Ovarian cancer-derived extracellular vesicles affect normal human fibroblast behavior

Abstract

It has become clear that non-tumor cells in the microenvironment, especially fibroblasts, actively participate in tumor progression. Fibroblasts conditioned by tumor cells become "activated" and, as such, are identified as CAFs (cancer-associated fibroblasts). These CAFs remodel the tumor stroma to make it more favourable for cancer progression. The aim of this work was to verify whether EVs (extracellular vesicles - whose role as mediators of information between tumor and stromal cells is well known) released from human ovarian cancer cells were able to activate fibroblasts. EVs isolated from SKOV3 (more aggressive) and CABA I (less aggressive) cells were administered to fibroblasts. The consequent activation was supported by morphological and molecular changes in treated fibroblasts; XTT assays, zymographies, wound healing tests and invasion assays also highlighted higher proliferation, motility, invasiveness and enzyme expression. The secretome of these "activated" fibroblasts was, in turn, able to modulate the responses (proliferation, motility and invasion) of fibroblasts, and of tumor and endothelial cells. These findings support the idea that ovarian cancer cells can modulate fibroblast behaviour through the release of EVs, activating them to a CAFs-like state; the latter are able, in turn, to stimulate the surrounding cells. EVs from SKOV3 rather than from CABA I seem to be more efficient in some processes.

Exosomes promote pre-metastatic niche formation in ovarian cancer

“…These researchers demonstrated the significance of this miRNA signature by transfecting miR-31 and miR-214 mimics or miR-155 inhibitors into normal fibroblasts, which caused them to convert to CAFs [65]. This showed ovarian cancer derived exosomes alone are sufficient to induce the phenotypic and functional changes in normal stromal fibroblasts to pathogenic CAFs [66] (Fig. 2c).…”

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…For example, they are implicated in the reprogramming of normal stromal fibroblasts to activated cancer-associated fibroblasts (CAFs) [155][156][157][158][159]. In turn, CAFs secrete EVs that boost tumorigenesis by instigating metabolic changes, proliferation, epithelial-mesenchymal transition (EMT), motility, and migration in cancer cells, endothelial cells, and other stromal fibroblasts [160][161][162][163]. Tumor-derived EVs also vehiculate pro-angiogenic molecules that promote endothelial proliferation, migration, cell-cell adhesion, and vascular tube formation [164,165].…”

Pathophysiological Role and Potential Therapeutic Exploitation of Exosomes in Ovarian Cancer

“…Table 1 and Figure 1 summarize the content of ovarian cancer-derived exosomes that promote ovarian cancer progression by affecting their microenvironment, which is composed of fibroblast, mesothelial cell, immune cells and actual tumor cells. Ovarian cancer-derived exosomes convert fibroblasts, which are essential for normal tissue homeostasis and function, into cancer-associated fibroblasts (CAFs) [48]. Further, CAF-derived exosomes contain TGFβ1; exosomal TGFβ1 enhanced the migration and invasion ability of ovarian cancer cells and the promotion of epithelial-mesenchymal transition (EMT) by activating the SMAD signaling [37].…”

“…(3) Ovarian cancer cell-derived exosomes convert fibroblasts into cancer associated fibroblasts (CAFs). Thereafter, CAF-derived exosomes promote epithelial-mesenchymal transition to ovarian cancer cells[48,49]. (4) Ovarian cancer cell-derived exosomes inhibit immune cells and facilitates the conversion of macrophages to tumor-associated macrophages[38,[40][41][42]44,45].…”