The Need for Anatomical MRI Staging in Orthotopic Brain Models Monitored by Bioluminescence

The use of MRI to monitor the progression of brain tumors has been an accepted method both in the clinic and preclinically as well. Glioblastoma multiforme (glioblastoma; GBM) is a fast-growing glioma that develops from star-shaped glial cells (astrocytes and oligodendrocytes) that support the health of the nerve cells within the brain. These tumors are usually highly malignant because the cells reproduce quickly and they are supported by a large network of blood vessels. GBM is the most common and most aggressive form of malignant primary brain tumors, affecting nearly 23,000 people in the United States annually. Most preclinical studies in glioma utilize survival as the primary endpoint, which provides limited information about disease progression or primary tumor response to treatment.

Bioluminescence imaging (BLI) of luciferase-enabled cell lines provides a rapid and highly sensitive method for detection and tracking of tumor growth in preclinical models of GBM. BLI allows for higher throughput compared to MRI, therefore allowing larger size experiments to be conducted. While overall study throughput is higher there can be limitations in the use of BLI for staging a study.

Covance has been performing orthotopic GBM studies for more than 12 years. We have a robust data set on a large number of our human and rodent models (Table 1).

Brain BT142, D54-MG-luc, DBTRG (tumor), DBTRG-05MG, Gli36-DsRed-R-Luc (rescued), LN-18, LN-229, LN-827(pMMP-LucNeo), M059K, SF-295, SF-539, SF-767, SNB-19, U-87 MG, U-87 MG-luc, U251, U251-Luc-mCh-Puro: Human Glioblastoma Human
GL261-Luc2 Mouse
9L, 9L-Luc, C6, C6/A Rat

In addition, about 50 percent of our GBM lines are luciferase enabled. Over time we have been able to evaluate certain models with both BLI and MRI, allowing us to better understand the advantages and limitations of each. Of course, imaging is only as good as the model itself. To this end, successful intracranial implantation procedures are faced with several hurdles. These include accidental implant into the ventricles, hydrocephalus, variability in placement that may affect lifespan, and significant tumor growth above the skull. Our data has shown that implantation results can determine the accuracy of BLI to correlate with tumor burden, as determined by MRI (Figures 1 and 2).

Fig 1: Correlation of BLI and MRI tumor burden in U87-MG Luc orthotopic brain tumors.
Fig 2: Accurate implantation of tumor cells allows for MRI/BLI correlation over time.

At times poor tumor placement can be obvious with BLI. In Figure 3A we can see tumor cells seeding down the spine. However, in other instances this is not possible. For example, in Figure 3B the BLI image appears to suggest that cell implant was appropriate. Evaluation by MRI demonstrates that the tumor has taken residence in the ventricle and significant hydrocephalus has developed. MRI is capable of detecting other deficits such as the development of blood clots within the tumor or the needle track (Figure 4) and tumor growth that can occur outside of the skull (Figure 5). Thus, in order to provide a robust study with meaningful outcomes, and yet remain sensitive to high throughput needs and cost efficiencies, we recommend the utilization of multiple imaging techniques. This will ensure enrollment of mice with equivalently sized tumor burdens in the appropriate anatomic location (MRI) that can be tracked easily, efficiently, and cost effectively (BLI) over time.1

Fig 3: A) Tumor growth within the ventricle and down the spine. B) Tumor growth within ventricle without growth down the spine.
Fig 4: Hemorrhage in brain tumor.
Fig 5: Tumor growth in the skull cap.

Contact us to set up your next glioblastoma study and find out how the enhancements of using both BLI and MRI together improve your study staging and accuracy.

1Jost SC, Collins L, Travers S, Piwnica-Worms D, Garbow JR. Measuring Brain Tumor Growth: A Combined BLI / MRI Strategy. Molecular imaging. 2009;8(5):245-253.

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