Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation

Exosomes of disseminated CSCs (a) with bulk cells of a primary tumor (PT) cooperating in the formation of a local metastatic niche near the tumor mass. We speculate that during further migration of tumor cells, the effects of migrating CSC-derived exosomes may have more impact than of exosomes secreted by the distant tumor mass (b). Induction of CAF differentiation is probably a multistep process (i.e., NF-activated fibroblast-CAF sequence). It is accompanied by the appearance of the tumor promoting effects of CAFs (c). CSC-derived exosomes are detectable both in the lymphatics and in blood circulation. They may originate from the stroma and may either annihilate the endothelial tight junctions (d) or they undergo an active transport by the endothelial cells (e). Evidently, these exosomes may also originate from circulating CSCs and may play a role in the formation of pro-metastatic site in distant organs (f