Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species

Abstract

Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies.

Antimicrobial Activity of Mesenchymal Stem Cells: Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies

“…The active biological role of cell-derived vesicles in pathological conditions such as ischemic heart disease, kidney injury, and wound healing have been shown to share many similar therapeutical features of their parent cells (15). While EVs [mainly microvesicles (MVs) and exosomes] are gaining momentum in the regenerative medicine field as a putative surrogate to cell-based therapeutics (168) their application in infectious diseases still requires further exploration.…”

“…This cell-to-cell interaction is doubt to be bi-directional, resulting in reprogramming of their secretome to respond to specific need of the tissue by transferring to the injured cells, factors restraining injury, and leading to tissue regeneration. MSCs-derived EVs have been implicated in the tissue restoring effects of MSCs including, anti-apoptotic (172), wound healing (173), and anti-tumoral activities (168). …”

Maternal and umbilical cord serum‐derived exosomes enhance endothelial cell proliferation and migration

“…MEs enhanced the tube formation of EC and stimulated neovascularization and angiogenesis (14,15). Exosomes derived from menstrual stem cells inhibit tumor angiogenesis (16). Serum exosomes stem from an extraordinary hodgepodge of various cell types from different tissues, such as platelets, ECs, endothelial colony-forming cells, mesenchymal stem cells, leukocytes, or trophoblasts.…”

Exosomes as a Source of Cancer Biomarkers: Advances in Electrochemical Biosensing of Exosomes

“…Exosomes mediate the interactions between cells, initiating and promoting/enhancing healing, thus can be useful for the stem‐cell‐based microRNA therapy of age‐related musculoskeletal disorders, as reviewed recently . Exosomes secreted by stem cells act as inhibitors of tumour angiogenesis and modulators of a tumour secretome and growth . Circulating myocardial microRNAs carried by exosomes are responsible for the cross‐talk between ischemic heart and bone marrow and thereby make possible the systemic response to cardiac injury required for cardiac repair and circulating microRNAs were involved in signalling causing pre‐term birth in mice .…”