Researchers develop novel glioblastoma mouse model

January 4, 2009

Researchers at the Salk Institute for Biological Studies have developed a versatile mouse model of glioblastoma—the most common and deadly brain cancer in humans—that closely resembles the development and progression of human brain tumors that arise naturally.

"Mouse models of human cancer have taught us a great deal about the basic principles of cancer biology," says Inder Verma, Ph.D., a professor in the Laboratory of Genetics. "By definition, however, they are just that: approximations that simulate a disease but never fully capture the molecular complexity underlying disease in humans."

Trying to mimic randomly occurring mutations that lie at the heart of all tumors, the Salk researchers used modified viruses to shuttle cancer-causing oncogenes into a handful of cells in adult mice. Their strategy, described in the Jan. 4, 2009 online issue of the journal Nature Medicine, could not only prove a very useful method to faithfully reproduce different types of tumors but also to elucidate the nature of elusive cancer stem cells.

The most frequently used mouse cancer model relies on xenografts: Human tumor tissue or cancer cell lines are transplanted in immuno-compromised mice, which quickly develop tumors. "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., a former postdoctoral researcher in the Verma lab and now an assistant professor at the Kobe Medical Center Hospital in Kobe, Japan. 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," explains postdoctoral researcher and co-author Dinorah Friedmann-Morvinski.

To sidestep the shortcomings of currently used cancer models, the Salk team 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. After initial experiments confirmed that the approach was working, Marumoto 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.

He specifically targeted astrocytes, star-shaped brain cells that are part of the brain's support system. They hold neurons in place, nourish them, digest cellular debris, 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.

The ability of adult stem cells to divide and generate both new stem cells (called self-renewal) as well as specialized cell types (called differentiation) is the key to maintaining healthy tissues. The cancer-stem-cell hypothesis posits that cancers grow from stem cells in the same way healthy tissues do. Known as tumor-initiating cells with stem like properties these cells have many characteristics in common with normal stem cells in that they are self-replicating and capable of giving rise to populations of differentiated cells.

To test whether the induced glioblastomas contained bona fide cancer stem cells, Marumoto isolated cultured individual tumor cells in the lab. These cells behaved and looked just like neural stem cells. They formed tiny spheres—often called tumor 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 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. Although the work described to date pertains to glioblastoma, Verma and his team are currently using this methodology to investigate lung, pancreatic, and pituitary cancers.

Source: Salk Institute

Explore further: Study explores use of checkpoint inhibitors after relapse from donor stem cell transplant

Related Stories

Study explores use of checkpoint inhibitors after relapse from donor stem cell transplant

December 10, 2017
Immunotherapy agents known as checkpoint inhibitors have shown considerable promise in patients with hematologic cancers who relapse after a transplant with donor stem cells. Preliminary results from the first clinical trial ...

Landmark CAR-T cancer study published

December 10, 2017
Loyola University Medical Center is the only Chicago center that participated in the pivotal clinical trial of a groundbreaking cancer treatment that genetically engineers a patient's immune system to attack cancer cells.

Phase 2 CAR-T study reports significant remission rates at 15-month follow up

December 10, 2017
A study involving the recently approved CD19-targeting chimeric antigen receptor (CAR) T cell therapy shows that 42 percent of patients with aggressive large B-cell lymphoma remained in remission at 15 months following treatment ...

Global CAR T therapy trial shows high rates of durable remission for NHL

December 10, 2017
In a pair of clinical trials stretching from Philadelphia to Tokyo, the chimeric antigen receptor (CAR) T cell therapy Kymriah (formerly known as CTL019) demonstrated long-lasting remissions in non-Hodgkin's lymphoma (NHL) ...

Novel harvesting method rapidly produces superior stem cells for transplantation

December 7, 2017
A new method of harvesting stem cells for bone marrow transplantation - developed by a team of investigators from the Massachusetts General Hospital (MGH) Cancer Center and the Harvard Stem Cell Institute - appears to accomplish ...

A common virus may help inform treatment planning for stem cell transplant patients

December 7, 2017
Most healthy people barely notice infection with the human cytomegalovirus (hCMV), a form of the herpes virus that has evolved with humans over thousands of years and usually lays dormant in the body after initial infection. ...

Recommended for you

How defeating THOR could bring a hammer down on cancer

December 14, 2017
It turns out Thor, the Norse god of thunder and the Marvel superhero, has special powers when it comes to cancer too.

Researchers track muscle stem cell dynamics in response to injury and aging

December 14, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) describes the biology behind why muscle stem cells respond differently to aging or injury. The findings, published in Cell Stem Cell, ...

'Human chronobiome' study informs timing of drug delivery, precision medicine approaches

December 13, 2017
Symptoms and efficacy of medications—and indeed, many aspects of the human body itself—vary by time of day. Physicians tell patients to take their statins at bedtime because the related liver enzymes are more active during ...

Estrogen discovery could shed new light on fertility problems

December 12, 2017
Estrogen produced in the brain is necessary for ovulation in monkeys, according to researchers at the University of Wisconsin-Madison who have upended the traditional understanding of the hormonal cascade that leads to release ...

Time of day affects severity of autoimmune disease

December 12, 2017
Insights into how the body clock and time of day influence immune responses are revealed today in a study published in leading international journal Nature Communications. Understanding the effect of the interplay between ...

3-D printed microfibers could provide structure for artificially grown body parts

December 12, 2017
Much as a frame provides structural support for a house and the chassis provides strength and shape for a car, a team of Penn State engineers believe they have a way to create the structural framework for growing living tissue ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

E_L_Earnhardt
not rated yet Jan 05, 2009
TEMPERATURE - the accelerated dance and flow of electrons, is a vital component of tumor development!

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.