Exosomal miRNAs and lncRNAs: The Modulator Keys of Cancer-Associated Fibroblasts in the Genesis and Progression of Malignant Neoplasms.

Julio César Villegas-Pineda,Adrián Ramírez-de-Arellano,Mélida del Rosario Lizarazo-Taborda,Ana Laura Pereira-Suárez

doi:10.3389/fcell.2021.717478

Julio César Villegas-Pineda, Adrián Ramírez-de-Arellano + Show 2 more

Open Access

https://doi.org/10.3389/fcell.2021.717478

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Abstract

The tumor microenvironment is made up of a universe of molecular and cellular components that promote or inhibit the development of neoplasms. Among the molecular elements are cytokines, metalloproteinases, proteins, mitochondrial DNA, and nucleic acids, within which the ncRNAs: miRNAs and lncRNAs stand out due to their direct modulating effects on the genesis and progression of various cancers. Regarding cellular elements, the solid tumor microenvironment is made up of tumor cells, healthy adjacent epithelial cells, immune system cells, endothelial cells, and stromal cells, such as cancer-associated fibroblasts, which are capable of generating a modulating communication network with the other components of the tumor microenvironment through, among other mechanisms, the secretion of exosomal vesicles loaded with miRNAs and lncRNAs. These ncRNAs are key pieces in developing neoplasms since they have diverse effects on cancer cells and healthy cells, favoring or negatively regulating protumoral cellular events, such as migration, invasion, proliferation, metastasis, epithelial-mesenchymal transition, and resistance to treatment. Due to the growing number of relevant evidence in recent years, this work focused on reviewing, analyzing, highlighting, and showing the current state of research on exosomal ncRNAs derived from cancer-associated fibroblasts and their effects on different neoplasms. A future perspective on using these ncRNAs as real therapeutic tools in the treatment of cancer patients is also proposed.

Highlights

H19 activated the β-catenin pathway by acting as an endogenous competitor for miR-141, a miRNA with antitumoral effect, in colorectal cancer (CRC) cells (Ren et al, 2018). These findings propose miRNAs and lncRNAs as important obstacles to achieving a successful chemotherapeutic treatment; TABLE 1 | Cellular and tumor effects and mechanisms exerted by exosomal miRNAs and lncRNAs derived from cancer-associated fibroblasts (CAFs) in various cancers
Exosomes loaded with miRNAs and lncRNAs are a key communication pathway between CAFs and the different elements of the tumor microenvironment (TME)
The conventional effect of two types of exosomal non-coding RNAs (ncRNAs) derived from CAFs: miRNAs and lncRNAs, has been reviewed; this effect inhibits the translation by binding to its target messenger RNAs (mRNAs) (Dragomir et al, 2018)

Summary

Introduction

Malignant tumors consist of cancer cells and tumor-associated host cells (De Wever et al, 2014), the interaction between tumor microenvironment (TME) and tumor cells plays a key role in cancer progression (Dayan et al, 2012; Ali et al, 2015; Shah et al, 2015; Vered et al, 2015; Ringuette Goulet et al, 2018; Zhang Y.-F. et al, 2019; Dou et al, 2020; Wu et al, 2020). This aspect has not yet been studied in-depth, there is a report where a protumoral role is proposed for lncRNA SNHG3, which positively regulated pyruvate kinase isozymes M1/M2 (PKM) expression, inhibited mitochondrial oxidative phosphorylation, increased glycolysis, and proliferation of breast tumor cells through a mechanism similar to a molecular sponge for antitumoral miR330-5p (Li Y. et al, 2020); this highlights the multifunctionality that CAFs-derived exosomal ncRNAs can exert on various processes related to carcinogenesis and tumor progression.

Results

Conclusion