title: Early recognition of lung cancer by integrin targeted imaging in K-ras mouse model.
abstract: 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.
authors.affiliation: Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ermolayev
authors.affiliation: Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
authors.forename: Pouyan
authors.initials: P
authors.lastname: Mohajerani
authors.affiliation: Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
authors.forename: Angelique
authors.initials: A
authors.lastname: Ale
authors.affiliation: Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Sarantopoulos
authors.affiliation: Research Unit Analytical Pathology-Institute of Pathology, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Institute of Pathology, Universitätsklinkum Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Gian
authors.initials: G
authors.lastname: Kayser
authors.affiliation: Research Unit Analytical Pathology-Institute of Pathology, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, Ingolstaedter Landstrasse 1 D-85764 Neuherberg, Germany.|Techniche Universitaet Muenchen, Chair for Biological Imaging, Arcisstrasse 21, D-80333, Munich.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Ntziachristos
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005453:Fluorescence; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D009928:Organ Specificity; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D039302:Integrin alphaVbeta3; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-ras; X-ray computer tomography; fluorescence molecular tomography; fluorescent contrast agent; integrin; non-small cell lung cancer; preclinical cancer models