Inter-heterogeneity and intra-heterogeneity of αvβ3 in non-small cell lung cancer and small cell lung cancer patients as revealed by 68Ga-RGD2 PET imaging
Inter-heterogeneity and intra-heterogeneity of αvβ3 in non-small cell lung cancer and small cell lung cancer patients as revealed by 68Ga-RGD2 PET imaging
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(68)Ga-RGD2 PET 成像揭示非小细胞肺癌和小细胞肺癌患者中 alphavbeta3 的内部异质性和间异质性。
DOI：
10.1007/s00259-017-3696-2
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发表时间：
2017-08-01
影响因子：
9.1
通讯作者：
Wang, Jing
中科院分区：
文献类型：
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作者：
Kang, Fei;Wang, Zhe;Wang, Jing
目的整合素α(V)β(3)是抗血管生成药物西伦吉肽的治疗靶点。应用正电子发射断层扫描(PET)示踪剂Ga-68标记的二聚化RGD(Ga-68-RGD2)，比较非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)患者血清中α(V)、β(3)的水平。用Ga-68-RGD2采集PET/CT图像。(18)连续一天采集FDG PET/CT图像作为参考。定量比较标准摄取值(SUV)和肿瘤/非靶区摄取值(T/NT)。结果非小细胞肺癌和小细胞肺癌患者的F-18-FDG SUVmax和SUV均值无明显差异。小细胞肺癌患者的Ga-68-RGD2摄取在SUV和T/NT测量中均处于背景水平，且显著低于非小细胞肺癌患者。Ga-68-RGD2SUV均值在非小细胞肺癌组为4.5，在小细胞肺癌组为2.2，在非小细胞肺癌和小细胞肺癌原发灶中的变异系数分别为36.2%和39.3%。在一些非小细胞肺癌病例中，原发灶和假定的远处转移灶之间也观察到了异质性。免疫组织化学染色显示α(V)β(3)整合素在非小细胞肺癌皮损的细胞和新生血管中有表达，而小细胞肺癌组织中无表达。结论小细胞肺癌患者对Ga-68-RGD2的摄取明显低于非小细胞肺癌患者，提示小细胞肺癌组织中α(V)β(3)整合素的靶水平较低。在非小细胞肺癌和小细胞肺癌中也存在明显的α(V)β(3)肿瘤内异质性。α(V)β(3)的这种内部和内部的异质性可能潜在地改善目前在肺癌中的α(V)β(3)靶向治疗和诊断成像的应用。
Purpose Integrin alpha(v)beta(3) is the therapeutic target of the antiangiogenic drug cilengitide. The objective of this study was to compare alpha(v)beta(3) levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer Ga-68-labeled dimerized-RGD (Ga-68-RGD2).Methods Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/ CT images were acquired using Ga-68-RGD2.(18)FDG PET/ CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/ nontarget (T/ NT) values were quantitatively compared. Expression of the angiogenesis marker alpha(v)beta(3) in NSCLC and SCLC lesions was analyzed by immunohistochemistry.Results The F-18-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The Ga-68-RGD2 uptake of SCLC patients was at background levels in both SUVand T/ NT measurements and was significantly lower than that of NSCLC patients. The range value of Ga-68-RGD2 SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that alpha(v)beta(3) integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression.Conclusions The uptake of Ga-68-RGD2 in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower alpha(v)beta(3) target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of alpha(v)beta(3) also exist in both NSCLC and SCLC. Such inter-and intra-heterogeneity of alpha(v)beta(3) may potentially improve current applications of alpha(v)beta(3)-targeted therapy and diagnostic imaging in lung cancer.