ABSTRACT
Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1ß (IL-1ß) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1ß axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.
Subject(s)
Breast Neoplasms/metabolism , Cathepsin C/metabolism , Extracellular Traps/metabolism , Lung Neoplasms/metabolism , Neutrophil Infiltration/physiology , Neutrophils/metabolism , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Neutrophils/pathology , Reactive Oxygen Species/metabolism , Tumor Microenvironment/physiologyABSTRACT
Infections by pathogens may lead to cardiovascular diseases, including acute/chronic myocarditis. (Coxsackieviruses B3) CVB3 is considered to be the most common causative agent in myocarditis, which can lead to dilated cardiomyopathy. The present study aimed to investigate the mechanism of CVB3infected myocardial microvascular endothelial cells. The CVB3 infection was detected by 50% tissue culture infective dose (TCID50). The role of fractalkine (FKN) in the infection was detected using western blotting and RNA interference. To assess mitogenactivated protein kinase signaling activity, levels of total and phosphorylated extracellular signalregulated kinase (ERK)1/2, cJun Nterminal kinase, and p38 were measured at 0, 20, 40, and 60 min after CVB3 infection by western blot analysis. The results showed that infection activated FKN via the ERK1/2 signaling pathway. Furthermore, the TCID50 of CVB3 in infected cells was lower compared with that in myocardial microvascular endothelial cells following ERK1/2 inhibition and FKN silencing. CVB3 infection of myocardial microvascular endothelial cells activates FKN via the ERK1/2 signaling pathway. These findings represent a foundation for the development of novel methods of treating CVB3induced myocarditis.