Invasive phenotype observed in 1,3-bis(2-chloroethyl)-1-nitrosourea—resistant sublines of 9L rat glioma cells: a tumor model mimicking a recurrent malignant glioma

Abstract

Chemotherapy is suspected of having an effect on the generation of phenotypical heterogeneity and the development of drug resistance in tumors. Recurrent gliomas feature drug resistance as well as greater invasive growth than original tumors. The authors investigated phenotypical changes in invasion observed in 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant sublines of the 9L rat gliosarcoma. Two established BCNU-resistant sublines, derived from 9L gliosarcoma cells by treating these cells with BCNU in vivo or in vitro, were used in the study. An in vitro examination confirmed the resistance of the cells to BCNU treatment. The cells were implanted into the striatum of Fisher 344 rats, and histological examinations were performed to compare the growth patterns of the resultant tumors. A new brain tumor model was established by implanting 9L-2 cells in Fisher 344 rats. The 9L-2 and BTRC-19 cells displayed a distinct increase in BCNU resistance compared with the 9L cells. Both BCNU-resistant sublines developed a tumor mass with invasive margins, which is not the case with 9L tumor models. The newly developed 9L-2 tumor model demonstrated 100% tumor uptake with consistent growth patterns. Cells that acquire drug resistance also demonstrated invasive growth. Because the 9L-2 and BTRC-19 cells were derived from 9L cells that had been treated with BCNU in vivo and in vitro, this change in phenotype was likely caused by the drug treatment, which may have implications for chemotherapy of gliomas. The tumor model that developed from the 9L-2 cells can be used as a model of a recurrent glioma, which features drug resistance and invasive growth.