In vivo MRI visualization of growth and morphology in the orthotopic xenotrasplantation U87 glioblastoma mouse SCID model. E. L. Zavjalov, I. A. Razumov, L. A. Gerlinskaya, A. V. Romashchenko


Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer with the average lifespan of patients about 9–12 months. The study of tumor formation and the evaluation of new therapies for GBM require accurate and reproducible experimental brain tumor animal models. In this study we used MRI for investigation of tumor morphology and growth dynamic in an orthopic xenotransplantation immunodeficient mouse model (SCID mouse line). Comparison of T1- and T2-weighed MRI scans preformed with a high-field MRI scanner (Bruker, BioSpec, 11,7 T) revealed insufficient tumor/normal tissue T1-contrast because of high longitudinal magnetization of the magnetic field in our scanner. Intravenous injection of paramagnetic manganese oxide (MnO) nanoparticles dramatically increased the tumor/normal tissue contrast in T1-weigthed MRI scans. The study of glioblastoma growth with T2-weighed images showed that a significant tumor development began not earlier than 3 weeks after cell culture intracranial injection and then the tumor grew exponentially. Thus, we developed a protocol of the characterization of glioblastoma U87 growth and morphology by T1- and T2-weighed and MnO-enhanced MRI in the orthopic xenotransplantation mouse model. The results demonstrate that this SCID model may be used as an in vivo preclinical model to test the efficacy and putative side effects of novel anticancer therapies.

About The Authors:

E. L. Zavjalov. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

I. A. Razumov. Institute of Cytology and Genetics SB RAS; State Research Center of Virology and Biotechnology «Vector», Russian Federation, Novosibirsk; Koltsovo, Novosibirsk region

L. A. Gerlinskaya. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

A. V. Romashchenko. Institute of Cytology and Genetics SB RAS; Design Technological Institute of Digital Technique SB RAS, Russian Federation, Novosibirsk


1. Abdollahi A., Schwager C., Kleeff J., Esposito I., Domhan S., Peschke P., Hauser K., Hahnfeldt P., Hlatky L., Debus J., Peters J.M., Friess H., Folkman J., Huber P.E. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc. Natl Acad. Sci. USA. 2007;104(31):12890-12895.

2. Arvizo R.R., Miranda O.R., Moyano D.F., Walden C.A., Giri K., Bhattacharya R., Mukherjee P. Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles. PloS One. 2011;6(9):24374.

3. Atkinson M., Juhasz C., Shah J., Guo X., Kupsky W., Fuerst D., Johnson R., Watson C. Paradoxical imaging findings in cerebral gliomas. J. Neurol. Sci. 2008;269(1/2):180-183.

4. Bachoo R.M., Maher E.A., Ligon K.L., Sharpless N.E., Chan S.S., You M.J., Tang Y., DeFrances J., Stover E., Weissleder R., Rowitch D.H., Louis D.N., DePinho R.A. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1(3):269-277.

5. Barker F.G. 2nd, Chang S.M., Huhn S.L., Davis R.L., Gutin P.H., McDermott M.W., Wilson C.B., Prados M.D. Age and the risk of anaplasia in magnetic resonance-nonenhancing supratentorial cerebral tumors. Cancer. 1997;80(5):936-941.

6. Becher O.J., Holland E.C. Genetically engineered models have advantages over xenografts for preclinical studies. Cancer Res. 2006; 66(7):3355-3359.

7. Castillo M., Smith J.K., Kwock L., Wilber K. Apparent diffusion coefficients in the evaluation of high-grade cerebral gliomas. AJNR Am. J. Neuroradiol. 2001;22(1):60-64.

8. Dass C.R., Choong P.F. GFP expression alters osteosarcoma cell biology. DNA Cell Biol. 2007;26(8):599-601.

9. Davis M.E., Shin D.M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Rev. Drug Discovery. 2008;7(9): 771-782.

10. Frosina G. Development of therapeutics for high grade gliomas using orthotopic rodent models. Curr. Med. Chem. 2013;20(26):3272-3299.

11. Gagner J.P., Law M., Fischer I., Newcomb E.W., Zagzag D. Angiogenesis in gliomas: imaging and experimental therapeutics. Brain Pathol. 2005;15(4):342-363.

12. Ginsberg L.E., Fuller G.N., Hashmi M., Leeds N.E., Schomer D.F. The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: histopathological evaluation of a series. Surg. Neurol. 1998;49(4):436-440.

13. Gossmann A., Helbich T.H., Kuriyama N., Ostrowitzki S., Roberts T.P., Shames D.M., van Bruggen N., Wendland M.F., Israel M.A., Brasch R.C. Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to antiangiogenic therapy in a xenograft model of glioblastoma multiforme. J. Magn. Reson. Imaging. 2002;15(3):233-240.

14. Jordan J.H., D’Agostino R.B., Hamilton C.A., Vasu S., Hall M.E., Kitzman D.W., Hundley W.G. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance. circulation: Cardiovascular imaging. 2014;7(6):872-879.

