Abstract
Breast cancer (BC) is the most prevalent type of malignancy in women. Extracellular vesicles (EVs) are subcellular membrane blebs that include exosomes and microparticles.Study aimsTo elucidate the effects of chemotherapy administration on BC patients’ EVs characteristics and their effects on endothelial cells (EC) functions.MethodsEVs were isolated from the blood samples of 54 BC patients treated by chemotherapy (25 neo-adjuvant, 29 adjuvant) and from 20 healthy women (control group). Blood samples were taken before chemotherapy and on the day of last chemotherapy administration. In some patients, samples were also evaluated 24 hours after chemotherapy treatment. EVs were characterized by cell origin, thrombogenicity and cytokine content. EVs effects on coagulation, migration, apoptosis and proliferation of endothelial cells were assessed as well.ResultsPatient characteristics of the two subgroups were similar except for tumor size. Change in EV expression of BC markers, MUC1 and EpCAM, were found in patient subgroups. EC-EVs were significantly higher in both patient subgroups compared to healthy controls. Higher EVs pro-coagulant activity was found at the end of chemotherapy and a significant increase in the ratio between tissue factor (TF) and TF pathway inhibitor was documented after the first 24hours of exposure to doxorubicin treatment. Furthermore, EVs of neo-adjuvant patients obtained before chemotherapy contained more pro-angiogenic proteins, reduced endothelial cells apoptosis and increased their migration compared to EVs obtained at the same timing from adjuvant patients.ConclusionsEVs may serve as a biomarker for chemotherapy-related thrombogenicity and may indicate vascular damage even before chemotherapy.
Highlights
Breast cancer (BC) is the most prevalent type of malignancy among women [1, 2], and the risk for developing venous thromboembolism (VTE) is higher in individuals with BC than in the general population [3], resulting in a significant increase in morbidity and mortality [4]
endothelial cells (EC)-Extracellular vesicles (EVs) were significantly higher in both patient subgroups compared to healthy controls
Higher EVs pro-coagulant activity was found at the end of chemotherapy and a significant increase in the ratio between tissue factor (TF) and TF pathway inhibitor was documented after the first 24hours of exposure to doxorubicin treatment
Summary
Breast cancer (BC) is the most prevalent type of malignancy among women [1, 2], and the risk for developing venous thromboembolism (VTE) is higher in individuals with BC than in the general population [3], resulting in a significant increase in morbidity and mortality [4]. EVs play a major role in intercellular communication within the tumor microenvironment and serve as a “vehicle” that modulates target cells by transferring proteins and genetic molecules (DNA, RNA, microRNA) [8]. These affect cell functions that are correlated in cancer patients with their tumor process, including differentiation, proliferation, migration, invasion and apoptosis, via changes in cell signaling pathways [9]. Previous studies demonstrated that the number of EVs is higher in the plasma of BC patients in all stages and with various tumors sizes (T2-T4 tumors), in comparison to control groups [12], and were more thrombogenic [13]
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