Hyperactive neutrophils infiltrate vital organs of tumor bearing host and contribute to gradual systemic deterioration via upregulated NE, MPO and MMP-9 activity

Abstract

Cancer is known to have systemic impact by targeting various organs that ultimately compromises the overall physiology of the host. Several reports have demonstrated the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, their role in mediating systemic effects during cancer progression has not been deciphered so far. Therefore, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern their systemic role, we evaluated neutrophil count and function at different stages of tumor growth in Dalton's Lymphoma mice model. Notably, our results displayed a gradual increase in Ly6G+ neutrophils in peripheral blood and their infiltration in vital organs including liver, lungs, spleen, kidney, lymph nodes and peritoneum of tumor bearing host. We showed remarkable alterations in histoarchitecture and serum enzyme levels that aggravated with tumor progression. We next examined neutrophil function by assessing its granular cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloproteinases (MMP-8 and MMP-9). Interestingly, blood neutrophils of tumor bearing mice exhibited a marked change in morphology with gradual increase in NE and MPO expression with tumor growth. In addition, we observed upregulated expression of NE, MPO, MMP-8 and MMP-9 in the vital organs of tumor bearing host. Taken together, our results demonstrate heightened infiltration and function of neutrophils in vital organs of tumor bearing host which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.