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

Abstract

Carcinomas are complex structures composed of hierarchically organized distinct cell populations such as cancer stem cells and non-stem (bulk) cancer cells. Their genetic/epigenetic makeup and the dynamic interplay between the malignant cell populations and their stromal fibroblasts are important determinants of metastatic tumor invasion. Important mediators of these interactions are the small, membrane-enclosed extracellular vesicles, in particular exosomes. Both cancer cell and fibroblast-derived exosomes carry a set of regulatory molecules, including proteins and different species of RNA, which cooperatively support metastatic tumor spread. Here, we briefly overview potential links between cancer stem cells and the exosome-mediated fibroblast-enriched metastatic niche formation to discuss their role in the promotion of tumor growth and metastatic expansion in breast carcinoma models.

En bloc release of MVB‐like small extracellular vesicle clusters by colorectal carcinoma cells

“…Here we primarily focused on individual, migrating CRC cells, because they were easily distinguishable by the detection of their cytokeratin (CK) intermediate filaments in the CK negative microenvironment [15]. Furthermore, these cells play a primary role in metastatic progression [16,17]. Surprisingly, CK positive, migrating tumour cells (Figure 1a and 1d) show CD63 and ALIX positive structures protruding from the cytoplasm into the extracellular space (Figure 1(a–f)).…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…Multi-vesicular body (MVB)-derived extracellular vesicles (EVs) are constantly secreted into the extracellular space. These nanoparticles called exosomes are key to maintain homeostasis of their releasing (originating) cells [169][170][171][172]. They facilitate specific cell-cell interactions and stimulate several signaling pathways in their target cells, including cancer cells [173].…”

“…That, bidirectional transport of exosomes containing different species of RNA (e.g. miRNA) and proteins between cancer stem cells and the fibroblast-rich microenvironment is shown to promote the growth of the tumor and the metastatic outbreak in breast carcinoma models [172]. Besides, exosomes are involved in acquired drug resistance, as evidenced by the observation that the transfer of the oncogene MET by exosomes modify surrounding icotinibsensitive cells to promote icotinib-resistant lung cancer cells, that produce MET-containing exosomes and elicit the migration and invasion properties in vitro [175].…”

Tumor-derived exosomes: the next generation of promising cell-free vaccines in cancer immunotherapy

“…Although their mechanisms of action are rarely investigated, CSC-TEXs can induce a stemness phenotype by stemness-related molecule transfer and targeting upstream or downstream genes, by recruiting and altering the phenotype and function of stromal cells, as well as by enhancing tumor aggression and metastatic features. [72][73][74] Thus, CSC-TEXs can remodel the tumor niche through influencing resident tumor cells as well as the tumor microenvironment including fibroblasts and immune cells, which leads to local tumor progression. 68 In prostate cancer, differential microRNA patterns were observed in bulk cell-TEXs and CSC-TEXs.…”