152 - Pulmonary and systemic nitric oxide deficiency in the early phase of lung metastasis in 4T1 metastatic breast cancer murine model

Abstract

The role of nitric oxide (•NO) in metastatic cancer progression has not been fully explained. In the present work we characterized the development of •NO deficiency in the lung and examined changes in •NO and prostacyclin (PGI2)-dependent endothelial function in the systemic conduit artery (aorta), in relation to the progression of 4T1 metastatic breast cancer injected orthotopically in Balb/c mice. Furthermore, orthotopic and intravenous models of 4T1 metastatic cancer in mice were used to study the differential effects of L-NAME-induced •NO deficiency on the primary tumor and the metastatic burden. •NO was assessed in isolated aorta and lungs using EPR spin-trapping and chemiluminescence, while NOx in blood were measured using either EPR, chemiluminescence or Griess reaction. Early pulmonary metastasis was correlated with lung inflammation. Pulmonary endothelial function and systemic •NO availability in 4T1 breast cancer-bearing mice were compromised prior to the development of pulmonary metastasis,preceding the onset of its phenotypic switch toward a mesenchymal phenotype (EndMT). 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. L-NAME-induced •NO-deficiency showed that •NO plays a major role in the primary tumor development, but it is not the key mediator responsible for the regulation of cancer cell extravasation to the lungs in our model, despite clear-cut •NO-deficiency in the lung, reflected by a fall in systemic •NO bioavailability, both occurring early in the pre-metastatic phase.