Department of Internal Medicine II, Würzburg University Clinics, Würzburg, Germany ; Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany.
PLoS One. 2013 Sep 30;8(9):e75737. doi: 10.1371/journal.pone.0075737. eCollection 2013.
Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4(+) T cells and CD4(+) forkhead box P3 (FoxP3)(+) regulatory T cells (Treg) but reduced numbers of CD8(+) T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8(+) T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
细胞因子肿瘤坏死因子 (TNF) 在健康和疾病中具有多种活性。特别是，TNF 被证明以多种方式影响肿瘤发生。这种细胞因子通过两种细胞表面受体的激活起作用，TNFR1 与炎症有关，而 TNFR2 被证明能引起抗炎信号。我们通过在 Panc02 细胞的同基因原位肿瘤小鼠模型中进行体内生物发光成像，评估了 TNF 及其两个受体对胰腺癌进展的影响。TNFR1 缺陷小鼠无法自发排斥 Panc02 肿瘤，并且肿瘤进展进一步增强。相比之下，野生型（37.5%）、TNF 缺陷型（12.5%）和 TNFR2 缺陷型（22.2%）小鼠中有一部分能够在两周内完全排斥肿瘤。TNFR1 缺陷型小鼠的胰腺肿瘤显示血管密度增加，CD4(+) T 细胞和 CD4(+)叉头框 P3 (FoxP3)(+)调节性 T 细胞（Treg）浸润增强，但 CD8(+) T 细胞数量减少。这些改变进一步伴随着 IL4 的转录上调。因此，TNF 和 TNFR1 在胰腺导管腺癌中是确保最佳 CD8(+) T 细胞介导的免疫监视和肿瘤排斥所必需的。然而，外源性全身给予与人 TNF 仅相互作用的鼠 TNFR1 加速了肿瘤进展。这表明 TNFR1 在 Panc02 模型中基本上具有触发促肿瘤和抗肿瘤作用的能力，但 TNF 的时空可用性似乎最终决定了整体结果。
