Abstract
Radiation resistance is a significant challenge in the treatment of breast cancer in humans. Human breast cancer is commonly treated with surgery and adjuvant chemotherapy/radiotherapy, but recurrence and metastasis upon the development of therapy resistance results in treatment failure. Exosomes are extracellular vesicles secreted by most cell types and contain biologically active cargo that, when transferred to recipient cells, can influence the cells’ genome and proteome. We propose that exosomes secreted by radioresistant (RR) cells may be able to disseminate the RR phenotype throughout the tumour. Here, we isolated exosomes from the human breast cancer cell line, MDA-MB-231, and the canine mammary carcinoma cell line, REM134, and their RR counterparts to investigate the effects of exosomes derived from RR cells on non-RR recipient cells. Canine mammary cancer cells lines have previously been shown to be excellent translational models of human breast cancer. This is consistent with our current data showing that exosomes derived from RR cells can increase cell viability and colony formation in naïve recipient cells and increase chemotherapy and radiotherapy resistance, in both species. These results are consistent in cancer stem cell and non-cancer stem cell populations. Significantly, exosomes derived from RR cells increased the tumoursphere-forming ability of recipient cells compared to exosomes derived from non-RR cells. Our results show that exosomes are potential mediators of radiation resistance that could be therapeutically targeted.
Highlights
Our results show that exosomes derived from the RR breast cancer cell lines can alter the phenotype of recipient cells and enhance their resistance to doxorubicin and irradiation
Our results show that exosomes isolated from RR cells significantly increased the percentage of cell viability for all recipient cancer stem cells (CSCs) when compared to exosomes isolated from non-RR cells or the PBS vehicle control (Figure 5A)
Our results indicate that exosomes derived from RR cell types can significantly increase the tumoursphere-forming ability of recipient cells and enhance the overall survival of CSCs, indicating that exosomes derived from RR cell lines may increase the size and hardiness of the CSC pool, and this may drive treatment failure in a clinical setting
Summary
Breast cancer is the most common female malignancy and the leading cause of cancerrelated deaths in women [1,2]. Naturally occurring canine mammary tumours are the most common cause of death in intact female dogs and have been proposed as a comparative model of the human disease [3]. Human breast cancer is commonly classified into molecularly distinct subtypes: normal breast-like, HER2+, luminal A, luminal B and triple negative. These subtypes differ in clinical outcomes, patient survival and treatment strategy. There is gene expression heterogeneity within these subtypes and breast cancer can be considered as a spectrum of diseases. 2012 [4] utilised microarray technology to highlight a 163-gene expression signature associated with prognosis, highlighting that, in the context of gene expression, this disease is highly heterogenous and individualised
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