15. Koutcher J.A., Hu X., Xu S., Gade T.P., Leeds N., Zhou X.J., Zagzag D., Holland E.C. MRI of mouse models for gliomas shows similarities to humans and can be used to identify mice for preclinical trials. Neoplasia. 2002;4(6):480-485.

16. Lee J., Kotliarova S., Kotliarov Y., Li A., Su Q., Donin N.M., Pastorino S., Purow B.W., Christopher N., Zhang W., Park J.K., Fine H.A. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9(5): 391-403.

17. Lorger M., Krueger J.S., O’Neal M., Staflin K., Felding-Habermann B. Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc. Natl Acad. Sci. USA. 2009;106(26):10666-10671.

18. Martinez-Murillo R., Martinez A. Standardization of an orthotopic mouse brain tumor model following transplantation of CT-2A astrocytoma cells. Histol. Histopathol. 2007;22(12):1309.

19. McConville P., Hambardzumyan D., Moody J.B., Leopold W.R., Kreger A.R., Woolliscroft M.J., Rehemtulla A., Ross B.D., Holland E.C. Magnetic resonance imaging determination of tumor grade, early response to temozolomide in a genetically engineered mouse model of glioma. Clin. Cancer Res. 2007;13(10):2897-2904.

20. Mintorovitch J., Moseley M.E., Chileuitt L., Shimizu H., Cohen Y., Weinstein P.R. Comparison of diffusion and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats. Magn. Reson. Med. 1991;18(1):39-50.

21. Moshkin M.P., Petrovski D.V., Akulov A.E., Romaschenko A.V., Gerlinskaya L.A., Muchnaya M.I., Fomin V.M. Aerosol deposition in nasal passages of burrowing and ground rodents when breathing dust-laden air. Biol. Bul. Rev. 2015;5(1):36-45.

22. Mystkowska D., Tutas A., Jezierska-Woźniak K., Mikołajczyk A., Bobek-Billewicz B., Jurkowski M.K. High resolution small animals dedicated magnetic resonance scanners as a tool for laboratory rodents central nervous system imaging. Pol. Ann. Med. 2013; 20(1):62-68.

23. Nelson S.J., Cha S. Imaging glioblastoma multiforme. Cancer J. 2003; 9(2):134-145.

24. Pope W.B., Lai A., Nghiemphu P., Mischel P., Cloughesy T.F. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology. 2006;66(8):1258-1260.

25. Rausch M., Hiestand P., Baumann D., Cannet C., Rudin M. MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE. Magn. Reson. Med. 2003;50(2):309-314.

26. Reardon D.A., Wen P.Y., Desjardins A., Batchelor T.T., Vredenburgh J.J. Glioblastoma multiforme: an emerging paradigm of antiVEGF therapy. Expert Opin. Biol. Ther. 2008;8(4):541-553.

27. Roberts H.C., Roberts T.P., Brasch R.C., Dillon W.P. Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR Am. J. Neuroradiol. 2000;21(5):891-899.

28. Stan R.V. Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis. J. Cell. Mol. Medicine. 2007;11(4):621-643.

29. Stockhammer F., Plotkin M., Amthauer H., van Landeghem F.K., Woiciechowsky C. Correlation of F-18-fluoro-ethyl-tyrosin uptake with vascular and cell density in non-contrast enhancing gliomas. J. Neurooncol. 2008;88(2):205-210.

30. Stupp R., Hegi M.E., Gilbert M.R., Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J. Clin. Oncol. 2007;25(26):4127-4136.

31. Sugahara T., Korogi Y., Kochi M., Ikushima I., Hirai T., Okuda T., Shigematsu Y., Liang L., Ge Y., Ushio Y., Takahashi M. Correlation of MR imaging-determined cerebral blood volume maps with histologic and angiographic determination of vascularity of gliomas. AJR Am. J. Roentgenol. 1998;171(6):1479-1486.

32. Szentirmai O., Baker C.H., Lin N., Szucs S., Takahashi M., Kiryu S., Kung A.L., Mulligan R.C., Carter B.S. Noninvasive bioluminescence imaging of luciferase expressing intracranial U87 xenografts: correlation with magnetic resonance imaging determined tumor volume and longitudinal use in assessing tumor growth and antiangiogenic treatment effect. Neurosurgery. 2006;58(2):365-372.

33. Winkler F., Kienast Y., Fuhrmann M., Von Baumgarten L., Burgold S., Mitteregger G., Kretzschmar H., Herms J. Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia. 2009;57(12):1306-1315.

34. Wong K., Young G.S., Makale M., Hu X., Yildirim N., Cui K., Wong S.T.C., Kesari S. Characterization of a human tumor sphere glioma orthotopic model using magnetic resonance imaging. J. Neurooncol. 2011;104:473-481.

This entry was posted in Tom 19-4. Bookmark the permalink.