Interleukin-33 enhances programmed oncosis of ST2L-positive low-metastatic cells in the tumour microenvironment of lung cancer.
Interleukin-33 enhances programmed oncosis of ST2L-positive low-metastatic cells in the tumour microenvironment of lung cancer.
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DOI：
10.1038/cddis.2015.418
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发表时间：
2016-01-21
影响因子：
9
通讯作者：
Takenaga K
中科院分区：
文献类型：
--
作者：
Akimoto M;Hayashi JI;Nakae S;Saito H;Takenaga K
促炎白细胞介素-33 （IL-33）与免疫细胞表面的受体ST2L结合，刺激Th2细胞因子的产生；然而，人们对IL-33对肿瘤细胞的作用知之甚少。本研究表明，与正常肺组织和细胞相比，ST2在人肺癌组织和细胞中明显下调。IL-33的表达也与人类肺癌的分期呈负相关。根据这一发现，来自Lewis肺癌的低转移细胞而非高转移细胞表达功能性ST2L。与高转移细胞形成的肿瘤相比，低转移细胞形成的肿瘤中IL-33含量丰富。尽管低转移细胞在体外几乎不表达IL-33，但这些细胞在体内却表达较少，可能是由于肿瘤内IL-1β和IL-33的刺激。重要的是，在葡萄糖耗尽、谷氨酰胺耗尽和缺氧条件下，IL-33通过p38 MAPK和mTOR激活，并以线粒体依赖的方式，增强了st2l阳性低转移细胞的细胞死亡，而不是st2l阴性高转移细胞的细胞死亡。细胞死亡的特征是细胞质起泡和核溶解，这是肿瘤的独特形态学特征。与野生型小鼠相比，IL-33−/−小鼠体内低转移细胞的生长速度明显快于野生型小鼠，而高转移细胞的生长速度则没有明显变化。此外，IL-33在模拟肿瘤微环境的条件下选择st2l阳性、抗肿瘤的高转移细胞。这些数据表明，IL-33通过在肿瘤微环境中选择更多的恶性细胞来促进肺癌的进展。
The proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L on the surface of immune cells and stimulates the production of Th2 cytokines; however, the effects of IL-33 on tumour cells are poorly understood. Here we show that ST2 was significantly downregulated in human lung cancer tissues and cells compared with normal lung tissues and cells. IL-33 expression was also inversely correlated with the stages of human lung cancers. In accordance with this finding, low-metastatic cells but not high-metastatic cells derived from Lewis lung carcinoma expressed functional ST2L. IL-33 was abundantly present in the tumours established by the low-metastatic cells compared with those formed by the high-metastatic cells. Although the low-metastatic cells scarcely expressed IL-33 in vitro, these cells did expry 6ess this molecule in vivo, likely due to stimulation by intratumoural IL-1β and IL-33. Importantly, IL-33 enhanced the cell death of ST2L-positive low-metastatic cells, but not of ST2L-negative high-metastatic cells, under glucose-depleted, glutamine-depleted and hypoxic conditions through p38 MAPK and mTOR activation, and in a mitochondria-dependent manner. The cell death was characterised by cytoplasmic blisters and karyolysis, which are unique morphological features of oncosis. Inevitably, the low-metastatic cells, but not of the high-metastatic cells, grew faster in IL-33−/− mice than in wild-type mice. Furthermore, IL-33 selected for the ST2L-positive, oncosis-resistant high-metastatic cells under conditions mimicking the tumour microenvironment. These data suggest that IL-33 enhances lung cancer progression by selecting for more malignant cells in the tumour microenvironment.