Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy
Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy
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DOI：
10.1038/s41416-021-01652-y
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发表时间：
2021-12-20
影响因子：
8.8
通讯作者：
Madlambayan，Gerard J.
中科院分区：
文献类型：
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作者：
Parsons，Tyler M.;Buelow，Katie L.;Madlambayan，Gerard J.
骨髓来源的造血干细胞和祖细胞（HSPCs）是高度复杂的肿瘤微环境（TME）的重要组成部分，它们定位于肿瘤内并维持造血能力。了解HSPCs在肿瘤生长和放射治疗（RT）反应中的作用可能会改善患者的治疗和结果。方法采用非小细胞肺癌小鼠模型，肿瘤暴露于RT方案单独或联合GW2580，集落刺激因子(CSF)-1受体的药理学抑制剂。采用RT-PCR、western blotting、免疫组化等方法定量分析影响HSPC分化的因子的表达水平。利用流式细胞术和共聚焦显微镜追踪DsRed+HSPC在肿瘤内的活性。结果研究人员证实，暴露于rt后，CSF-1在TME中增强。CSF-1信号传导诱导肿瘤内HSPC分化为M2极化肿瘤相关巨噬细胞（tam），有助于rt后肿瘤存活和再生。相比之下，超分割/脉冲放射治疗（PRT）和GW2580消除了这一过程，从而提高了肿瘤杀伤和小鼠存活率。结论肿瘤通过CSF-1信号来决定瘤内HSPC的命运，从而克服rt的影响。因此，限制瘤内HSPC的活性是改善实体瘤临床治疗的一种有吸引力的策略。
BackgroundBone-marrow-derived haematopoietic stem and progenitor cells (HSPCs) are a prominent part of the highly complex tumour microenvironment (TME) where they localise within tumours and maintain haematopoietic potency. Understanding the role HSPCs play in tumour growth and response to radiation therapy (RT) may lead to improved patient treatments and outcomes.MethodsWe used a mouse model of non-small cell lung carcinoma where tumours were exposed to RT regimens alone or in combination with GW2580, a pharmacological inhibitor of colony stimulating factor (CSF)-1 receptor. RT-PCR, western blotting and immunohistochemistry were used to quantify expression levels of factors that affect HSPC differentiation. DsRed+HSPC intratumoural activity was tracked using flow cytometry and confocal microscopy.ResultsWe demonstrated that CSF-1 is enhanced in the TME following exposure to RT. CSF-1 signaling induced intratumoural HSPC differentiation into M2 polarised tumour-associated macrophages (TAMs), aiding in post-RT tumour survival and regrowth. In contrast, hyperfractionated/pulsed radiation therapy (PRT) and GW2580 ablated this process resulting in improved tumour killing and mouse survival.ConclusionsTumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours.