*3.2.1 Cancer-associated fibroblasts*

TDE and MV were also shown to modify fibroblasts in the tumor stroma. When normal human fibroblasts were exposed to oral squamous carcinoma derived MV [20] the fibroblasts were altered into a cancer phenotype. This switch to CAFs was largely mediated via metabolic reprogramming of the fibroblasts to aerobic glycolysis, with an increase in glucose uptake and lactate secretion. Some TDEs contain surface TGF-β along with betaglycan, which could trigger SMAD-dependent signaling and regulate the differentiation of fibroblasts to myofibroblasts [21]. This was further proved by co-culturing the generated CAF with cancer cells which led to enhanced cancer cell invasion and migration, creating a bidirectional cross-talk that favors tumor promotion and spread. The MVs-induced fibroblast activation and spreading seem to occur in the matrix milieu in the tumor periphery [22]. In prostate cancer, TDE were shown to induce the expression of RANKL and Metalloproteinases in CAFs, through miR-100, -21, and -139, further promoting its metastasis [23]. Hypoxia seems to stimulate prostate cancer cells to release protein-rich Exo which further induces activation of CAFs [24], promotes epithethelial mesenchymal transition (EMT), stemness, and angiogenesis by prostate cancer cells.

Additionally, TDE were also described as regulators of metabolism in the tumor microenvironment, for example, breast cancer tumors could suppress glucose uptake by lung fibroblasts, via secretion of Exo containing miR-122, increasing glucose availability and facilitating metastasis [25]. The cell-to-cell communication mediated by Exo is also affected by the genetic profile of the recipient fibroblasts. For example, fibroblasts lacking the BRCA1, a tumor suppressor gene, internalize larger amounts of serum-derived Exo when compared to BRCA1 containing fibroblasts [26]. Furthermore, these cells were found to undergo a malignant transformation when exposed to Exo derived from sera of cancer patients, implying that oncosuppressor genes can prevent exosome information from tumor cells from being integrated and thus shelter these cells from their pro-oncogenic signals [26].
