Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the Spine
Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the Spine
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DOI：
10.3389/fonc.2020.00174
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发表时间：
2020-02-19
影响因子：
4.7
通讯作者：
Vajkoczy, Peter
中科院分区：
文献类型：
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作者：
Kratzsch, Tobias;Piffko, Andras;Vajkoczy, Peter
目的：脊柱转移性疾病仍然是肿瘤疾病的主要问题。受影响的患者可能会出现疼痛、脊柱不稳定和严重的神经功能障碍。今天，姑息性手术和放射治疗是治疗的主要手段。相反，缺乏早期的预防性治疗策略或治疗概念。在此，我们使用小鼠同基因的实验性脊柱转移模型来测试mTOR抑制和抗血管生成对脊柱黑色素瘤转移形成和进展的影响。方法：通过将荧光素转染的B16黑色素瘤细胞注射到颈总动脉，使用我们之前建立的小鼠同基因脊柱转移模型。注射后，小鼠接受依维莫司治疗，依维莫司是雷帕霉素（mTOR）复合物的哺乳动物靶点抑制剂，阿西替尼是酪氨酸激酶抑制剂，阻断血管内皮生长因子受体（VEGFR） 1-3，以及安慰剂。每天通过神经学评估和重复体内生物发光成像对动物进行随访。出现神经功能缺损时，进行脊柱MRI检查，并处死小鼠。全脊柱游离解剖，免疫组化技术分析。结果：对照组总生存期为23天，依维莫司组显著延长至30天（p = 0.04），阿西替尼组显著延长至28天（p = 0.04）。安慰剂组78%的小鼠出现症状性转移性硬膜外脊髓压迫，而治疗组只有50%出现这种情况。对照组至出现麻痹症状的平均时间为22天，依维莫司组为26天（p = 0.10），阿西替尼组为27天（p = 0.06）。在两个不同的时间点通过生物发光成像筛查脊柱转移显示，与对照组相比，治疗组的转移性肿瘤形成减少。免疫组织化学分析证实了两种化合物的生物活性：依维莫司组Ki67增殖标记指数降低，阿西替尼组CD31阳性内皮细胞数量减少。结论：mTOR抑制剂依维莫司和VEGFR抑制剂阿西替尼的抗血管生成作用均显示出预防和延缓症状性脊柱转移形成的潜力。然而，在这个实验模型中，治疗效果只是轻微的。
Objective: Spinal metastatic disease remains a major problem of oncological diseases. Patients affected may suffer pain, spinal instability, and severe neurological deficits. Today, palliative surgery and radiotherapy are the mainstays of therapy. In contrast, preventive treatment strategies or treatment concepts for an early stage are lacking. Here, we have used a syngeneic, experimental spine metastases model in the mouse to test the efficacy of mTOR inhibition and anti-angiogenesis on the formation and progression of spinal melanoma metastases.Methods: We used our previously established syngeneic spinal metastases mouse model by injecting luciferin-transfected B16 melanoma cells into the common carotid artery. Following injection, mice were treated with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) complex, axitinib, a tyrosine kinase inhibitor, that blocks vascular endothelial growth factor receptors (VEGFR) 1-3, as well as placebo. Animals were followed-up daily by neurological assessment and by repeat in vivo bioluminescence imaging. With occurrence of neurological deficits, a spinal MRI was performed, and mice were sacrificed. The whole spine was dissected free and analyzed by immunohistochemical techniques.Results: Overall survival was 23 days in the control group, significantly prolonged to 30 days (p = 0.04) in the everolimus group, and to 28 days (p = 0.04) in the axitinib group. While 78% of mice in the placebo group developed symptomatic metastatic epidural spinal cord compression, only 50% did so in the treatment groups. The mean time to manifestation of paralysis was 22 days in the control group, 26 days (p = 0.10) in the everolimus group, and 27 days (p = 0.06) in the axitinib group. Screening for spinal metastases by bioluminescence imaging on two different time points showed a decrease in metastatic tumor formation in the treatment groups compared to the controls. Immunohistochemical analysis confirmed the bioactivity of the two compounds: The Ki67 proliferation labeling index was reduced in the everolimus group and numbers of CD31 positive endothelial cells were reduced in the axitinib group.Conclusion: Both, the mTOR inhibitor everolimus as well as antiangiogenetic effects by the VEGFR inhibitor axitinib showed potential to prevent and retard formation of symptomatic spinal metastases. However, the therapeutic efficacy was only mild in this experimental model.