Exosomal non-coding RNAs: mediators of crosstalk between cancer and cancer stem cells

Current advances in oncology have recognized two distinct cell subpopulations in tumors that include (1) a rare subpopulation, cancer stem cells (CSCs), which is considered to be the "seed" of the tumor, with therapy-resistant properties and as key drivers of tumor aggressiveness, and (2) the remaining bulk one, non-CSCs, all differentiated from the CSCs. Within the tumor microenvironment (TME), exosomes secreted by either CSCs or non-CSCs, containing multiple biomolecular cargos, mediate communication between both of the tumor cell subpopulations and play a vital role in promoting tumor progression. Specifically, a class of biomolecular cargo, non-coding RNAs (ncRNAs) that do not code for proteins during translation, has recently been highlighted to be a key participant in oncobiological processes. To comprehensively illuminate the mechanism of exosomal ncRNAs in mediating bidirectional communication between CSCs and differentiated tumor cells within the TME, we systematically analyzed the state-of-the-art literature from PubMed on this topic. It is revealed that: (1) Non-CSC exosomal ncRNAs enhance CSC stemness via upregulating stemness marker expression and activating stemness-reinforcing signaling pathways; (2) CSC-derived exosomal ncRNAs reciprocally mediate tumor progression by enhancing stemness, metastasis, angiogenesis, chemoresistance, and immune suppression of non-CSCs; (3) These tumor-derived exosomal ncRNAs possess the potentials as liquid biopsy biomarkers for early metastasis detection, and treatment targets or drug delivery systems for precision cancer therapy. It is therefore concluded that exosomal ncRNAs serve as critical communication bridges within TME, creating a self-reinforcing tumor-promoting loop, and therapeutically targeting exosomal ncRNAs could disrupt the crosstalk between CSCs and non-CSCs to delay the tumor progression. These findings provide a framework for developing combinatorial strategies against therapy-resistant malignancies.