https://scholars.lib.ntu.edu.tw/handle/123456789/414806
標題: | The use of PET imaging for prognostic integrin α2β1 phenotyping to detect non-small cell lung cancer and monitor drug resistance responses | 作者: | C. W. Huang W. C. Hsieh S. T. Hsu Y. W. Lin Y. H. Chung W. C. Chang H. Chiu Y. H. Lin C. P. Wu T. C. Yen F. T. Huang |
關鍵字: | Integrin α2β1; Non-small cell lung cancer; Phenotyping imaging; Positron emission tomography; Treatment response monitoring | 公開日期: | 2017 | 出版社: | Ivyspring International Publisher | 卷: | 7 | 期: | 16 | 起(迄)頁: | 4013-4028 | 來源出版物: | Theranostics | 摘要: | PURPOSE: Growing evidence has demonstrated that aberrant expression of integrin α2β1 might contribute to the invasion, metastasis and drug resistance of non-small cell lung cancer (NSCLC). Thus, the integrin α2β1 targeting 68Ga-DOTA-A2B1 tracer was validated in NSCLC in contrast to accumulation of the clinically used 18F-FDG PET tracer to see if 68Ga-DOTA-A2B1-PET imaging can offer a valuable and critical diagnostic imaging criterion for the identification of phenotypes of aggressive lung cancer. METHODS: To verify the prognostic value of integrin α2β1, several quantitative and functional in vitro assays were validated in different NSCLC cell lines (CL1-0, CL1-5, A549 and selected A549++ cells). Positron emission tomography (PET) imaging studies using both standard 18F-FDG and a newly developed 68Ga-labeled integrin α2β1 (68Ga-DOTA-A2B1) tracer were sequentially performed on mice with lung tumor xenografts in different anatomic locations (subcutaneous, orthotopic and osseous) to validate the targeting capability of the 68Ga-DOTA-A2B1 tracers. Treatment responses were monitored by injecting animals with metastatic bone tumors with 5 mg/kg doxorubicin. All in vivo treatment responses in each treatment subgroup were monitored with a PET imaging system to evaluate the up-regulation of integrin expression at the earliest stage of treatment (6 h). RESULTS: The PET and computed tomography (CT) images from NSCLC xenograft animals unambiguously demonstrated accumulation of the integrin tracer 68Ga-DOTA-A2B1 in the tumor lesions at all locations. The average tumor uptake and tumor-to-normal (T/N) ratio were 2.51 ± 0.56 %ID/g and T/N = 2.82, 3.40 ± 0.42 %ID/g and T/N = 1.52, and 1.58 ± 0.108 %ID/g and T/N = 2.31 in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05). The xenograft tumors were all clearly visible. In contrast, the accumulation of 18F-FDG reached 3.6 ± 0.76 %ID/g, 1.39 ± 0.075 %ID/g and 3.78 ± 0.73 %ID/g in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05). However, due to the high background uptake by normal tissue, the T/N values were less than or close to 1, making the tumors almost indistinguishable in the PET imaging analysis. Furthermore, 68Ga-DOTA-A2B1-PET imaging of the treated osseous tumor model demonstrated more than 19% tracer uptake in A549 lesions (1.72 ± 0.95 %ID/g vs. pretreatment 1.44 ± 0.12 %ID/g,p = 0. 015) 6 h post-treatment with doxorubicin. The elevated intensity of tracer uptake was in accordance with the results of in vitroWestern blot and ex vivo integrin staining, demonstrating elevated integrin α2β1 expression. CONCLUSION: In this study, integrin α2β1 was identified as a biomarker of aggressive malignant NSCLC. Thus, efforts should be devoted to validating integrin α2β1 as a potential target for non-invasive diagnosis and as a predictive marker for monitoring treatment responses using a preclinical PET imaging system. ? Ivyspring International Publisher. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/414806 | ISSN: | 18387640 | DOI: | 10.7150/thno.19304 | SDG/關鍵字: | doxorubicin; fluorodeoxyglucose f 18; gallium 68; very late activation antigen 2; very late activation antigen 2; animal experiment; animal model; Article; cancer diagnosis; cancer prognosis; controlled study; human; human cell; image analysis; in vitro study; in vivo study; lung cancer cell line; male; mouse; non small cell lung cancer; nonhuman; phenotype; positron emission tomography; protein expression; single drug dose; treatment response; tumor localization; upregulation; A-549 cell line; animal; diagnostic imaging; drug resistance; genetics; immunohistochemistry; lung tumor; metabolism; non small cell lung cancer; positron emission tomography; procedures; tumor cell line; A549 Cells; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Integrin alpha2beta1; Lung Neoplasms; Mice; Positron-Emission Tomography |
顯示於: | 生化科技學系 |
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