Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals

Abstract

Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1b, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.Cancer Res; 75(13); 2653-62. Ó2015 AACR.

Interleukin-17–Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer

“…In addition to contactdependent mechanisms, neutrophils secrete soluble factors that can activate endothelial and parenchymal cells, enhancing tumor cell adhesion in distant sites (11)(12)(13)(14). Circulating tumor cells are trapped in neutrophil extracellular traps (NET) in vitro, and NET trapping is associated with increased formation of hepatic micrometastases and compromised organ function in murine models (15,16). These novel aspects of neutrophil biology may contribute to cancer progression and metastasis.…”

Tumor-induced neutrophil extracellular traps—drivers of systemic inflammation and vascular dysfunction

“…Administration of DNase restored the vascular function in the kidney and heart to levels seen in non-tumor-bearing mice, and also suppressed the inflammatory response. 7 The impact of DNase treatment was remarkable and strongly implicates NETs as a cause of the systemic inflammation and impaired peripheral vessel function that we observed in mice with cancer. It is well recognized that cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions.…”

“…1). 7 Tumor-bearing mice displayed an average reduction in renal perfusion by 50% compared to mice without tumors. Since NETs have a high content of extracellular DNA, they can be dissolved by DNase treatment.…”

“…We found that the adhesion molecules ICAM-1, VCAM-1 and E-selectin, as well as the proinflammatory cytokines IL-1ß, IL-6 and the chemokine CXCL1, is significantly upregulated in kidney tissue from tumor-bearing mice compared to healthy individuals. 7 Hypothetically, this pro-inflammatory state with upregulated adhesion molecules on the peripheral endothelium could enhance tumor cell extravasation in distant organs. We are currently addressing this issue in our lab and if this is indeed the case, it would strongly motivate further investigations on NET-inhibiting drugs as prophylactic tools for metastasis in the clinical management of cancer.…”

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

“…The company filed a first patent in 2011 on PI3K/mTOR inhibitors,334 of which one, SPR965, has reached the preclinical evaluation stage 335, 336. The compound is likely to be structurally related, if not identical to a compound recently described in a publication 337.…”