Increased TIA‐1 gene expression in the tumor microenvironment after locoregional administration of tumor necrosis factor‐α to patients with soft tissue limb sarcoma

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Abstract
Although it is known that TNF‐α is effective in the treatment of advanced solid tumors such as melanoma and soft tissue sarcoma, the molecular mechanism underlying its anticancer activity remains unclear. Nineteen patients with locally advanced soft tissue sarcoma underwent isolated limb perfusion with doxorubicin alone (n = 9) or combined with TNF‐α (n = 10). mRNA from posttreatment tumor biopsies was linearly amplified to create an RNA bank. The transcriptional levels of 22 genes were analyzed by qrt‐PCR. On the basis of in vivo findings, we investigated the in vitro gene expression of different cell types representing the tumor microenvironment cell population. TIA‐1, which encodes an RNA‐binding protein with translation‐regulatory functions, was the only gene differentially expressed between the 2 study groups, its transcriptional levels in tumor biopsies from patients receiving TNF‐α being higher than in those from patients not given the cytokine. In vitro, TIA‐1 was expressed by endothelial cells, fibroblasts, CTLs and NK cells. TNF‐α significantly upregulated TIA‐1 gene expression only in endothelial and NK cells. Furthermore, TIA‐1 transcriptional levels significantly increased during NK activity, which was enhanced by TNF‐α. These findings support the hypothesis that TNF‐α‐induced TIA‐1 overexpression might sensitize endothelial cells to proapoptotic stimuli present in the tumor microenvironment and enhance NK cell cytotoxic activity against cancer cells.