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The Secretory Leukocyte Protease Inhibitor Is a Type 1 Insulin-Like Growth Factor Receptor–Regulated Protein that Protects against Liver Metastasis by Attenuating the Host Proinflammatory Response

¹ Department of Surgery, Royal Victoria Hospital, McGill University Health Centre, McGill University, ² Department of Experimental Medicine, Montreal, Quebec, Canada; and ³ Department of Microbiology and Immunology, Weill Medical School of Cornell University, New York, New York

Requests for reprints: Pnina Brodt, Surgical Labs, Royal Victoria Hospital, Room H6.25, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Phone: 514-934-1934, ext. 36692; Fax: 514-843-1411; E-mail: pnina.brodt{at}muhc.mcgill.ca.

The secretory leukocyte protease inhibitor (SLPI) can attenuate the host proinflammatory response by blocking nuclear factor B (NF-B)–mediated tumor necrosis factor (TNF-) production in macrophages. We have previously shown that highly metastatic human and mouse carcinoma cells, on their entry into the hepatic microcirculation, trigger a rapid host proinflammatory response by inducing TNF- production in resident Kupffer cells. Using GeneChip microarray analysis, we found that in mouse Lewis lung carcinoma subclones, SLPI expression was inversely correlated with tumor cell ability to induce a proinflammatory response and metastasize to the liver and with type 1 insulin-like growth factor receptor expression levels. To establish a causal relationship between SLPI expression and the metastatic phenotype, we generated, by transfection, multiple clones of the highly metastatic subline (H-59) that overexpress SLPI. We show here that the ability of these cells to elicit a host proinflammatory response in the liver was markedly decreased, as evidenced by reduced TNF- production and vascular E-selectin expression, relative to controls. Moreover, these cells formed significantly fewer hepatic metastases (up to 80% reduction) as compared with mock-transfected controls. Our findings show that SLPI can decrease the liver-metastasizing potential of carcinoma cells and that this protective effect correlates with a decrease in the production of hepatic TNF- and E-selectin. They suggest that factors that attenuate the host proinflammatory response may have a therapeutic potential in the prevention of liver metastasis. (Cancer Res 2006; 66(6): 3062-70)

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