NETosis in cancer

Abstract

A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. Although the awareness of tumor-induced systemic effects has increased significantly in recent years, current knowledge is still mainly restricted to metastatic sites. Surprisingly little is known about the situation in organs that are not targets for metastasis or directly affected by the primary tumor. We therefore decided to look deeper into this relatively unexplored field of cancer research. For obvious reasons human biopsy material from tissues not affected by tumor cells, in an individual with cancer, are rare and mouse models therefore become important tools for such investigations. Using two different orthotopic and spontaneously metastasizing tumor models - the RIP1-Tag2 model for insulinoma with metastasis to the liver and the MMTV-PyMT model for mammary carcinoma with lung metastasis - we analyzed the presence of hematopoietic cells in organs which do not represent sites for primary tumor growth. There was a significant increase in the number of neutrophils in heart and kidneys of tumor-bearing mice compared to healthy individuals [1]. In mice with cancer, peripheral organs displayed systemic inflammation and impaired vascular function, which was restored upon neutrophil depletion. Platelet/neutrophil complexes, indicative of neutrophil extracellular traps (NETs), were found in kidney and heart from tumor-bearing mice, while these complexes were completely absent in the corresponding tissues from healthy mice. Indeed, analysis of peripheral blood confirmed the presence of neutrophils with extracellular DNA-tails in tumor-bearing mice.