Presenting Author Virginia Commonwealth University
Background: Triple Negative Breast Cancer (TNBC) is an aggressive form of cancer and accounts for 10-20 % of all breast cancer types. TNBC patients are widely treated with chemotherapeutic drugs such as doxorubicin (Dox), which is a primary standard of care. Dox treatment results in unwanted side effects including cardiac dysfunction and skeletal muscle weakness. We previously demonstrated the anti-tumor effects and cardioprotective effects of embryonic stem cell derived exosomes (Es-Exos) in the xenograft model of TNBC. The purpose of this study was to identify the biomolecules present in Es-Exos, which may be linked to the anti-tumor effects in the xenograft model.
Methods and
Results: Orthotopic xenograft model of TNBC was generated by injecting human MDA-MB-231-Tom-Luc cell line in mammary intraductal T4 region of nude mice. Non-tumor bearing female mice were used as control (NT-Con;n=6) as applicable. The animals (n=10/group) were randomized to receive Saline (Con); Dox (5 mg/kg/week); Es-Exos (50 ug/animal/twice a week; Dox+Es-Exos; Es-Exos alone and MEF-Exos-(mouse embryonic fibroblast cell derived exosomes 50 ug/animal/twice a week) for up to 4 weeks. Skeletal muscle grip strength declined both in Con and upon treatment with Dox in tumor bearing mice as compared to NT-Con, which was restored upon treatment with Es-Exos. Cardiac function measured by echocardiography showed decline in ejection fraction (EF) in saline treated tumor bearing Con and in Dox group, when compared to NT-Con. Treatment with Dox+Es-Exos and Es-Exos improved ejection fraction compared to Con and Dox cohort. Treatment with Es-Exos significantly reduced the tumor size compared to Dox and saline treated Con groups (Con Vs Dox and Dox+Es-Exos; p-value lt;0.05). Picro Sirius red staining showed increased deposition of collagen in saline treated Con, which was reduced in Dox+Es-Exos and Es-Exos groups. RNA seq analysis of Es-Exos identified several anti-proliferative genes including a 6-fold expression of Transcription Factor 7 (TCF7) and 6.5-fold higher expression of E-Cadherin (CDH1). Immunohistochemistry analysis of tumor tissue showed abundant expression of VEGF in untreated Con, which was reduced by combined treatment with Es-Exos and Dox.
Conclusion: Embryonic stem cells derived exosomes contain anti-proliferative genes which may possibly lead to their anti-tumor property in the TNBC tumor model.
This study was supported by NIH (5RO1CA221813) to RCK amp;amp; DKS
