Abstract
BackgroundMetastasis is the main cause of death for lung cancer patients. The ex vivo 4D acellular lung model has been shown to mimic this metastatic process. However, the main concern is the model’s lack of cellular components of the tumor’s microenvironment. In this study, we aim to determine if the intact lung microenvironment will still allow lung cancer metastasis to form.MethodsWe harvested a heart-lung block from a rat and placed it in a bioreactor after cannulating the pulmonary artery, trachea and tying the right main bronchus for 10–15 days without any tumor cells as a control group or with NSCLC (A549, H1299 or H460), SCLC (H69, H446 or SHP77) or breast cancer cell lines (MCF7 or MDAMB231) through the trachea. We performed lobectomy, H&E staining and IHC for human mitochondria to determine the primary tumor’s growth and formation of metastatic lesions. In addition, we isolated circulating tumor cells (CTC) from the model seeded with GFP tagged cells.ResultsIn the control group, no gross tumor nodules were found, H&E staining showed hyperplastic cells and IHC showed no staining for human mitochondria. All of the models seeded with cancer cell lines formed gross primary tumor nodules that had microscopic characteristics of human cancer cells on H&E staining with IHC showing staining for human mitochondria. CTC were isolated for those cells labeled with GFP and they were viable in culture. Finally, all cell lines formed metastatic lesions with cells stained for human mitochondria.ConclusionThe cellular ex vivo 4D model shows that human cancer cells can form a primary tumor, CTC and metastatic lesions in an intact cellular environment. This study suggests that the natural matrix scaffold is the only necessary component to drive metastatic progression and that cellular components play a role in modulating tumor progression.
Highlights
Metastasis is the main cause of death for lung cancer patients
There are significant differences in the spatial organization of the tumor cells where the primary tumor grew in a pattern along the airway and the metastatic lesion formed in a distribution that is consistent with cancer distributed along the vasculature
There is no difference in the number of live circulating tumor cells (CTC) from the Four dimensional (4D) model when they are placed in the petri dish, with or without Cisplatin, while the same dose for the parental cells (2D) placed in the model showed a significant reduction of live cells [9]
Summary
Metastasis is the main cause of death for lung cancer patients. The ex vivo 4D acellular lung model has been shown to mimic this metastatic process. The acellular 4D lung model shows that when tumor cells are placed into the trachea, they form perusable nodules in the lung matrix [6]. In order for the tumor cells to enter the right lung, the cells would need to leave the epithelial space in the left side, enter the vasculature, and enter the other epithelial space on the right side Over time, this process occurred as metastatic lesions formed in the right lung and grew over time in the 4D model [2]. There are significant differences in the spatial organization of the tumor cells where the primary tumor grew in a pattern along the airway and the metastatic lesion formed in a distribution that is consistent with cancer distributed along the vasculature. Previous studies show that the CTC form metastatic lesions in the 4D model [2]
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