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

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Article number559548
JournalFrontiers in Oncology
Volume10
DOIs
StatePublished - Nov 26 2020

Bibliographical note

Funding Information:
The author would like to thank the following sponsors of research work in this field in the Lou Lab: several patients with cancer and/or friends and family in honor of patients with cancer treated at the Masonic Cancer Center, Minneapolis, Minnesota; the Minnesota Ovarian Cancer Alliance; The Randy Shaver Cancer Research and Community Fund; the Litman Family Fund for Cancer Research; the Mu Sigma Chapter of the Phi Gamma Delta Fraternity, University of Minnesota; and the American Association for Cancer Research (2019 AACR-Novocure Tumor-Treating Fields Research Grant, grant number 1-60-62-LOU).

Publisher Copyright:
© Copyright © 2020 Lou.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • cancer pathophysiology
  • confocal microscopy
  • intercellular communication
  • mesothelioma
  • ovarian cancer
  • peritoneal cancers
  • tumor microtubes
  • tunneling nanotubes

PubMed: MeSH publication types

  • Journal Article
  • Review

Fingerprint Dive into the research topics of 'A Ticket to Ride: The Implications of Direct Intercellular Communication via Tunneling Nanotubes in Peritoneal and Other Invasive Malignancies'. Together they form a unique fingerprint.

Cite this