Exosome-Based Cell-Cell Communication in the Tumor Microenvironment.

Joana Maia,Bruno Costa-Silva,Maria Carolina Strano Moraes,Nuno Couto,Sergio Caja

doi:10.3389/fcell.2018.00018

Joana Maia, Bruno Costa-Silva + Show 3 more

Open Access

https://doi.org/10.3389/fcell.2018.00018

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Abstract

Tumors are not isolated entities, but complex systemic networks involving cell-cell communication between transformed and non-transformed cells. The milieu created by tumor-associated cells may either support or halt tumor progression. In addition to cell-cell contact, cells communicate through secreted factors via a highly complex system involving characteristics such as ligand concentration, receptor expression and integration of diverse signaling pathways. Of these, extracellular vesicles, such as exosomes, are emerging as novel cell-cell communication mediators in physiological and pathological scenarios. Exosomes, membrane vesicles of endocytic origin released by all cells (both healthy and diseased), ranging in size from 30 to 150 nm, transport all the main biomolecules, including lipids, proteins, DNAs, messenger RNAs and microRNA, and perform intercellular transfer of components, locally and systemically. By acting not only in tumor cells, but also in tumor-associated cells such as fibroblasts, endothelium, leukocytes and progenitor cells, tumor- and non-tumor cells-derived exosomes have emerged as new players in tumor growth and invasion, tumor-associated angiogenesis, tissue inflammation and immunologic remodeling. In addition, due to their property of carrying molecules from their cell of origin to the peripheral circulation, exosomes have been increasingly studied as sources of tumor biomarkers in liquid biopsies. Here we review the current literature on the participation of exosomes in the communication between tumor and tumor-associated cells, highlighting the role of this process in the setup of tumor microenvironments that modulate tumor initiation and metastasis.

Highlights

The tumor microenvironment is anything but simple. Be it the primary or the metastatic tumor, its complex and heterogeneous microenvironment is comprised of a network of both cellular and acellular constituents. While the former consists of tumor cells and diverse non-transformed cells, such as cancer-associated fibroblasts, macrophages, and endothelial cells, the latter is formed by secreted factors and components of the extracellular matrix (ECM)
In addition to effects in local tumor microenvironments, exosomes released from tumors were shown to mediate distant cell-cell communication processes which result in the setup of pro-tumorigenic microenvironments supportive of metastatic dissemination
In addition to the current efforts in investigating the application of exosomes as anti-tumor tools, the further comprehension of the basic biology of exosomes, including the identification of exosomal components relevant for tumor progression, may represent an opportunity for novel therapeutic strategies based on the targeting of pro-tumorigenic exosomes-based cell-cell communication

Summary

Introduction

The tumor microenvironment is anything but simple. Be it the primary or the metastatic tumor, its complex and heterogeneous microenvironment is comprised of a network of both cellular and acellular constituents. Exosomes derived from lung-tropic tumors, such as some types of breast cancers, express high levels of Integrins α6β1 and/or α6β4, which allow them to bind to lung fibroblasts, induce upregulation of S100A4, A6, A10, A11, A13, and A16, and lead to the formation of lung-pre-metastatic niches supportive of metastasis (Hoshino et al, 2015). Gastric cancer-derived exosomes were shown to induce NF-κB activation in macrophages, leading to an increase in the expression of pro-inflammatory factors such as IL-6 and TNF-α, in turn promoting the proliferation of gastric cancer cells (Wu et al, 2016).

Results

Conclusion