Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions

Abstract

Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that b1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that b1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that b1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process.

Primary tumors induce neutrophil extracellular traps with targetable metastasis-promoting effects

“…Our previous work has demonstrated a tumor-promoting role for NETs in preclinical models of cancer (15,32). Here, we investigate whether circulating NET levels are elevated in patients with several high-lethality malignancies, including lung, esophageal, and gastric adenocarcinoma, and we show that higher NET level is associated with disease stage.…”

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

“…In this context, Najmeh et al have shown that β1-integrins, expressed on both tumor cells and NETs, mediate adhesion of circulating tumor cells to NETs [120]. In addition, interactions between β2-integrins on neutrophils and ICAM-1 on melanoma cells have been shown to anchor these cells to vascular endothelium, promoting extravasation [121]. Interestingly, Albrengues et al, using a murine model of experimental, tolerogenic, pulmonary tumor cell dormancy based on administration of breast cancer cell lines, observed that sustained lung inflammation caused by exposure to cigarette smoke or lipopolysaccharide triggered reactivation of dormant tumor cells [122].…”

Neutrophil Extracellular Traps as an Adhesion Substrate for Different Tumor Cells Expressing RGD-Binding Integrins

“…α5β1 seems to play a primary role in adhesion to NETs. To this respect, a recent study reported that silencing of the β1 integrin with targeted siRNA in A549 lung cancer cells caused a decrease in cell adhesion to NETs in liver sinusoids as assessed by intravital microscopy in a mouse model of metastatic dissemination [25]. The maximal reduction of integrin-dependent adhesion to NETs was similar to that obtained after DNase 1 treatment, confirming that both DNA and fibronectin were relevant in determining cell attachment to NETs.…”