Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci

Molecular Cancer

Isabel Tovar¹  José Expósito¹  Francisco Martín²  Per Anderson²  Francisco O’Valle³  Virgínea de Araujo Farias³  Ana Nieto³  José Mariano Ruiz de Almodóvar³  Ana Santos³  Jesús López-Peñalver³  Santiago Serrano-Saenz⁴  Eduardo Andrés⁴  F. Javier Oliver⁴ 

[1] Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada;GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada;Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III);Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, 18016 and CIBERONC (Instituto de Salud Carlos III);

关键词: Experimental radiotherapy;    Bystander effect;    Abscopal effect;    Mesenchymal stem cells;    Cell therapy;    Metastasis spread;   

DOI  :  10.1186/s12943-018-0867-0

来源: DOAJ

【 摘 要 】

Abstract Background We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). Methods We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment. Results The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. Conclusions Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.

【 授权许可】

Unknown