Neutrophil extracellular traps as potential therapeutic targets to prevent tumor-induced organ failure and metastasis

Abstract: Cancer does not only affect surrounding tissues, but also leads to complications at distant sites. The reason for this is that tumors secrete factors and prime cells that travel through the body, making cancer a systemic disease. In fact, cancer death is mostly caused by systemic complications such as metastasis, organ failure or thrombosis. However, surprisingly little is known about the effect of cancer on distant organs that are not sites of tumor growth.Neutrophil extracellular traps (NETs) are web-like structures consisting of neutrophil DNA and granular proteins that are released from the neutrophil in response to a stimulus. NETs are not only formed in bacterial infections but also in noninfectious inflammatory disorders like cancer. While NETs can be beneficial for the host in severe infections they come with a cost. NETs are pro-thrombotic, cause damage to the vessel-lining endothelial cells, are involved in metastasis formation and impair organ function. The removal of NETs by DNase I an enzyme that breaks the NET backbone can therefore be of use as a therapy for certain conditions.The aim of this thesis was to investigate the mechanisms leading to systemic effects of cancer and potential therapeutic strategies with a special focus on NETs.In paper I we investigated how the presence of a primary tumor affected heart function. We conclude that tumor-induced NETs contribute to inflammation and myocardial strain in malignant disease and identify NETs as potential therapeutic targets in cancer patients to prevent cardiac inflammation and dysfunction.In paper II we investigated if the long-term removal of NETs by the use of a murine DNase I expressing adeno-associated virus vector was possible and how this affected organ function and metastasis formation in tumor-bearing mice. We conclude that long-term, species-specific expression of DNase I is possible. Elevated DNase I expression improved kidney function and reduced the proportion of mice with metastasis.In paper III we investigated how cancer and cancer-associated NETs affect endothelial gene expression in distant organs. We found that the number of differentially expressed genes increased with tumor size and that it was higher in metastatic organs. In response to a tumor, the kidney vasculature showed signs of renal hepatization, a state of kidney stress. In conclusion, this study gives a global overview of the gene expression changes that take place in the vasculature of distant organs in individuals with cancer and the potential role of NETs.