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

SIMPLE SUMMARY: Cancer aggressiveness is the result of a proficient bidirectional interaction between tumor and stromal cells within the tumor microenvironment, among which a major role is played by the so-called cancer-associated fibroblasts. Upon such interplay, both cancer cells and fibroblasts are reprogrammed to sustain malignancy, with changes in the repertoire of noncoding RNAs, mainly microRNAs and long noncoding RNAs. Such molecules are also exchanged between the two cell types through extracellular vesicles. In this review, we summarize the current knowledge of microRNAs and long noncoding RNAs that act intracellularly or extracellularly to sustain tumor-stroma interplay. We also provide our view regarding the possible clinical utility of such noncoding RNAs as therapeutic target/tools or biomarkers to predict patient outcome or response to specific treatments. 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.