Glioma cells showing IDH1 mutation cannot be propagated in standard cell culture conditions

Abstract

Background:It has recently been reported by several sources that original (i.e., present in vivo) glioma cell phenotypes or genotypes cannot be maintained in vitro. For example, glioblastoma cell lines presenting EGFR amplification cannot be established.Methods and results:IDH1 sequencing and loss of heterozygosity analysis was performed for 15 surgery samples of astrocytoma and early and late passages of cells derived from those and for 11 archival samples. We were not able to culture tumour cells presenting IDH1 mutations originating from currently proceeded 10 tumours; the same results were observed in 7 samples of archival material.Conclusion:The IDH1 mutation is expected to be almost mutually exclusive with EGFR amplification, so glioma cells with IDH1 mutations seem to represent a new group of tumour cells, which cannot be readily analysed in vitro because of their elimination. The reasons for this intriguing phenomenon should be investigated since its understanding can help to define a new therapeutic approach based on simulating in vivo conditions, responsible for tumour cells elimination in vitro. Moreover, a new model for culturing glioma cells in vitro should be designed since the current one does not provide conditions corresponding to in vivo growth.

IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

“…Despite their frequent occurrence, glioma xenografts carrying these mutations are very scarce (41,52,53), and in vitro propagation of IDH1-mutated glioma cell lines is challenging (54). Interestingly, and in line with clinical observations, E478 xenografts present with lower proliferation rates than IDHwt counterparts, as established via the Ki67 index, and mice carrying these xenografts have a longer survival time than mice carrying IDHwt xenografts (see Supplementary Materials).…”

N-Acetylaspartate (NAA) and N-Acetylaspartylglutamate (NAAG) Promote Growth and Inhibit Differentiation of Glioma Stem-like Cells

“…Inasmuch as mutant IDH status is associated with a favorable prognosis in glioma (40), our finding that physiologically relevant doses of NAA and NAAG facilitate GSC growth and differentiation resistance is consistent with the reduction of these metabolites in less aggressive IDH mutant tumors. Despite the prevalence of mutant IDH in oligodendroglioma (41) and proneural GBM (37), the GSCs lines in this study expressed wild-type IDH1 and -2, 3 likely owing to the negative selection of cells with IDH mutations in culture (42). Mutant IDH is hypothesized to drive oncogenesis, in part, by promoting epigenetic dysregulation and the induction of a CpG island methylator phenotype (43); however, why IDH mutations are simultaneously associated with reduced glioma malignancy remains elusive.…”

The Definition of Primary and Secondary Glioblastoma

“…Conditional IDH1 (R132H) knockin mice with expression in all hematopoietic cells or cells of the myeloid lineage caused an increased number of early hematopoietic progenitors with splenomegaly, anemia, and extramedullary hematopoiesis (42), whereas brain-specific IDH1 (R132H)-conditional knockin mice exhibited hemorrhage and perinatal lethality (43). Like EGFR amplification in primary glioblastomas, IDH1 mutations in secondary glioblastomas are typically lost during culture in vitro (44). This is enigmatic, since selective suppression of endogenous mutant IDH1 expression in a fibrosarcoma cell line with a native IDH1R132C heterozygous mutation significantly inhibits cell proliferation (45).…”