Signalling pathways of T-helper-1-cell-cytokine-induced senescence

除了手术切除、化疗和放射治疗外，肿瘤免疫治疗已成为一种很有前途的抗癌新疗法。与此同时，研究人员发现了新的生物学原理，这些原理并不完全旨在通过破坏细胞来根除肿瘤。特别是细胞衰老，即肿瘤细胞的永久生长停滞，以及免疫系统对肿瘤的衰老监测被描述为非常有效的抗癌机制。我们最近证明，衰老程序不仅是癌基因触发的对抗肿瘤生长的内在屏障，而且它也可以被外部因素诱导，如炎性细胞因子干扰素-γ(干扰素-γ)和肿瘤坏死因子(TNF)。在拟议的项目中，我们希望重点关注最终导致细胞因子治疗后永久细胞周期停滞的信号通路。为此，我们可以使用多种小鼠肿瘤模型，包括不同的转基因受体或信号转导敲除小鼠。将使用已建立的癌细胞株来研究所描述的诱导人类细胞衰老的信号转导途径的生物学相关性。这些结果将极大地拓宽我们对参与细胞因子诱导衰老的信号级联反应的分子的了解。

Besides surgical excision, chemotherapy and radiation therapy, immunotherapy of tumours has emerged as a promising new anticancer regimen. In the meantime, researchers found new biological principles that do not exclusively aim to eradicate tumours by cellular destruction. Especially cellular senescence, i.e. the permanent growth arrest of tumour cells, and the senescence surveillance of tumours by the immune system were described as very efficient anticancer mechanisms. We could recently demonstrate that the senescence program is not only an oncogene-triggered intrinsic barrier to fight cancer growth but that it can also be induced by extrinsic factors, such as the inflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF). In the proposed project, we want to focus on the signalling pathways that ultimately lead to permanent cell cycle arrest after cytokine treatment. For this, we can use multiple mouse tumour models including different transgenic receptor- or signal transducer knock-out mice. The biological relevance of the described signal transduction pathways for senescence induction in human cells will be investigated using established cancer cell lines. The results will substantially broaden our knowledge about the molecules involved in the signalling cascades of cytokine-induced senescence.