Alterations in NO- and PGI2- dependent function in aorta in the orthotopic murine model of metastatic 4T1 breast cancer: relationship with pulmonary endothelial dysfunction and systemic inflammation

Abstract

BackgroundPatients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. The aim of the present work was to examine changes in nitric oxide (NO)- and prostacyclin (PGI2)-dependent endothelial function in the systemic conduit artery (aorta), in relation to the formation of lung metastases and to local and systemic inflammation in a murine orthotopic model of metastatic breast cancer.MethodsBALB/c female mice were orthotopically inoculated with 4T1 breast cancer cells. Development of lung metastases, lung inflammation, changes in blood count, systemic inflammatory response (e.g. SAA, SAP and IL-6), as well as changes in NO- and PGI2-dependent endothelial function in the aorta, were examined 2, 4, 5 and 6 weeks following cancer cell transplantation.ResultsAs early as 2 weeks following transplantation of breast cancer cells, in the early metastatic stage, lungs displayed histopathological signs of inflammation, NO production was impaired and nitrosylhemoglobin concentration in plasma was decreased. After 4 to 6 weeks, along with metastatic development, progressive leukocytosis and systemic inflammation (as seen through increased SAA, SAP, haptoglobin and IL-6 plasma concentrations) were observed. Six weeks following cancer cell inoculation, but not earlier, endothelial dysfunction in aorta was detected; this involved a decrease in basal NO production and a decrease in NO-dependent vasodilatation, that was associated with a compensatory increase in cyclooxygenase-2 (COX-2)- derived PGI2 production.ConclusionsIn 4 T1 metastatic breast cancer in mice early pulmonary metastasis was correlated with lung inflammation, with an early decrease in pulmonary as well as systemic NO availability. Late metastasis was associated with robust, cancer-related, systemic inflammation and impairment of NO-dependent endothelial function in the aorta that was associated with compensatory upregulation of the COX-2-derived PGI2 pathway.

Fourier transform infrared spectroscopic signature of blood plasma in the progression of breast cancer with simultaneous metastasis to lungs

“…As seen in Figure , the greatest variance is found for IR spectra from the micrometastatic (week 3) and macrometastatic phases (week 4), particularly in the 3600‐2800 cm −1 region. This observation could be congruent with the largest variability of a number of metastatic foci present in lungs on weeks 3 and 4 as discussed in our reports . Indeed, it indicates that plasma IR spectra reflect variation in the rate of tumor growth among animals.…”

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors

“…Recent studies utilizing the model of mouse mammary gland cancer 4T1, reflecting a basal-like phenotype (in human: negative for nuclear estrogen receptor (ER) α, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), i.e., triple-negative, and positive for epidermal growth factor receptor (EGFR)) [1][2][3][4], have shown a predominant role of endothelium damage during the metastatic process of these cells [5][6][7]. For instance, it is evidenced that endothelial dysfunction in the lungs, which was assessed as decreased activity and phosphorylation of endothelial nitric oxide synthase (eNOS) resulting in a low nitric oxide (NO) production state, was an early event in breast Literature data [4] and our histopathological analyses confirmed that no cancer cells were detected in the lungs of 67NR tumor-bearing mice ( Figure S1A).…”

High and ultra‐high definition of infrared spectral histopathology gives an insight into chemical environment of lung metastases in breast cancer

“…In this work, we focused on high definition (HD) and ultra‐high definition (UHD) FTIR spectroscopic imaging of metastatic foci from a murine model of pulmonary metastasis in a 4 T1 carcinoma model of breast cancer, described in detail elsewhere . For this purpose, we used a new optic configuration introduced by Agilent Technologies in its IR microscope which provides additional 5× enhanced magnification.…”

“…At this stage, metastasis is mainly defined as macrometastasis—a group of more than 10 cancer cells . On the week five after cancer cells transplantation, the advanced metastatic phase is recognized by extensive metastatic sites as well as progressive leucocytosis and systemic inflammation . Therefore, we aimed here to determine HD and UHD FTIR spectroscopic definition of various metastases developed in different lung locations after inoculation with 4 T1 breast cancer cells at the early and advanced phases.…”