Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer
Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer
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DOI：
10.1136/gutjnl-2015-310049
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发表时间：
2017-07-01
期刊：
影响因子：
24.5
通讯作者：
Michl, Patrick
中科院分区：
文献类型：
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作者：
Griesmann, Heidi;Drexel, Christof;Michl, Patrick
目的 肿瘤相关巨噬细胞在介导肿瘤进展中发挥重要作用。在胰腺癌中，已知浸润巨噬细胞可介导肿瘤进展，并且已在侵袭性肿瘤和早期侵袭前胰腺上皮内前体病变中得到鉴定。我们的目的是研究脂质体氯膦酸盐对胰腺癌遗传小鼠模型中药理学巨噬细胞耗竭的影响。方法用脂质体氯膦酸盐或对照脂质体治疗 KPC 小鼠 (LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre) 12 周。分析了肿瘤和转移的形成以及局部和循环免疫细胞和细胞因子的变化。结果氯膦酸脂质体治疗有效减少了胰腺和其他器官（如肝、肺和脾）中的 CD11b 阳性巨噬细胞。虽然肿瘤发生率和生长仅略有减少，但巨噬细胞耗竭后，肝脏和肺部的转移形成明显减少。这种抗转移作用与内源性原发肿瘤的存在无关，因为在尾静脉注射同源胰腺癌细胞系后，在氯膦酸盐预处理的小鼠中也检测到肺部定植减少。脂质体氯膦酸盐抑制巨噬细胞与血管生成显着受损、循环血管内皮生长因子水平降低和循环 CD4+CD25+ T 细胞减少相关。这些改变可以在使用 CD11b-白喉毒素受体小鼠的独立巨噬细胞耗竭模型中得到证实。 结论 在胰腺癌遗传小鼠模型中，药理学耗竭巨噬细胞显着减少了转移形成，并与血管生成受损和 CD4+CD25+ T 细胞水平降低有关。浸润巨噬细胞的药理学靶向代表了抗转移治疗方法的一种有前途的新工具。
Objectives Tumour-associated macrophages play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages are known to mediate tumour progression and have been identified in invasive tumours and in early preinvasive pancreatic intraepithelial precursor lesions. We aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in a genetic mouse model of pancreatic cancer.Methods KPC mice (LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre) were treated for 12 weeks with liposomal clodronate or control liposomes. Tumour and metastasis formation as well as alterations in local and circulating immune cells and cytokines were analysed.Results Treatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. While tumour incidence and growth were only slightly reduced, metastasis formation in the liver and lungs was significantly diminished after macrophage depletion. This antimetastatic effect was independent of the presence of an endogenous primary tumour, since reduced pulmonary colonisation was also detected in clodronate-pretreated mice after tail vein injection of syngeneic pancreatic cancer cell lines. Macrophage inhibition by liposomal clodronate was associated with significantly impaired angiogenesis, reduced circulating vascular endothelial growth factor levels and decreased circulating CD4+CD25+ T cells. These alterations could be confirmed in an independent macrophage depletion model using CD11b-diphtheria toxin receptor mice.Conclusions Pharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with impaired angiogenesis and reduced CD4+CD25+ T cell levels. Pharmacological targeting of infiltrating macrophages represents a promising novel tool for antimetastatic therapeutic approaches.