Strategy, published in Nature Medicine, used lentiviruses.



A team of scientists have developed a mouse model of glioblastoma. They used modified viruses to shuttle cancer-causing oncogenes into a handful of cells in adult mice.  


The most frequently used mouse cancer model relies on xenografts. “These tumors are very reproducible, but this approach ignores the fact that the immune system can make or break cancer,” says first author, Tomotoshi Marumoto, Ph.D., an assistant professor at the Kobe Medical Center Hospital.


Other animal models either express oncogenes in a tissue-specific manner or shut down the expression of tumor suppressor genes in the whole tissue. “But we know that tumors generally develop from a single cell or a small number of cells of a specific cell type, which is one of the major determinants of the characteristics of tumor cells,” adds postdoctoral researcher and coauthor Dinorah Friedmann-Morvinski, Ph.D.


The Salk team decided to use lentiviral vectors to infect nondividing as well as dividing cells and ferry activated oncogenes into a small number of cells in adult, fully immunocompetent mice. After initial experiments confirmed that the approach was working, Dr. Marumoto injected lentiviruses carrying two well-known oncogenes, H-Ras and Akt, into mice lacking one copy of the gene encoding the tumor suppressor p53.


The lentivirues were injected into three separate brain regions: the hippocampus, the subventricular zone, and the cortex. He specifically targeted astrocytes, star-shaped brain cells that are part of the brain’s support system and are suspected to be the origin of glioblastoma.


Within a few months, massive tumors that displayed all the histological characteristics of glioblastoma multiforme preferentially developed in the hippocampus and the subventricular zone.


To test whether the induced glioblastomas contained bona fide cancer stem cells, Dr. Marumoto isolated cultured individual tumor cells in the lab. These cells behaved and looked just like neural stem cells, he says. They formed tiny spheres and expressed proteins typically found in immature neural progenitor cells. When given the right chemical cues, these brain cancer stem cells matured into neurons and astrocytes.


“They displayed all the characteristics of cancer stem cells, and less than 100 and as few as 10 cells were enough to initiate a tumor when injected into immunodeficient mice,” says Dr. Friedmann-Morvinski. Most xenograft models for brain tumors using tumor cell lines require at least 10,000 cells, the researchers note.


Researchers from the Salk Institute for Biological Studies, the Kavli Institute for Systems Neuroscience in Trondheim, Norway, and the UCSD Center for Functional MRI in La Jolla collaborated on this study. Results appear in the January 4 online issue of Nature Medicine.








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