Abstract 554: Crosstalk between TNF-α and IGF signalling increases IL-6 production and protects tumor cells from TNF-α-induced apoptosis in the liver
Authors: Shun Li, Long Yang, Rongtuan Lin, John Hiscott, Pnina Brodt
Journal: Cancer Research (2010)

Abstract Background: Liver metastasis is a common and often fatal occurrence in cancer patients. A better understanding of the biology of liver metastasis is essential to improve survival statistics for these patients. We have previously shown that metastatic lung and colon carcinoma cells that invade the liver initiate a rapid host inflammatory response that entails increased production of cytokines TNF-α and IL-1 and results in increased tumor adhesion, transmigration and metastasis. TNF-α is a pleiotropic cytokine that can also induce tumor cell apoptosis. We hypothesized that the ability of tumor cells to form liver metastases in the face of increased local TNF-α levels is due to an acquired resistance to the tumoricidal effects of TNF-α. The objective of the present study was therefore to identify molecular mechanism(s) that regulate the tumor cell response and sensitivity to TNF-α. Methodology: We used a Lewis lung carcinoma-based tumor model consisting of poorly metastatic subline M-27 cells in which ectopic expression of the type 1 insulin-like growth factor receptor (IGF-IR) markedly increased the liver-metastasizing potential of the cells. TNF-α-mediated signalling in these (M-27IGFIR) and wild-type (M-27) cells were analyzed by a combination of Western blotting, electrophoretic mobility shift assays, cytokine profiling, immunofluorescence labelling and flow cytometry. Results: We found that IGF-I receptor overexpression in the tumor cells altered TNF-α-mediated signalling by accelerating TNF-α-induced IκBα phosphorylation and degradation and enhancing nuclear translocation of NFκB. This resulted in increased IL-6 production in M-27IGFIR, but not M-27 cells in response to TNF-α. IL-6 expression could be further augmented by co-stimulation with IGF-I, an effect that was mediated via PI3-K signalling. Furthermore, the level of activated STAT-3 in M-27IGFIR cells was significantly increased, suggesting that IL-6 could activate STAT-3 in these cells through an autocrine mechanism. Finally, when apoptosis induction by TNF-α in these cells was compared using antibodies to cleaved caspase 3, a significant reduction in the proportion of apoptotic cells was seen in TNF-α-treated M-27IGFIR as compared to M-27 cells. Conclusions: Taken together, the results suggest that overexpression of IGF-IR altered TNF-α signalling in the tumor cells, shifting the response towards increased IL-6 production and autocrine STAT-3 activation, thereby providing the cells with a survival advantage in the presence of TNF-α. Supported by Canadian Institute for Health Research grant MOP- 81201 (PB) and a McGill University Health Center Research Institute fellowship (SL). 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 554.