Frontiers in Bioengineering and Biotechnology (Jun 2023)

A novel ex vivo lung cancer model based on bioengineered rat lungs

  • Satoshi Mizoguchi,
  • Tomoshi Tsuchiya,
  • Tomoshi Tsuchiya,
  • Ryoichiro Doi,
  • Tomohiro Obata,
  • Mayumi Iwatake,
  • Shintaro Hashimoto,
  • Hirotaka Matsumoto,
  • Hiroshi Yukawa,
  • Hiroko Hayashi,
  • Tao-Sheng Li,
  • Kazuko Yamamoto,
  • Keitaro Matsumoto,
  • Takuro Miyazaki,
  • Koichi Tomoshige,
  • Takeshi Nagayasu

DOI
https://doi.org/10.3389/fbioe.2023.1179830
Journal volume & issue
Vol. 11

Abstract

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Introduction: Two-dimensional cell cultures have contributed substantially to lung cancer research, but 3D cultures are gaining attention as a new, more efficient, and effective research model. A model reproducing the 3D characteristics and tumor microenvironment of the lungs in vivo, including the co-existence of healthy alveolar cells with lung cancer cells, is ideal. Here, we describe the creation of a successful ex vivo lung cancer model based on bioengineered lungs formed by decellularization and recellularization.Methods: Human cancer cells were directly implanted into a bioengineered rat lung, which was created with a decellularized rat lung scaffold reseeded with epithelial cells, endothelial cells and adipose-derived stem cells. Four human lung cancer cell lines (A549, PC-9, H1299, and PC-6) were applied to demonstrate forming cancer nodules on recellularized lungs and histopathological assessment were made among these models. MUC-1 expression analysis, RNA-seq analysis and drug response test were performed to demonstrate the superiority of this cancer model.Results: The morphology and MUC-1 expression of the model were like those of lung cancer in vivo. RNA sequencing revealed an elevated expression of genes related to epithelial-mesenchymal transition, hypoxia, and TNF-α signaling via NF-κB; but suppression of cell cycle-related genes including E2F. Drug response assays showed that gefitinib suppressed PC-9 cell proliferation equally well in the 3D lung cancer model as in 2D culture dishes, albeit over a smaller volume of cells, suggesting that fluctuations in gefitinib resistance genes such as JUN may affect drug sensitivity.Conclusions: A novel ex vivo lung cancer model was closely reproduced the 3D structure and microenvironment of the actual lungs, highlighting its possible use as a platform for lung cancer research and pathophysiological studies.

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