VCAM-1-targeted MRI Improves Detection of the Tumor-brain Interface.
VCAM-1-targeted MRI Improves Detection of the Tumor-brain Interface.
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DOI：
10.1158/1078-0432.ccr-21-4011
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发表时间：
2022-06-01
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尽管局部治疗效果最佳，但实体瘤患者肿瘤细胞侵入正常脑实质经常会导致复发。这项研究的目的是确定是否可以通过血管细胞黏附分子-1(VCAM-1)靶向的MRI来靶向微血管炎症来更好地描绘肿瘤-脑界面。采用MDA231BR-GFP(乳腺癌)、GFP(脑转移瘤)和U87 MG(胶质母细胞瘤)大鼠脑内移植模型，对肿瘤-脑界面进行组织学检查，并检测VCAM-1靶向MRI对该区域的检测效果。对脑转移瘤和胶质母细胞瘤边缘的人活检样本进行了内皮VCAM-1的表达检测。肿瘤与周围正常脑组织的界面显示内皮细胞VCAM-1表达增加，微血管密度增加。在脑转移模型中，肿瘤增殖和干细胞标记物在肿瘤边缘也显著上调。静脉注射VCAM-MPIO后，T2加权MRI比Gd-DTPA增强的T1加权MRI更广泛地突出了两种肿瘤模型的肿瘤-脑界面。与VCAM-MPIO结合的部位，在MR图像上明显为低信号，与组织学检测到的内皮VCAM-1上调和结合的VCAM-MPIO微珠在空间上相关。这些发现在原位髓母细胞瘤模型中得到了进一步的验证。最后，人脑转移瘤和胶质母细胞瘤样本中的肿瘤-脑界面类似地具有微血管炎症的特征，超出了常规MRI可以检测到的区域。这项工作说明了VCAM-1靶向MRI在改善原发和继发性脑肿瘤中肿瘤-脑界面的描绘方面的潜力。
Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1–targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2*-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA–enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI. This work illustrates the potential of VCAM-1–targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.