An Indian-origin scientist at the Salk Institute for Biological Studies claims that his team have created a mouse model of the most common and deadly brain cancer called glioblastoma, which closely resembles the development and progression of naturally arising human brain tumours.
"Mouse models of human cancer have taught us a great deal about the basic principles of cancer biology. By definition, however, they are just that: approximations that simulate a disease but never fully capture the molecular complexity underlying disease in humans," Nature Medicine quoted Dr. Inder Verma, a professor in the Laboratory of Genetics, as saying.
AdvertisementHe revealed that with a view to mimicking randomly occurring mutations that lie at the heart of all tumours, his team used modified viruses to shuttle cancer-causing oncogenes into a handful of cells in adult mice.
He said that his group's strategy could not only prove a very useful method to faithfully reproduce different types of tumours, but also to elucidate the nature of elusive cancer stem cells.
Presently, the most frequently used mouse cancer model relies on xenografts: Human tumour tissue or cancer cell lines are transplanted in immuno-compromised mice, which quickly develop tumours.
"These tumors are very reproducible, but this approach ignores the fact that the immune system can make or break cancer," says first author Dr. Tomotoshi Marumoto, a former postdoctoral researcher in the Verma lab and now an assistant professor at the Kobe Medical Center Hospital in Kobe, Japan.
There are other animal models too, which either express oncogenes in a tissue-specific manner or shut down the expression of tumour 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," explains postdoctoral researcher and co-author Dinorah Friedmann-Morvinski.
With an eye on avoiding the shortcomings of currently used cancer models, the Salk researchers harnessed the power of 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.
Once the initial experiments conducted by the researchers confirmed that their approach was working, they injected lentiviruses carrying two well-known oncogenes, H-Ras and Akt, into three separate brain regions of mice lacking one copy of the gene encoding the tumor suppressor p53: the hippocampus, which is involved in learning and memory; the subventricular zone, which lines the brain's fluid-filled cavity; and the cortex, which governs abstract reasoning and symbolic thought in humans.
The group particularly targeted astrocytes, star-shaped brain cells that are part of the brain's support system that hold neurons in place, nourish them, digest cellular debris, and are suspected to be the origin of glioblastoma.
The researchers observed that massive tumours displaying all the histological characteristics of glioblastoma multiforme preferentially developed in the hippocampus and the subventricular zone within a few months.
For confirming whether the induced glioblastomas contained bona fide cancer stem cells, the researchers isolated cultured individual tumour cells in the lab, and found that they behaved and looked just like neural stem cells.
They also observed that the cultured tumour cells formed tiny spheres-often called tumour spheres-and expressed proteins typically found in immature neural progenitor cells.
According to them, those brain cancer stem cells matured into neurons and astrocytes when given the right chemical cues.
"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 Friedmann-Morvinski. Most xenograft models for brain tumors using tumor cell lines require at least 10,000 cells.
"These findings show that our cancer model will not only allow us to start understanding the biology of glioblastoma but will also allow us to answer many questions surrounding cancer stem cells," says Verma.
Verma and his colleagues are using the same methodology to investigate lung, pancreatic, and pituitary cancers also.
Their work has been described in a research article published in the journal Nature Medicine.