Brain Cancer (medulloblastoma) - -

Posted: Thu Apr 06, 2006 1:58 pm

For additional information visit
http://www.pathway2curis.com/childhood-brain-cancer-medulloblastoma-vt1255.html

Posted: Tue Apr 25, 2006 10:41 pm

Cell lines are different from animal models and animal models are different from human... Animal models are closer to the human model than Cell lines to the human model. This is pretty straight forward.

You can add cancer cells directly to the animal model causing cancer in the animal or you have cancer cell lines in a dish and do tests on this cell line model.

In this experiment, they examined the effects of a hedgehog inhibitor and its effects on brain cancer cell lines and then in the mouse model.

”Here, we compared the responses of mouse medulloblastoma cells propagated in flank allografts, either directly or after culture in vitro, to HhAntag.”

two parts, 1) they put the cells in a dish added a Hh inhibitor and waited then transplanted them into the mouse, 2) they added cancer cells directly into the mouse.

”We found that Shh pathway activity was suppressed in medulloblastoma cells cultured in vitro and it was not restored when these cells were transplanted into the flank of nude mice. The growth of these transplanted tumor cells was not inhibited by treatment of mice with doses of HhAntag that completely suppressed Smo activity.”

This says 2 things,
1) after they put the cancer cells that were in the dish and exposed to the Hh inhibitor and planted into the mouse, the Hh inhibitor given to the mouse had no effect on cancer growth.
2) The cells that were not exposed to the Hedgehog inhibitor prior to plantation were eradicated.

”These findings indicate that propagation of tumor cells in culture inhibits Smo activity in a way that cannot be reversed by transplantation in vivo, and they raise concerns about the use of cultured tumor cells to test the efficacy of Shh pathway inhibitors as anticancer therapies.”

Over all this is an interesting experiment, and creates a few concerns. The main one is why do the Hh cancer cell lines not respond to an Hh inhibitor (in vivo) after an exposer in vitro?

Clinically I guess make sure the cancer is eradicated before you stop treatment!

Posted: Wed Apr 26, 2006 1:33 pm

Better Model of Deadly Brain Cancer
Researchers have created a mouse model that closely mimics human medulloblastoma, the most common type of childhood brain tumor. The new model, which was created by knocking out a key component of the DNA repair machinery, will aid in exploring the genetic roots of this deadly brain cancer.

The researchers, led by Howard Hughes Medical Institute investigator Frederick W. Alt, published their findings the week of April 24, 2006, in the early online edition of the Proceedings of the National Academy of Sciences. Catherine Yan, who is in Alt's laboratory at Children's Hospital Boston, was lead author of the article. Other co-authors were from Brigham & Women's Hospital, CBR Institute of Biomedical Research, Children's Hospital and Dana-Farber Cancer Institute, all of Harvard Medical School.

“Only in our wildest dreams had we hoped to see these kinds of recurrent translocations.”
Frederick W. Alt

Although childhood cancers are rare, brain tumors are among the most common. About one out of five childhood brain tumors is medulloblastoma, an aggressive cancer of the cerebellum. Alt and his colleagues produced the mouse model of medulloblastoma by knocking out a gene called XRCC4, which produces a protein that plays an important role in stitching together the ends of broken DNA. These breaks which can occur in all cell types from exposure to radiation, chemicals, or other insults, occur specifically in the immune system when genes are snipped and rearranged to produce a vast array of antibodies. The abnormal swapping of chromosomal regions that ensues when such repair goes awry—known as chromosomal translocations—is sometimes harmless, but can contribute to cancer and other diseases.

In earlier studies, Alt and his colleagues discovered that XRCC4 is a component of nonhomologous end-joining, a process that is essential for the repair of chromosome breaks. They found that knocking out this gene in mice led to widespread death of newly generated neurons and death late in embryonic development. The researchers then combined these experiments with the elimination of a gene for a sentinel protein called p53, which triggers the death of malfunctioning cells. With both p53 and XRCC4 missing, neurons survive and the mice live into early adulthood, but then die of lymphomas caused by translocations of antibody genes. The researchers noted that by this time, the mice were also beginning to develop medulloblastomas.

After they made that observation, Alt's team wanted to zero in on the possible role of XRCC4 deficiency in medulloblastomas. While their earlier studies involved knocking out the XRCC4 gene throughout the animals' bodies, now “the major goal was to eliminate this protein only in the developing nervous system, so we could specifically determine whether there was a role for nonhomologous end-joining in suppressing cancers of cells besides those of the immune system,” he said. “We also wanted to know whether getting rid of both XRCC4 and p53 in the nervous system would predispose the animals to neuronal tumors, and whether or not those tumors would also be associated with particular chromosomal translocations.”

