Abstract 4278: IFN-γ and TNF-α favor the progression of prostate cancer in distinct ways

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction Although screening methods for prostate cancer (PCa) have substantially improved, the outcome for patients with advanced PCa remains poor. The elucidation of the molecular mechanism that drives the progression from a slow-growing, organ-confined tumor to a highly invasive and castration-resistant cancer (CRPC) is therefore important. Although a causal correlation between inflammation and PCa has not been established, literature suggests that inflammation might play an important role in its onset and progression. The aim of this study is to investigate the effect of inflammation on progression of PCa. We have evaluated the effect of IFN-γ and TNF-α on proliferation, migration, and invasion of PCa cells, and potentially identified the molecular mechanisms underlying these effects. Materials and Methods The CA-HPV-10 and PC3 cell-lines were stimulated with 300U/ml of IFN-γ or TNF-α. Relative gene expressions were quantified by RT-PCR. Protein quantification was performed by HPLC or ELISA. Functionality of cells was tested using: acridine orange (viability), WST-1 (proliferation), Tscratch (migration) and the Chemicon Cell Invasion Assay (invasion). Results IFN-γ induced de-novo expression of both IDO1 and IDO2 genes in CA-HPV-10 and their over expression in PC3. TNF-α induced over-expression of MMP9, TNF- ≤ and IL-6 in CA-HPV-10, and of 7 genes in PC3 (MMP9, IDO1 and IDO2, TNF-α, IL-6, IL-1α and ROS1). IFN-γ and TNF- ≤ do neither induce apoptosis nor affect the proliferation of both cell-lines. TNF-α significantly increases migraton of metastatic cells (p<0.001) and markedly affects the invasiveness of both CA-HPV-10 and PC3 (increase of 32% and 51%, respectively), whereas IFN-γ has no or little effect. Discussion IFN-γ induces IDO1 and IDO2, whose roles in modulating immune tolerance have been extensively investigated. Conversely, IFN-γ does not affect other mechanism of cancer progression, such as cell migration and invasion. TNF-α, on the other hand, induces stable over-expression of MMP9 in localized cancer, and of 6 other genes in metastatic cells. MMP9 plays an important role in proliferation, migration and invasion and its elevated levels have been reported in many tumors. These notions could explain our findings showing that TNF-α enhances PCa cell migration and invasion. Furthermore TNF-α enhances the ability of cancer cells to actively maintain a pro-inflammatory microenvironment, due to the over-production of TNF-α, IL-6 and IL-1α. High levels of these cytokines in patients with advanced PCa have been hypothesized to play an important role in the onset of a CRPC. In conclusion, IFN-γ and TNF-α favor cancer progression by enhancing its malignant features in distinct ways. IFN-γ favors tumor immune-escape by inducing over-expression of IDO1 and IDO2, while TNF-α enhances PCa cell migration and invasion, sustains the active maintenance of a pro-inflammatory microenvironment and favors the onset of a CRPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4278. doi:1538-7445.AM2012-4278