Stem cell-derived exosomes: roles in stromal remodeling, tumor progression, and cancer immunotherapy

Abstract

Stem cells are known to maintain stemness at least in part through secreted factors that promote stem-like phenotypes in resident cells. Accumulating evidence has clarified that stem cells release nano-vesicles, known as exosomes, which may serve as mediators of cell-to-cell communication and may potentially transmit stem cell phenotypes to recipient cells, facilitating stem cell maintenance, differentiation, self-renewal, and repair. It has become apparent that stem cell-derived exosomes mediate interactions among stromal elements, promote genetic instability in recipient cells, and induce malignant transformation. This review will therefore discuss the potential of stem cell-derived exosomes in the context of stromal remodeling and their ability to generate cancer-initiating cells in a tumor niche by inducing morphologic and functional differentiation of fibroblasts into tumor-initiating fibroblasts. In addition, the immunosuppressive potential of stem cell-derived exosomes in cancer immunotherapy and their prospective applications in cell-free therapies in future translational medicine is discussed.

Fig. 1

Biogenesis of exosomes and their role in maintaining stemness: exosome formation follows the endocytic-exocytic pathway, which is initiated upon receiving extrinsic or intrinsic signals in a context-dependent manner, i.e., in response to either a disease signal or a reparative signal related to tissue injury. The regions of plasma membrane enriched in lipid-raft microdomains (red bars) are inveginated, resulting in the formation of early endosomes and their maturation into late endosomes (steps 1–3), with a series of changes occurring under the influence of multicomponent sorting machinery [20]. Multivesicular bodies (MVBs) fuse with the plasma membrane and secrete exosomes outwardly; these exosomes may interact with resident cells and may facilitate stemness, i.e., self-renewal, clonal expansion, differentiation, and repair. MSCs, mesenchymal stem cells

Fig. 2

Stem cell-derived exosomes and tumor progression: exosomes derived from stem cells or cancer cells express a variety of molecules, comprising oncogenic microRNAs (miRNAs) and proteins, growth factors, and adhesion molecules that exhibit pro-metastatic and pro-angiogenic activities through activating signaling pathways. VEGF vascular endothelial growth factor, PDGF platelet-derived growth factor, KIT mast/stem cell growth factor receptor, MMPs matrix metalloproteinases, ERK1/2 extracellular signal-regulated kinase 1/2, SCF stem cell factor

Fig. 3

Stem cell-derived exosomes and tumor inhibition: exosomes express and deliver antitumor molecules that exhibit tumor suppressor activities in recipient cells and that potentially inhibit tumor growth by targeting angiogenic, growth-regulatory, and other signaling pathways

Fig. 4

Stem cell-derived exosomes, their role in maintenance of stemness and tumor propagation, and their clinical potential in immunotherapy and organ transplantation. ESCs embryonic stem cells, iPSCs induced pluripotent stem cells, CAFs cancer-associated fibroblasts, CSC cancer stem cells