Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer
Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer
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DOI：
10.1016/j.tranon.2020.01.004
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发表时间：
2020-03-01
影响因子：
5
通讯作者：
van Pelt, Jos
中科院分区：
文献类型：
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作者：
Bulle, Ashenafi;Dekervel, Jeroen;van Pelt, Jos
背景：胰腺导管腺癌(PDAC)是一种非常致命的疾病，随着时间的推移会产生治疗抵抗。PDAC中致密的间质在肿瘤的进展和耐药中起着关键作用。这种间质是如何与肿瘤细胞相互作用的，以及化疗是如何影响这种作用的，目前仍知之甚少。方法：本研究的主干是在两个具有分子和临床代表性的患者来源的肿瘤异种移植模型中对人肿瘤和小鼠基质进行平行转录组分析。小鼠(每组8只)用吉西他滨或对照组治疗4周。我们研究了肿瘤生长、间质中RNA的表达、免疫荧光法检测肿瘤相关巨噬细胞(TAMs)以及血清中的细胞因子。结果：优化了平行转录组分析方法。我们发现，肿瘤(分化、基因表达)决定了巨噬细胞向间质的渗透。在侵袭性PDAC(上皮向间充质转化高)中，我们发现更多M2极化的TAM以及细胞因子和生长因子(肿瘤坏死因子α、转化生长因子β1和白介素6)的激活。间质糖酵解增加，脂肪酸氧化减少，线粒体氧化(三羧酸循环和氧化磷酸化)减少。吉西他滨治疗导致先天免疫细胞的转移，特别是前列腺癌M2 TAMs的额外渗透(P<；.001)和代谢重新编程。结论：吉西他滨治疗PDAC异种移植可刺激前列腺癌巨噬细胞表型，与我们先前报道的肿瘤细胞向间充质表型转变相结合，有助于肿瘤进展和治疗耐药。靶向M2极化的TAMs可能有利于有可能对当前抗癌方案无效的PDAC患者。(C)2020作者。爱思唯尔公司代表Neopasia Press，Inc.出版。
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease that can develop therapy resistance over time. The dense stroma in PDAC plays a critical role in tumor progression and resistance. How this stroma interacts with the tumor cells and how this is influenced by chemotherapy remain poorly understood. METHODS: The backbone of this study is the parallel transcriptome analysis of human tumor and mouse stroma in two molecular and clinical representative patient-derived tumor xenografts models. Mice (8 animals per group) were treated for 4 weeks with gemcitabine or control. We studied tumor growth, RNA expression in the stroma, tumor-associated macrophages (TAMs) with immunofluorescence, and cytokines in the serum. RESULTS: A method for parallel transcriptome analysis was optimized. We found that the tumor (differentiation, gene expression) determines the infiltration of macrophages into the stroma. In aggressive PDAC (epithelial-to-mesenchymal transition high), we find more M2 polarized TAMs and the activation of cytokines and growth factors (TNF alpha, TGF beta 1, and IL6). There are increased stromal glycolysis, reduced fatty acid oxidation, and reduced mitochondrial oxidation (tricarboxylic acid cycle and oxidative phosphorylation). Treatment with gemcitabine results in a shift of innate immune cells, especially additional infiltration of protumoral M2 TAMs (P < .001) and metabolic reprogramming. CONCLUSIONS: Gemcitabine treatment of PDAC xenografts stimulates a protumoral macrophage phenotype, and this, in combination with a shift of the tumor cells to a mesenchymal phenotype that we reported previously, contributes to tumor progression and therapeutic resistance. Targeting M2-polarized TAMs may benefit PDAC patients at risk to become refractory to current anticancer regimens. (C) 2020 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc.