A Ticket to Ride: The Implications of Direct Intercellular Communication via Tunneling Nanotubes in Peritoneal and Other Invasive Malignancies

Abstract

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 µm in length; 50–1000+ 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 in vitro and also in vivo and ex vivo 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 via 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.

Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

“…We show that TNT enables mitochondria exchange and other cytoplasmic factors from the tumor cell into the non-tumor cells. Mitochondrial exchange via TNT is not a new concept, as previously published by several groups 12 , 22 , 58 , 63 . The function of the mitochondrial transfer was suggested but not demonstrated.…”

“…Seventh, TNT are positive for several TNT markers that do not present in filopodia, including TTHY1, GAP43, and protein 14-3-3γ 16 . Lastly, TNT and other similar structures defined by other groups 4 , 12 , 47 , 109 corresponded to tangled processes with both characteristic, open-ended, and enclosed; however, whether other names such as cytonemes and tumor microtubes correspond to TNT needs to be determined. Thus, the definition of TNT structure is strict and separate from other cellular processes, including filopodium, lamellipodium, and pseudopods.…”

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

“…Many studies have shown that mitochondrial transfer between tumor cells as a mechanism of metabolic adaptation promotes tumorigenesis, invasiveness and metastasis [96][97][98] . And preventing the formation of TNTs may be a novel approach to treat cancer 99,100 . Researchers showed that TNTs formation and the transfer of cargo between neuronal cells are regulated by the Wnt/Ca 2+ pathway, thus intervention of Wnt/Ca 2+ pathway may be a way to reduce TNTs-caused damage 101 .…”

Intercellular transfer of mitochondrial DNA carrying metastasis-enhancing pathogenic mutations from high- to low-metastatic tumor cells and stromal cells via extracellular vesicles

“…In addition, mitovesicles are a recently identified novel population of EVs of mitochondrial origin that contain abundant mitochondrial markers and reflect the alteration of pathophysiological processes where mitochondrial dysfunction occurs and are much smaller than native mitochondria [ 21 ]. TNTs are actin-based direct cell-to-cell communication channels that serve to transfer a variety of molecules and organelles, including mitochondria and exosomes, which are thought to be the main delivery route to transfer intact mitochondria in solid tumors [ 18 , 22 , 23 ]. EV- and TNT-mediated cell-to-cell communication between cancer cells and stromal cells, such as bone marrow-derived mesenchymal stem cells, fibroblasts and endothelial cells, is reported to play roles in alterations in cancer cell bioenergetics, chemoresistance, invasion and metastasis [ 16 – 18 , 22 , 23 ].…”

“…TNTs are actin-based direct cell-to-cell communication channels that serve to transfer a variety of molecules and organelles, including mitochondria and exosomes, which are thought to be the main delivery route to transfer intact mitochondria in solid tumors [ 18 , 22 , 23 ]. EV- and TNT-mediated cell-to-cell communication between cancer cells and stromal cells, such as bone marrow-derived mesenchymal stem cells, fibroblasts and endothelial cells, is reported to play roles in alterations in cancer cell bioenergetics, chemoresistance, invasion and metastasis [ 16 – 18 , 22 , 23 ]. However, because a variety of cellular components, such as cellular proteins, lipids, mRNAs and microRNAs, are transferred via EVs and TNTs from stromal cells to tumor cells and vice versa [ 19 , 23 ], the exact functional roles of transferred mitochondria, particularly tumor-derived mutant mtDNAs, remain unknown.…”