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.
Highlights
Patients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events
We showed that an early decrease in pulmonary and systemic nitric oxide (NO) availability coincided with the development of lung inflammation in the early metastatic phase, while late systemic endothelial dysfunction in aorta coincided with robust, systemic, cancer-related inflammation
The mean number of metastases developed in lungs isolated from tumour-bearing mice 4, 5 or 6 weeks after cancer cell transplantation gradually increased, reaching a mean of 35.2 ± 9.3 metastatic nodules at week 6 of the study (Fig. 1b)
Summary
Patients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. In target organs for metastatic spread, endothelial inflammation may promote cancer metastasis. The endothelium acts as a barrier to cancer cell migration from blood to tissue. It has been proposed that the migration and invasion of circulating cancer cells into distant tissues is supported by the same mechanisms as those involved in leukocyte recruitment [7]. Recent in vitro studies have demonstrated that factors released from dysfunctional endothelium activate NF-κB and STAT3 signalling pathways within cancer cells, and promote their invasiveness in vitro [10]. Vasoprotective endothelial mediators such as for example prostacyclin (PGI2) display anti-metastatic activity, further supporting a crucial relationship between endothelial function and cancer metastasis [11, 12]
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