Cancer cells with a long breath: seeking the origin of brain tumors in children

August 12, 2008

Medulloblastoma is one of the most common and most malignant brain tumours among children and teenagers. These tumours grow very rapidly, and fifty percent of patients in the long term die from the condition. The details of the processes that lead to the growth of these tumours have remained unknown until now. In two studies, working together with international scientific teams, LMU medical scientist Dr. Ulrich Schüller has now successfully revealed certain molecular mechanisms that lead to the development of these cerebellar tumours. As reported in the current issue of the journal Cancer Cell, the researchers triggered genetic changes in cell populations in the brains of mice in order to provoke the growth of tumours. It turned out that medulloblastomas arose from only one type of cell - granule cells - and only if these were already fully committed. "Medulloblastomas are presently treated with nonspecific methods," states Schüller. "Our results could contribute to the development of targeted therapies, and thus improve the treatment of cerebellar tumours in children."

When children develop cancer, about every fifth tumour is a brain tumour - and every fifth of those in turn is a medulloblastoma. This common tumour occurs most of all in children under ten years of age, but also occurs in adults, albeit very infrequently. Up to now, medulloblastomas have only been treatable with the standard tools of cancer medicine: operation, radiotherapy and chemotherapy. Surgical interventions to treat this condition, like all operations on the brain, are particularly delicate, since it is difficult to remove the tumour completely without affecting healthy tissue. Because these cerebellar tumours scatter easily throughout the brain and even in the medullary canal, many cases result in metastases, that is the growth of secondary tumours, and not infrequently to a relapse of the original tumour - often even after successful conclusion of the treatment.

That is why patients and doctors are hoping for more targeted therapies that promise better therapeutic outcomes. "But for that to be possible, we first need to understand the principles of how the tumours develop," says Schüller. "If we know how a tumour arises at the molecular level, we can also develop specific therapies that actually treat the cause of that particular condition." Since it was still unknown from what type of cell and at what stage of development medulloblastomas arise, the researchers induced specific genetic changes in various cell populations in the brains of mice. This "conditional knock-out" method provoked changes in the so-called sonic hedgehog signalling pathway. Various processes in the development of nerve cells are controlled by this molecular signalling cascade. "Normally, the signalling pathway ensures a balance of growth and maturation of cells," says Schüller. "But if disrupted, it can lead to uncontrolled growth of cells - and thus the onset of cancer".

In another step, the research team investigated the effects of mutations on nerve cells in various stages of development. Multipotent progenitor cells have the ability - almost like stem cells - to develop into many different types of cell, while "unipotent" progenitor cells can only develop into one specific type of cell. "All of our studies have shown that medulloblastomas can only develop from granule cells and their progenitors," Schüller tells us. "Other cells on the other hand, such as the large Purkinje cells of the cerebellum, do not become tumourigenic. They don't seem bothered by these mutations at all." And there is yet another distinctive result that the researchers achieved: the genetic changes only triggered one specific type of tumour: the medulloblastoma. Other brain tumours such as astrocytomas or oligodendrogliomas did not occur, even though, normally, the genetically attacked multipotent progenitors could have just as easily developed into astrocytes or oligodendrocytes.

It was especially surprising that even mutations in very early, immature cells triggered corresponding changes that only became tumourigenic if and when the cells had developed the characteristics of granule cells. The researchers were also surprised to find that the medulloblastomas appeared completely identical both morphologically and molecularly, no matter what stage of development they were triggered at. The researchers identified yet another factor in the development of medulloblastomas: the protein Olig2 has so far only been linked to the formation of glial cells in the brain, which primarily provide support for neurons. "But we also found Olig2 in progenitors of the granule cells of the cerebellum and in tumour cells," reports neuropathologist Schüller. "That means this protein also influences the formation and multiplication of cancer cells - which makes it clear once again just how closely normal and malignant development processes resemble one another. We hope our results will contribute to a targeted therapy for medulloblastomas. That will require further research, however, which we already have in the planning."

One of the funders of the studies was the German Cancer Aid, with whose assistance Schüller established one of two Max-Eder Young Investigator Groups at LMU.
-end-
Ludwig-Maxmilians-Universität (LMU) München is one of the leading research universities in Europe with over 500 years of tradition. It builds upon its success in the Excellence Initiative, a Germany-wide competition promoting top-level university research, to further enhance its research profile and strengthen its position at an international level.

LMU Munich offers a broad spectrum of all areas of knowledge, ranging from the humanities and cultural sciences, law, economics and social studies, to medicine and the sciences. As a genuine "universitas" it has the special task to deal with the ever more complex questions facing humankind, society, culture, the environment and technology by creating interdisciplinary solutions.

The know-how and creative intelligence of 700 professors, 3,300 academic staff members and 44,000 students form the foundation of LMU's outstanding research and teaching record as recognized by many national and international university rankings.

www.lmu.de

Ludwig-Maximilians-Universität München

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.