Metabolism of Orthotopic Mouse Brain Tumor Models

Abstract

We used magnetic resonance spectroscopy to determine whether orthotopic mouse brain tumors grown as xenografts in immunocompromised mice either from human brain tumor cells implanted immediately after surgery or from cultured human tumor lines show metabolic profiles comparable to those of the original tumors. Using a 7 T scanner, spectra were acquired from mice with a human atypical teratoid/rhabdoid tumor (AT/RT) either implanted directly from the surgical specimen or first grown in culture, directly implanted choroid plexus carcinoma (CPC), and two medulloblastoma cell lines. The results were compared with spectra from these same tumors or tumor types in patients and with controls. Metabolic variability of tumors from a single cell line was also evaluated using the medulloblastoma lines. The main metabolic features of human tumors were qualitatively replicated in xenografts. AT/RTs in mice exhibited choline, creatine, and myo-inositol levels comparable to those observed in the patient. As in patients, choline was prominent in experimental CPC. Tumors from a single cell line were comparable. Significant correlations were found with key metabolites in humans and mice; however, differences including lower lipids in the implanted AT/RTs than in patient spectra and taurine observed in all animal spectra were also noted. The causes of these dissimilarities warrant further investigation.

1H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors

“…The metabolite concentrations we report for normal mouse brain fall within the range of reported values for normal rodents with four exceptions, Asp, GABA, Gly, and GSH, for which the concentrations were higher than values reported elsewhere (1,2,6,25). Factors that may account for the difference between our values and other reported values include differences in quantification methods and in rodent strains investigated.…”

“…The presence of larger signals from lipids and macromolecules in control mice is similar to what was found for direct implantation of human atypical teratoid/rhabdoid tumors in mice (6). One reason for such discrepancies in reported levels of lipids in tumors relative to control tissue may be that the approach for estimating lipid and macromolecule concentrations varies between studies.…”

“…Studies in humans have also shown differences in the neurochemical profiles of tumors of primary brain tumors versus metastases (7,8). The data clearly show that significant differences in neurochemical profiles can be obtained in mouse brain tumor MRS simply as a result of the strain of mouse being used, the cell line being studied (9), and the means by which the cells were handled prior to intracranial injection (6,10). These differences have the potential to limit the value of MRS studies in mouse brain tumor models.…”

“…The number of metabolites that can be reliably detected increases with field strength (3,4). The sensitivity of high field 1 H in vivo MRS is sufficient to detect differences in the neurochemical profiles of post-natal mice from 10 through 90 days of age (3), between mouse strains (5), and between tumors derived from cultured human tumor cell lines or directly implanted human tumor cells (6). Studies in humans have also shown differences in the neurochemical profiles of tumors of primary brain tumors versus metastases (7,8).…”

Multiparametric MR imaging of tumor response to intraarterial chemotherapy in orthotopic xenograft models of human metastatic brain tumor

“…In brain tumor studies, therapies that have been effective in animal studies frequently show dismal performance in clinical trials. Many investigators have indicated that heterotopic models in which tumor cells were injected subcutaneously was one of the main reasons for this discrepancy [19]. Specifically, the tumor microenvironment is a significant factor in tumor growth and response to treatment [20].…”