Nakano Kiyotaka, Nishizawa Takashi, Komura Daisuke, Fujii Etsuko, Monnai Makoto, Kato Atsuhiko, Funahashi Shin-Ichi, Ishikawa Shumpei, Suzuki Masami
Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
J Toxicol Pathol. 2018 Oct;31(4):293-300. doi: 10.1293/tox.2018-0020. Epub 2018 Aug 13.
In xenograft models, orthotopic (ORT) engraftment is thought to provide a different tumor microenvironment compared with subcutaneous (SC) engraftment. We attempted to characterize the biological difference between OE19 (adenocarcinoma of the gastroesophageal junction) SC and ORT models by pathological analysis and CASTIN (CAncer-STromal INteractome) analysis, which is a novel method developed to analyze the tumor-stroma interactome framework. In SC models, SCID mice were inoculated subcutaneously with OE19 cells, and tumor tissues were sampled at 3 weeks. In ORT models, SCID mice were inoculated under the serosal membrane of the stomach wall, and tumor tissues were sampled at 3 and 6 weeks after engraftment. Results from the two models were then compared. Histopathologically, the SC tumors were well circumscribed from the adjacent tissue, with scant stroma and the formation of large ductal structures. In contrast, the ORT tumors were less circumscribed, with small ductal structures invading into abundant stroma. Then we compared the transcriptome profiles of human tumor cells with the mouse stromal cells of each model by species-specific RNA sequencing. With CASTIN analysis, we successfully identified several interactions that are known to affect the tumor microenvironment as being selectively enhanced in the ORT model. In conclusion, pathological analysis and CASTIN analysis revealed that ORT models of OE19 cells have a more invasive character and enhanced interaction with stromal cells compared with SC models.
在异种移植模型中，与皮下（SC）移植相比，原位（ORT）移植被认为可提供不同的肿瘤微环境。我们试图通过病理分析和CASTIN（癌症-基质相互作用组）分析来表征OE19（胃食管交界腺癌）SC和ORT模型之间的生物学差异，CASTIN分析是一种为分析肿瘤-基质相互作用组框架而开发的新方法。在SC模型中，将OE19细胞皮下接种到SCID小鼠体内，并在3周时采集肿瘤组织。在ORT模型中，将SCID小鼠接种到胃壁浆膜下，并在移植后3周和6周采集肿瘤组织。然后比较两个模型的结果。组织病理学上，SC肿瘤与相邻组织界限清楚，基质稀少，形成大导管结构。相比之下，ORT肿瘤界限不清，小导管结构侵入丰富的基质中。然后，我们通过物种特异性RNA测序比较了每个模型中人类肿瘤细胞与小鼠基质细胞的转录组图谱。通过CASTIN分析，我们成功鉴定出几种已知影响肿瘤微环境的相互作用在ORT模型中被选择性增强。总之，病理分析和CASTIN分析表明，与SC模型相比，OE19细胞的ORT模型具有更强的侵袭性，与基质细胞的相互作用增强。
