The Tumor-Promoting Effect of TNF-α Involves the Induction of Secretory Leukocyte Protease Inhibitor

Abstract

According to the cancer immunoediting concept, inflammatory mediators play not only a critical role in promoting host protection against cancer but also contribute to cancer cell growth and survival. TNF-α is a critical factor in this network. However, the mechanisms underlying the tumor-promoting effect of TNF-α have not been fully elucidated yet. We previously reported that in vitro culture of Lewis lung carcinoma 3LL cells with TNF-α-producing macrophages resulted in enhanced resistance toward TNF-α-mediated lysis and increased malignancy of the 3LL cells. In this study, we analyzed the effects of endogenous TNF-α on TNF-α resistance and malignant behavior in vivo of low-malignant/TNF-α-sensitive 3LL-S cells and cancer cells derived from 3LL-S tumors that developed in wild-type or TNF-α−/− mice. Interestingly, 3LL-S cells acquired a malignant phenotype in vivo depending on the presence of host TNF-α, whereas acquisition of TNF-α resistance was TNF-α-independent. This result suggested that malignancy-promoting characteristics of 3LL-S cells other than TNF-α resistance are influenced in vivo by TNF-α. We previously identified the malignancy-promoting genes, secretory leukocyte protease inhibitor (SLPI) and S100A4, as being up-regulated in 3LL-S cells upon their s.c. growth in wild-type mice. In this study, we show that SLPI, but not S100A4, was induced in 3LL-S cells both in vitro and in vivo by TNF-α, and that silencing of in vivo induced 3LL-S SLPI expression using RNA interference abrogated in vivo progression but did not influence TNF-α resistance. These data indicate that SLPI induction may be one mechanism whereby TNF-α acts as an endogenous tumor promoter.