Ermolayev Vladimir, Mohajerani Pouyan, Ale Angelique, Sarantopoulos Athanasios, Aichler Michaela, Kayser Gian, Walch Axel, Ntziachristos Vasilis
Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
Research Unit Analytical Pathology-Institute of Pathology, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
Int J Cancer. 2015 Sep 1;137(5):1107-18. doi: 10.1002/ijc.29372. Epub 2015 Jan 14.
Non-small cell lung cancer is characterized by slow progression and high heterogeneity of tumors. Integrins play an important role in lung cancer development and metastasis and were suggested as a tumor marker; however their role in anticancer therapy remains controversial. In this work, we demonstrate the potential of integrin-targeted imaging to recognize early lesions in transgenic mouse model of lung cancer based on spontaneous introduction of mutated human gene bearing K-ras mutation. We conducted ex vivo and fluorescence molecular tomography-X-ray computed tomography (FMT-XCT) in vivo imaging and analysis for specific targeting of early lung lesions and tumors in rodent preclinical model for lung cancer. The lesions and tumors were characterized by histology, immunofluorescence and immunohistochemistry using a panel of cancer markers. Ex vivo, the integrin-targeted fluorescent signal significantly differed between wild type lung tissue and K-ras pulmonary lesions (PL) at all ages studied. The panel of immunofluorescence experiments demonstrated that PL, which only partially show cancer cell features were detected by αvβ3-integrin targeted imaging. Human patient material analysis confirmed the specificity of target localization in different lung cancer types. Most importantly, small tumors in the lungs of 4-week-old animals could be noninvasively detected in vivo on the fluorescence channel of FMT-XCT. Our findings demonstrated αvβ3-integrin targeted fluorescent imaging to specifically detect premalignant pleural lesions in K-ras mice. Integrin targeted imaging may find application areas in preclinical research and clinical practice, such as early lung cancer diagnostics, intraoperative assistance or therapy monitoring.
非小细胞肺癌的特点是肿瘤进展缓慢且异质性高。整合素在肺癌的发生和转移中起重要作用，并被认为是一种肿瘤标志物；然而，它们在抗癌治疗中的作用仍存在争议。在这项研究中，我们基于自发引入携带K-ras突变的人类突变基因，在肺癌转基因小鼠模型中证明了整合素靶向成像识别早期病变的潜力。我们对啮齿动物肺癌临床前模型中的早期肺部病变和肿瘤进行了离体和荧光分子断层扫描-X射线计算机断层扫描（FMT-XCT）体内成像及分析，以实现特异性靶向。使用一组癌症标志物通过组织学、免疫荧光和免疫组织化学对病变和肿瘤进行了表征。在离体实验中，在所有研究年龄的野生型肺组织和K-ras肺部病变（PL）之间，整合素靶向荧光信号存在显著差异。免疫荧光实验表明，仅部分表现出癌细胞特征的PL可通过αvβ3整合素靶向成像检测到。对人类患者材料的分析证实了不同类型肺癌中靶点定位的特异性。最重要的是，4周龄动物肺部的小肿瘤可在FMT-XCT的荧光通道上在体内被无创检测到。我们的研究结果表明，αvβ3整合素靶向荧光成像可特异性检测K-ras小鼠的癌前胸膜病变。整合素靶向成像可能在临床前研究和临床实践中找到应用领域，如早期肺癌诊断、术中辅助或治疗监测。