So Yan and her colleagues engineered two strains of mice in which XRCC4 was knocked out only in neural progenitor cells in the developing nervous system. One strain had only the XRCC4 knockout, and the other also had a deficiency in both XRCC4 and p53. These mice appeared to develop normally without XRCC4, they found. But every mouse lacking both XRCC4 and p53 died very early of medulloblastomas. Furthermore, “those tumors strongly resembled human medulloblastomas,” said Alt.

Analyzing the tumors for genetic abnormalities, Alt and his colleagues found that specific genes were frequently altered in association with recurrent chromosomal translocations—and that affected genes often were those activated or inactivated in human medulloblastomas. Thus, the tumors often showed amplifications of two genes called N-myc and Cyclin D2, which are characteristic of many human neural tumors, including medulloblastomas. The animals also showed the loss of one copy of a gene called patched, which is also characteristic of some human medulloblastomas.

“Only in our wildest dreams had we hoped to see these kinds of recurrent translocations,” said Alt. “It's quite exciting to us that we'll be able to explore mechanistically why they happen when the basic process of end-joining is compromised.”

Other mouse models of medulloblastoma have been created by knocking out patched or other individual genes that have been implicated in the development of medulloblastoma. However, said Alt, “what we did was different. We created an environment in which end-joining was defective and let the biology of the cell sort out the consequences. And while in most other models not every mouse develops medulloblastomas, in our case every animal very reproducibly develops these tumors at a very young age. It's really quite intriguing, too, how this general genomic instability very specifically leads to the selection of tumor cells that have deregulated particular genes such as N-myc, patched and Cyclin D2.”

According to Alt, the new mouse model will prove valuable in understanding why N-myc is so frequently amplified in human tumors, including neuroblastomas and medulloblastomas, and the consequences of that amplification. The model also will enable the researchers to better explore causes of the chromosomal translocations, deletions, and amplifications in neuronal cells.

The mouse model should also be useful in testing potential treatments for medulloblastoma. Alt said that other laboratories have consulted them on the possibility of using the model for drug testing. “This model could be very useful for such a purpose because every mouse gets tumors with an early onset and the tumors show activation or inactivation of a set of genes that is implicated in human tumors,” he said. “So, if one wants to test therapies that interfere with pathways involved in human tumors, this should be a good model.”

http://www.hhmi.org/news/alt20060425.html

Posted: Wed May 31, 2006 8:28 pm

Linking cholesterol to tumors

THE QUESTION: What makes some pediatric brain tumor cells grow?

THE DISEASE: Medulloblastoma is one of the most common brain tumors in children. About 20 to 40 percent of kids with this type of tumor die, and others may suffer permanent health problems both from the tumor and from the surgery, radiation and chemotherapy commonly used as treatment.

BACKGROUND: A signaling molecule known as "Sonic hedgehog" is important in the development of many different cell types. It induces the expression of certain genes by binding to and activating a receptor on the cell surface called Patched 1. Researchers had previously shown that about 15 percent of mice missing one of the two copies of the gene for Patched 1 develop medulloblastoma. Although these and other findings suggest that the Sonic hedgehog signaling pathway is involved in the development of medulloblastoma, they don't identify which part of the signaling pathway is out of whack in tumors.

THE STUDY: It compared levels of gene expression between mouse medulloblastoma cells and non-cancerous mouse brain cells, seeking to better define the workings of the Sonic hedgehog pathway.

FINDINGS: The study determined that many genes involved in the synthesis and uptake of sterols—a subgroup of steroids important in the formation of cell membranes and in developmental signaling—are expressed more highly in the cancer cells. The discovery was particularly interesting because sterol synthesis is required for Sonic hedgehog signaling. Researchers found that compounds that block the synthesis of cholesterol, a well-known member of the sterol family, slowed the growth of the cancer cells. The compounds also reduced the expression of a Sonic hedgehog-sensitive gene.

HOW THEY CONFIRMED IT: Adding cholesterol or a choleterol derivative back into the experiment restored proliferation of the cancer cells and the expression of the gene. Artificially inducing the expression of Sonic hedgehog-sensitive genes also restored proliferation. These findings suggest that the sterol inhibitors are exerting their effects primarily through the Sonic-hedgehog-signaling pathway.

WHY IT MATTERS: The results suggest that it may be possible to curtail the growth of medulloblastoma and other Sonic hedgehog-sensitive tumors by administering inhibitors of sterol synthesis. Statins, commonly used to lower cholesterol levels, may be one possible therapy. If so, it may be possible to treat these deadly childhood tumors with something other than surgery, chemotherapy and radiation.

THE STANFORD CONNECTION: The study was conducted by graduate student Ryan Corcoran, working in the laboratory of Mathew Scott, PhD, professor of developmental biology, of genetics and of bioengineering.

WHERE TO FIND IT: The work was published in the May 30 issue of the Proceedings of the National Academy of Sciences.

http://news-service.stanford.edu/news/2006/may31/med-quickstudy-053106.html