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.
The secretory leukocyte protease inhibitor (SLPI) can attenuate the host proinflammatory response by blocking nuclear factor kappaB (NF-kappaB)-mediated tumor necrosis factor alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha and E-selectin. They suggest that factors that attenuate the host proinflammatory response may have a therapeutic potential in the prevention of liver metastasis.
Department of Surgery, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.
Ni
N
Wang
Thusanth
T
Thuraisingam
Lucia
L
Fallavollita
Aihao
A
Ding
Danuta
D
Radzioch
Pnina
P
Brodt
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000276:immunology; D053481:Secretory Leukocyte Peptidase Inhibitor; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D019040:E-Selectin; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D014409:Tumor Necrosis Factor-alpha; D017526:Receptor, IGF Type 1