ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome
ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome
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DOI：
10.1007/s00586-015-3811-7
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发表时间：
2015-10-01
影响因子：
2.8
通讯作者：
Vajkoczy, Peter
中科院分区：
文献类型：
--
作者：
Broggini, Thomas;Czabanka, Marcus;Vajkoczy, Peter
脊柱转移瘤的临床治疗越来越复杂，而潜在的生物学仍然未知。生物学认识不足是由于缺乏合适的实验动物模型。细胞间粘附分子-1（ICAM 1）与转移形成有关。其在脊柱转移中的作用尚不清楚。这是一个目的是产生一个可靠的小鼠脊柱转移模型，并探讨下ICAM 1 depletion.Materials和方法转移形成B16黑色素瘤细胞感染慢病毒含有萤火虫荧光素酶（B16-luc）。将稳定的细胞克隆（B16-luc）逆行注射到主动脉弓远端。使用体内生物发光成像/MRI监测脊柱转移形成。每天监测神经功能缺损。分离体内选择的转移肿瘤细胞（mB 16-luc）并动脉内再注射。在ICAM 1 KO小鼠中动脉内注射mB 16-luc细胞。结果动脉内注射B16-luc和mB 16-luc均能诱导脊髓转移瘤形成，并伴有神经功能缺损（B16-luc：26.5，mB 16-luc：21 d，p < 0.05）。体内选择增加了转移侵袭性，并导致骨特异性归巢表型。因此，在脊柱中，mB 16-luc细胞表现出更高的数量（B16-luc：1.2 +/- A 0.447，mB 16-luc：3.2 +/- A 1.643）和增加的总转移体积（B16-luc：2.87 +/- A 2.453 mm（3），mB 16-luc：11.19 +/- A 3.898 mm（3），p < 0.05）。ICAM 1耗竭导致脊髓转移的数量显著减少（mB 16-luc：1.2 +/- A 0.84），神经学结果改善（29天）。在ICAM 1耗竭的情况下，一般转移负荷显著降低（对照：3.47 x 10（7）+/- A 1.66 x 10（7）; ICAM-1（-/-）：5.20 × 10（4）+/-A4.44 × 10（4），p < 0.05 vs. control）结论应用本实验建立的脊柱转移瘤动物模型可靠，ICAM 1耗竭减少脊柱转移形成，这是由于转移发展的器官非特异性减少。
Introduction Clinical treatment of spinal metastasis is gaining in complexity while the underlying biology remains unknown. Insufficient biological understanding is due to a lack of suitable experimental animal models. Intercellular adhesion molecule-1 (ICAM1) has been implicated in metastasis formation. Its role in spinal metastasis remains unclear. It was the aim to generate a reliable spinal metastasis model in mice and to investigate metastasis formation under ICAM1 depletion.Materials and methods B16 melanoma cells were infected with a lentivirus containing firefly luciferase (B16-luc). Stable cell clones (B16-luc) were injected retrogradely into the distal aortic arch. Spinal metastasis formation was monitored using in vivo bioluminescence imaging/MRI. Neurological deficits were monitored daily. In vivo selected, metastasized tumor cells were isolated (mB16-luc) and reinjected intraarterially. mB16-luc cells were injected intraarterially in ICAM1 KO mice. Metastasis distribution was analyzed using organ-specific fluorescence analysis.Results Intraarterial injection of B16-luc and metastatic mB16-luc reliably induced spinal metastasis formation with neurological deficits (B16-luc:26.5, mB16-luc:21 days, p < 0.05). In vivo selection increased the metastatic aggressiveness and led to a bone specific homing phenotype. Thus, mB16-luc cells demonstrated higher number (B16-luc: 1.2 +/- A 0.447, mB16-luc:3.2 +/- A 1.643) and increased total metastasis volume (B16-luc:2.87 +/- A 2.453 mm(3), mB16-luc:11.19 +/- A 3.898 mm(3), p < 0.05) in the spine. ICAM1 depletion leads to a significantly reduced number of spinal metastasis (mB16-luc:1.2 +/- A 0.84) with improved neurological outcome (29 days). General metastatic burden was significantly reduced under ICAM1 depletion (control: 3.47 x 10(7) +/- A 1.66 x 10(7); ICAM-1 (-/-): 5.20 x 10(4) +/- A 4.44 x 10(4), p < 0.05 vs. control)Conclusion Applying a reliable animal model for spinal metastasis, ICAM1 depletion reduces spinal metastasis formation due to an organ-unspecific reduction of metastasis development.