Abstract 1346: Neutrophils facilitate metastasis by increasing cancer cell recruitment to liver sinusoids

Abstract Background: Mounting evidence suggests that acute inflammation can facilitate the implantation and growth of circulating tumor cells. Previously, we have shown that bacterial lipopolysaccharide (LPS)-induced acute systemic inflammation promotes cancer cell recruitment to liver sinusoids in a neutrophil (PMN) dependent manner. This present study focuses on the various levels at which PMNs and their products can affect metastasis. Methods: In vitro adhesion assays were conducted to test for interactions between Lewis lung carcinoma H-59 cells, isolated mouse PMNs and human umbilical vein endothelial cells (HUVECs). In vivo real-time, single-cell H-59 adhesion to liver sinusoids was measured by hepatic intravital microscopy (IVM). C57BL/6 mice received intra-arterial injections of GFP-tagged H-59 cells. PMN depletion was achieved by IV injection of RB6-8C5 mAb. Some mice received LPS IV 4 hours prior to IVM. Some PMN-depleted mice received isolated PMNs from littermates intra-arterially 10 minutes prior to cancer cell inoculation. The effect of PMNs on gross metastasis formation was assessed after intra-splenic injection of H-59 cells in control and PMN-depleted mice. Results are presented as mean +/- SEM and MWU-test determined significance (* = p<0.05). Results: LPS-activated PMNs adhered 2.5 fold more to a monolayer of H-59 cells than control PMNs (12.3 +/− 1.2 vs 4.9 +/− 3.1 cells/field)*. H-59 adhesion to a HUVEC monolayer was increased when HUVECs were pre-incubated with PMNs versus control RPMI (40.5 +/− 2.6 vs 27.8 cells/field)*. Similarly, HUVECs pre-incubated with LPS-activated PMN-condition media resulted in 70% increased H-59/HUVEC adhesion compared to control RPMI*. Co-incubation of H-59 with control and LPS-treated PMNs prior to co-culture with HUVECs resulted in a 2.8 and 3.5 fold increase in H-59/HUVEC adhesion. These in vitro results correlated with in vivo findings from intravital microscopy and intra-splenic injection. PMN depletion resulted in a significant decrease in H-59 adhesion in both control and LPS-inflamed mice. Pre-infusion of LPS-treated PMNs in a PMN-depleted mouse prior to H-59 infusion caused a 42% increase in H-59 adhesion to liver sinusoids as compared to PBS pre-infusion (16.5 +/− 0.5 vs 11.7 +/− 0.5)*. Finally, PMN depletion prior to intra-splenic injection of H-59 cells decreased gross surface metastases at 2 weeks by 88% from a mean of 48 +/− 12.2 to 6 +/− 2.6*. Conclusions: PMNs may facilitate liver metastasis by direct interactions with cancer cells as well as remotely via PMN derived factors. LPS-activated PMNs were sufficient to promote early cancer cell recruitment to liver sinusoids. PMNs are key participants in the development of gross metastasis. Together, these results suggest that PMNs are important contributors to the implantation and growth of circulating tumor cells in the liver and constitute a possible target for anti-metastatic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1346.

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