Abstract
Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future.
Highlights
Lung cancer is the major cause of cancer related death worldwide [1]
We introduce an organotypic 3D human lung cancer model that can be used to explore basic tumor biology and metabolism and to simulate a biomarker-guided therapy
We are convinced that this innovative combination of advanced tissue engineering with functional imaging will enable longitudinal studies regarding tumor growth, -metabolism and –heterogeneity and the evolution of resistance as well as the evaluation of new therapeutic strategies and long-term effects of treatment
Summary
Lung cancer is the major cause of cancer related death worldwide [1]. Despite vigorous research efforts, the 5 year-survival rate of lung cancer patients remains at about 15% [2]. In recent years improved molecular characterization of non-small cell lung cancer (NSCLC) led PLOS ONE | DOI:10.1371/journal.pone.0160282. PET-Imaging of a 3D In Vitro Lung Tumor Model to a better understanding of certain driver mutations and new targeted treatment options. Only the small subset of NSCLC patients carrying this genetic mutation benefits from such treatments and secondary mutations often lead to drug resistance, followed by tumor progression and death of the patients [4]. There is an urgent scientific and medical need for a refined understanding of lung tumor biology including mechanisms of tumor heterogeneity and resistance to provide optimal strategies and promising drug combinations [5] to treat lung cancer in an individual patient
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