Efficient intrahepatic tumor generation by cell sheet transplantation to fabricate orthotopic hepatocarcinoma‐bearing model mice for drug testing

Abstract

Subcutaneous tumor‐bearing mice are commonly used to evaluate antitumor activity in preclinical studies of anticancer drugs. However, these models often exhibit excessive antitumor responses to anticancer drug candidates. In this study, intrahepatic tumor‐bearing mice as orthotopic tumor models were fabricated by transplanting hepatocarcinoma cell monolayers (sheets) to investigate differences in ectopic versus orthotopic antitumor response. Cell sheets, harvested from temperature‐responsive cell culture dishes using thin gelatin gel supporters, were transferred onto mouse liver surfaces. Cell sheet transplantation drastically improved intrahepatic tumor formation compared with direct intrahepatic injection of dispersed cells. In particular, all cell sheet‐transplanted mice formed well‐developed tumors inside the liver following removal of the mesothelial membrane at the liver surface. Notably, these mice exhibited comparable life spans, indicating similar intrahepatic tumor development rates. Antitumor activity of doxorubicin (DOX) was examined using both subcutaneous and intrahepatic tumor‐bearing mice. Although DOX administration yielded decreased subcutaneous tumor volumes, intrahepatic tumors exhibited no significant antitumor response. The results were considered to represent pharmacokinetic and histological structure differences between ectopic and orthotopic tumors, and partially supported the clinical uses of DOX. Therefore, cancer cell sheet transplantation constitutes a promising method to fabricate intrahepatic tumor‐bearing mice for drug screening test in preclinical studies. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1071–1079, 2019.

Efficient and Consistent Orthotopic Osteosarcoma Model by Cell Sheet Transplantation in the Nude Mice for Drug Testing

“…Basically, the cell sheet method has obvious advantage over the cell suspension method; this was proved in other previous studies (Suzuki et al, 2014). Akimoto transplanted hepatocarcinoma cell sheet orthotopically and successfully to induce efficient intrahepatic tumor (Akimoto et al, 2019). He also compared the immunological reaction between immunodeficient mice and immunocompetent mice by comparing cell sheet transplantation and cell suspension injection with mouse lung squamous cancer cells (KLN-205) and found that the inoculated cells had a better survival rate and a lower immunological reaction in the cell sheet group (Akimoto et al, 2018).…”

“…For the immunodeficient mice, despite the decreased inflammatory response, the scaffold might still affect cell growth and activities (Rodriguez et al, 2009;Bouvet-Gerbettaz et al, 2014). Recently, because of the development of tissue engineering and tumor organ technology, cell sheet technology has earned attention of researchers recently (Suzuki et al, 2014;Kobayashi et al, 2018;Akimoto et al, 2019;Lu et al, 2019).…”