellular mechanism for induction and emergence of drug resistance and contribute to increased invasive and metastatic potential. They have been imaged <jats:italic>in\u00a0vitro<\/jats:italic> and also <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> in tumors from human patients as well as animal models, thus not only proving their existence in the TME, but opening further speculation about their exact role in the dynamic niche of tumor ecosystems. TNT cellular networks are upregulated between cancer and stromal cells under hypoxic and other conditions of physiologic and metabolic stress. Furthermore, they can connect malignant cells to benign cells, including vascular endothelial cells. The field of investigation of TNT-mediated tumor-stromal, and tumor-tumor, cell-cell communication is gaining momentum. The mixture of conditions in the microenvironment exemplified by hypoxia-induced ovarian cancer TNTs playing a crucial role in tumor growth, as just one example, is a potential avenue of investigation that will uncover their role in relation to other known factors, including EVs. If the role of cancer heterocellular signaling <jats:italic>via<\/jats:italic> TNTs in the TME is proven to be crucial, then disrupting formation and maintenance of TNTs represents a novel therapeutic approach for ovarian and other similarly invasive peritoneal cancers.<\/jats:p>","DOI":"10.3389\/fonc.2020.559548","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T15:15:37Z","timestamp":1606403737000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["A Ticket to Ride: The Implications of Direct Intercellular Communication via Tunneling Nanotubes in Peritoneal and Other Invasive Malignancies"],"prefix":"10.3389","volume":"10","author":[{"given":"Emil","family":"Lou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2017.00024","article-title":"The Unique Molecular and Cellular Microenvironment of Ovarian Cancer","volume":"7","author":"Worzfeld","year":"2017","journal-title":"Front Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"12 10 1","DOI":"10.1002\/0471143030.cb1210s67","article-title":"Identification and Characterization of Tunneling Nanotubes for Intercellular Trafficking","volume":"67","author":"Abounit","year":"2015","journal-title":"Curr Protoc Cell Biol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"16029","DOI":"10.1038\/mto.2016.29","article-title":"Tunneling nanotubes: an alternate route for propagation of the bystander effect following oncolytic viral infection","volume":"3","author":"Ady","year":"2016","journal-title":"Mol Ther Oncolyt"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00400","article-title":"Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes","volume":"5","author":"Ady","year":"2014","journal-title":"Front Physiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00333","article-title":"Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions","volume":"10","author":"Ariazi","year":"2017","journal-title":"Front Mol Neurosci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2399","article-title":"Membrane nanotubes: dynamic long-distance connections between animal cells","volume":"9","author":"Davis","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fpls.2013.00504","article-title":"Exploring the role of lipids in intercellular conduits: breakthroughs in the pipeline","volume":"4","author":"Delage","year":"2013","journal-title":"Front Plant Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9504","article-title":"Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells","volume":"7","author":"Desir","year":"2016","journal-title":"Oncotarget"},{"key":"B9","doi-asserted-by":"publisher","first-page":"9484","DOI":"10.1038\/s41598-018-27649-x","article-title":"Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer","volume":"8","author":"Desir","year":"2018","journal-title":"Sci Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070892","article-title":"S. 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