Inhibitory effect of carbonyl reductase 1 against peritoneal progression of ovarian cancer: evaluation by ex vivo 3D-human peritoneal model.

The current authors previously reported that a carbonyl reductase 1 (CR1) DNA-dendrimer complex could potentially be used in gene therapy for peritoneal metastasis of ovarian cancer. The aims of the current study were to observe the cellular dynamics of peritoneal metastasis of epithelial ovarian cancer cells and to ascertain changes in the dynamics of ovarian cancer cells as a result of transfection of CR1 DNA. (1) Artificial human peritoneal tissue (AHPT) was seeded with serous ovarian cancer cells, and the process leading to development of peritoneal carcinomatosis was observed over time. (2) Peritoneal carcinomatosis was produced in mice and compared to a model using AHPT to determine the appropriateness of AHPT. (3) CR1 DNA was transfected into cancer cells seeded on AHPT, and the dynamics of cancer cells were observed over time. (1) Cancer cells perforated the mesothelium, leaving normal mesothelium intact. However, the cells proliferated between the layers of the mesothelium, forming a mass. After 24 h, cancer cells had invaded the lymphatics, and after 48-72 h cancer cells had invaded deep into the mesothelium, where they formed a mass. (2) Invasion of the peritoneum by cancer cells in a murine model of peritoneal carcinomatosis resembled that in a model using AHPT, and results substantiated the reproducibility of peritoneal carcinomatosis in AHPT. (3) Proliferation of cells transfected with CR1 DNA was significantly inhibited on AHPT, and necrosis was evident. Nevertheless, cancer cell invasion deep into the mesothelium was not inhibited. Use of a new tool, AHPT, in an in vitro model of peritoneal metastasis revealed that CR1 DNA inhibited cancer cell proliferation. CR1 DNA does not play a role in inhibiting invasion of the mesothelium during peritoneal metastasis, but it does affect cancer cell proliferation. Results suggested that CR1 DNA inhibits cancer cell proliferation via necrosis.