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

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.

Programmed Cell Death Tunes Tumor Immunity

“…The occurrence of PCD in the TME is accompanied by the release of intracellular components, including cytokines, small molecules, mtDNA ( 172 ), ncRNA ( 173 , 174 ), and exosomes ( 175 ), etc. which are altogether involved in shaping the immune landscape of the TME.…”

Cancer-associated fibroblasts in gynecological malignancies: are they really allies of the enemy?

“…The difficulty of diagnosing ovarian cancer in its early stages is mainly due to the anatomical site where the ovaries are located and the lack of early biomarkers; in search of new candidates for biomarkers, Lawrenson et al, have non-invasively detected natriuretic peptide B (NPPB), a hormone initially unrelated to ovarian neoplasia and that is secreted from cardiac ventricular myocytes in response to myocardial stretch and stress, in the stroma of 60% primary OC tissues and the blood of 50% of women with OC (129). Although NPPB was expressed by only 28% of early-stage OCs, it could be part of the design of a panel of early biomarkers that together increase their sensitivity and specificity.…”

“…There are several reports in which it is shown that CAFs non-coding RNAs (ncRNAs) promote the development of various cancers ( 130 ). A predictive functional analysis identified 39 lncRNAs differentially expressed in CAFs compared to fibroblasts, 17 lncRNAs were up-regulated in CAFs and 22 lncRNAs were downregulated.…”

The hidden messengers: cancer associated fibroblasts—derived exosomal miRNAs as key regulators of cancer malignancy

“…Exosomes provide an optimal environment for carrying miRNA because miRNA is unstable when it exists alone in vitro and can be degraded by RNA enzymes in the human body ( Qiu et al, 2022 ). Several studies have pointed out that miRNAs in CAF-derived exosomes play an essential role in tumor regulation, and these miRNAs can interact with different cells in the TME through exosomes ( Villegas-Pineda et al, 2021 ). The impact of extracellular miRNAs secreted by immune cells, cancer cells, and other cell types in TME has been briefly outlined by others and will not be further discussed in this work ( Alizadeh et al, 2019 ; Xin et al, 2021 ; Hao et al, 2023 ).…”