Li Jiahui, Wu Xiaolin, Schiffmann Lars, MacVicar Thomas, Zhou Chenghui, Wang Zhefang, Li Dai, Camacho Oscar Velazquez, Heuchel Reiner, Odenthal Margarete, Hillmer Axel, Quaas Alexander, Zhao Yue, Bruns Christiane J, Popp Felix C
Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
Max-Planck-Institute for Biology of Ageing, 50931 Cologne, Germany.
Cancers (Basel). 2021 Oct 24;13(21):5338. doi: 10.3390/cancers13215338.
In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.
在胰腺导管腺癌（PDAC）中，肿瘤基质构成了大部分细胞团，并导致治疗抗性和疾病进展。在此，我们展示了胰腺星状细胞（PSC）与肿瘤细胞之间通过白细胞介素17B/白细胞介素17B受体（IL-17B/IL-17RB）信号传导的一种前所未知的代谢合作。肿瘤来源的携带细胞外囊泡（EV）的IL-17B激活了基质PSC，并诱导了IL-17RB的表达。PSC增加了氧化磷酸化，同时减少了线粒体更新。PSC在一个反馈回路中激活肿瘤细胞。肿瘤细胞随后部分通过IL-6增加了氧化磷酸化并减少了糖酵解。在体内，PSC中IL-17RB的过表达在共注射异种移植小鼠模型中加速了肿瘤生长。我们的结果证明了一个肿瘤到基质的反馈回路，该回路在最佳营养条件下增加肿瘤代谢以加速肿瘤生长。
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