Noncoding RNAs in the Interplay between Tumor Cells and Cancer-Associated Fibroblasts: Signals to Catch and Targets to Hit

Abstract

Cancer development and progression are not solely cell-autonomous and genetically driven processes. Dynamic interaction of cancer cells with the surrounding microenvironment, intended as the chemical/physical conditions as well as the mixture of non-neoplastic cells of the tumor niche, drive epigenetic changes that are pivotal for the acquisition of malignant traits. Cancer-associated fibroblasts (CAF), namely fibroblasts that, corrupted by cancer cells, acquire a myofibroblast-like reactive phenotype, are able to sustain tumor features by the secretion of soluble paracrine signals and the delivery extracellular vesicles. In such diabolic liaison, a major role has been ascribed to noncoding RNAs. Defined as RNAs that are functional though not being translated into proteins, noncoding RNAs predominantly act as regulators of gene expression at both the transcriptional and post-transcriptional levels. In this review, we summarize the current knowledge of microRNAs and long noncoding RNAs that act intracellularly in either CAFs or cancer cells to sustain tumor-stroma interplay. We also report on the major role of extracellular noncoding RNAs that are bidirectionally transferred between either cell type. Upon presenting a comprehensive view of the existing literature, we provide our critical opinion regarding the possible clinical utility of tumor-stroma related noncoding RNAs as therapeutic target/tools or prognostic/predictive biomarkers.

(In)Distinctive Role of Long Non-Coding RNAs in Common and Rare Ovarian Cancers

“…The cancer-associated fibroblasts-derived exosomes were shown to carry lncRNA H19, which is highly expressed in tumor stroma in comparison to tumor tissue. This lncRNA promotes stemness and chemoresistance of cancer cells and increases the frequency of tumor-initiating cells [77].…”

“…A recent literature survey of Salamini-Montemurri et al, has identified 215 lncRNAs being involved in OCs, of which for 157 there is experimental proof [8]. Apart from initiation, lncRNAs have been associated with many biological processes associated with metastasis [80], such as the immune response [73], radiation response [81], epithelial to mesenchymal transition (EMT) and stemness [82], cell-to-cell communication, and regulation of the microenvironment in which cells reside [77].…”

“…The most abundant and relevant cell types in this microenvironment are the cancer-associated fibroblasts (CAF), which respond to the cytokines produced by the tumor to support tumor growth and dissemination. Many lncRNAs are upregulated in the CAF compared to normal fibroblasts, such as MALAT1, NEAT1, H19, GAS5, and MEG3 [77,111]. The communication also goes in the opposite direction, from tumor cells to fibroblasts, reprogramming them into CAF-like cells [77].…”

“…Many lncRNAs are upregulated in the CAF compared to normal fibroblasts, such as MALAT1, NEAT1, H19, GAS5, and MEG3 [77,111]. The communication also goes in the opposite direction, from tumor cells to fibroblasts, reprogramming them into CAF-like cells [77]. Interrupting this cell-to-cell communication between tumor and stromal cells through lncRNAs is also a promising approach to tumor treatment, as the microenvironment plays a major role in the ability of tumors to grow, progress, and ultimately metastasize.…”

Cancer-associated fibroblasts-derived extracellular vesicles carrying lncRNA SNHG3 facilitate colorectal cancer cell proliferation via the miR-34b-5p/HuR/HOXC6 axis

“…Furthermore, CAFs carry out their role of maintaining tumor characteristics by means of secreting soluble paracrine signals and releasing extracellular vesicles (EVs) [ 8 ]. Meanwhile, the aforementioned EVs, as a group of membrane-enclosed vesicles, serve as the crucial medium of intercellular communication in TME and participate in a plethora of processes associated with tumor progression, including proliferation, angiogenesis, and metastasis [ 9 ].…”