Abstract
BackgroundWe 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).MethodsWe 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care [1]
Previously we have shown that mesenchymal cells (MSC) increased their tumor suppressor activity when they are activated with radiotherapy
Our results demonstrate that the A375 human skin-melanoma cancer cell line, when implanted as xenografts, in the NOD/SCID-gamma mice growth faster than G361 and MCF-7 cell line xenografts A375 xenografts are able to spread from its initial location to produce metastases in the internal organs of the mice, whereas, in our model, the cell lines G361 and MCF7 lack this potentiality (Additional file 1: Table S1). 60 out of the 97 mice bearing A375 xenografts showed metastatic spread (Fig. 1a)
Summary
Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care [1]. It is estimated that about half of cancer patients would benefit from radiotherapy for treatment of localized disease, local control, and palliation [2]. The success of RT in eradicating tumors depends on the total radiation dose being delivered accurately [3]. Cell membranes are intimately involved in the biochemical events that define cancers, and in particular, they are intensely involved in cancer metastasis [8]. We have recently shown that radiotherapy may be a successful local and regional treatment but, when combined with MSCs, may 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)
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