Correlation between genetic alterations and growth of human malignant glioma xenografted in nude mice

Abstract

In order to develop preclinical models of malignant astrocytomas and oligodendrogliomas, a series of 54 resected gliomas (37 from oligodendroglial lineage and 17 from astrocytic lineage) were xenografted subcutaneously into nude mice. Molecular alterations commonly observed in gliomas subtypes, including LOH 1p and 1q, LOH 19q, LOH 10p and 10q, LOH 9p, TP53 and PTEN mutations, EGFR amplification, CDKN2A homozygous deletion and telomerase reactivation were systematically screened in the original and xenografted tumours. In all, 23 gliomas grew in nude mice. The most anaplastic tumours were selected as shown by pathological and molecular studies of the original tumour as well as shorter survival in patients whose tumours were successfully grafted. Comparison between the two growth profiles showed that 10q LOH and EGFR amplification gave a tumorigenic advantage. With a few exceptions, the genetic pattern was remarkably stable before and after growth in nude mice. These results suggest that subcutaneous xenografts are useful and reproducible models to analyse the molecular profile of malignant astrocytoma and oligodendroglioma. This represents the first step to improve our understanding of the correlations between molecular alterations and response to standard or experimental therapies.

Figure 1

Representative histology of two tumours before and after xenograft on nude mice. (A) GIR in situ tumour, anaplastic oligodendroglioma morphology, haematoxylin–eosin HE staining (magnification × 200); (B) ODA-17-GIR corresponding xenograft, passage 1, dedifferentiated morphology, HE staining (× 400); (C) ROM in situ tumour, GBM histology, haematoxylin–eosin (HE) staining (× 200); (D) GBM-7-ROM corresponding xenograft, passage 3, dedifferentiated morphology, HE staining (× 400).

Figure 2

Loss of heterozygosity patterns before and after establishment on nude mice. Genescan patterns showed a hardly detectable LOH in the initial tumour, which in contrast appeared very clearly after the first passage onto nude mice.