Oncotarget

Research Papers:

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

Francisca Alcayaga-Miranda _, Paz L. González, Alejandra Lopez-Verrilli, Manuel Varas-Godoy, Carolina Aguila-Díaz, Luis Contreras, Maroun Khoury

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Oncotarget. 2016; 7:44462-44477. https://doi.org/10.18632/oncotarget.9852

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Abstract

Francisca Alcayaga-Miranda1,2, Paz L. González1,2, Alejandra Lopez-Verrilli2, Manuel Varas-Godoy3, Carolina Aguila-Díaz5, Luis Contreras4, Maroun Khoury1,2,5

1Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile

2Cells for Cells, Santiago, Chile

3Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile

4Servicio de Anatomía Patológica, Clínica Universidad de los Andes, Santiago, Chile

5Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile

Correspondence to:

Francisca Alcayaga-Miranda, email: falcayaga@uandes.cl

Keywords: mesenchymal stem cells, exosomes, tumor angiogenesis, ROS pathway, prostate cancer

Received: January 18, 2016     Accepted: May 19, 2016     Published: June 6, 2016

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.


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