Abstract
Over 90% of clinical phase 3 studies in oncology fail. Reason for this might be the lack of a predictive preclinical model. Therefore, we developed an innovative organotypic tumor invasion model by adding cancer cells to living human Precision-Cut Lung Slices (PCLS). AdGFP-transduced human breast cancer cell line MDA-MB-231 was cultivated in co-culture with human PCLS over a period of one week. Immunohistology of Ki67 and GFP signals were used to visualise proliferating MDA-MB-231 cells. Local immune response and neoangiogenesis were determined by the cytokines VEGF and GM-CSF. Cancer cell invaded PCLS were treated with either angiogenesis inhibitor bevacizumab or apoptosis-inducing cisplatin. Cancer cells integrated in the human lung tissue and proliferated there. The VEGF/GM-CSF release correlated with MDA-MB-231 growth curves. Treatment with bevacizumab suppressed VEGF release up to 16fold, using the highest concentration of 200 µg/mL. Cisplatin treatment led to a decline of viability and reduced cancer cell number after application of 50 µM cisplatin for 72h by up to 51%. This newly established model is able to mimic cancer cell proliferation and growth in the microenvironment of human lung tissue. In addition, pharmacological intervention with established drugs showed the expected results regarding biomarkers for toxicity, proliferation, immune response and angiogenesis. Therefore, we propose this model as a new option for preclinical drug testing of anti-tumor drugs in human tissue including analysis of local immunological responses.
Published Version
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