Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity

Abstract

Background Breast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC. Methods Immune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5 mg/kg) and trastuzumab (4 mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro. Results The growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4 months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e’). Histological staining with Masson’s trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells. Conclusions An orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.

Smad3 promotes adverse cardiovascular remodeling and dysfunction in doxorubicin-treated hearts

“…Whereas the doses of the drug in the clinical setting are determined using patients’ body surface area, ratio of body surface area to body mass and the rates of doxorubicin metabolism are vastly different in mice, as compared with humans. The dose of 5 mg/kg used in the present study was reported by others ( 71 ) to steadily reduce breast tumor volumes in mice and therefore regarded as clinically relevant. We found that at this dose, cardiac endothelial cells had higher nuclear concentrations of doxorubicin compared with other cells, and thus likely constitute a target of doxorubicin in the heart.…”

“…Endothelial cells account for over 60% of non-myocyte cells and are the most abundant cell type in the heart ( 72 ). Several recent studies have also emphasized an important role of endothelial cells in development of doxorubicin cardiomyopathy ( 19 , 71 , 73 ).…”

Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer

“…To explore the potential of MM1-EVs in combination with DOX in vivo, we generated an orthotopic mouse model of breast cancer by implanting 4T1 cells in the fourth left breast of BALB/c mice. M1-DOX and MM1-DOX were used at a concentration of 2 mg/kg and compared with free DOX at a dose of 5 mg/kg, which had been previously established as an effective dose to reduce tumor growth in this breast cancer model [ 30 ]. The experiment revealed that all samples were able to reduce tumor growth when compared to the groups treated with saline solution.…”

Exploring the Involvement of Gut Microbiota in Cancer Therapy-Induced Cardiotoxicity

“…Owing to their well-known cardiovascular side effects and comparatively high incidence of heart failure, anthracyclines have been the most extensively researched medication for decades [ 67 ]. Hoffmann et al [ 68 ] reported that doxorubicin and trastuzumab treatment of nude mice in an orthotopic mouse model of human breast cancer led to a cardiovascular defect. In order to effectively treat cancer, new strategies are urgently needed to prevent potential cardiovascular diseases.…”