Study identifies growth factor essential to the most common malignant pediatric brain tumor

February 28, 2013

A multi-institutional team led by Massachusetts General Hospital (MGH) researchers has identified a molecular pathway that appears to be essential for the growth and spread of medulloblastoma, the most common malignant brain tumor in children. In their report in the Feb. 28 issue of Cell, they show that blocking this pathway - which involves interactions between tumor cells and the surrounding tissues - leads to regression of all four molecular subtypes of medulloblastoma in several mouse models.

"Our finding that a pathway carrying signals from host cells to tumor cells via placental growth factor and its receptor neuropilin 1 is critical to the growth of medulloblastoma, regardless of molecular subtype, strongly supports evaluating antibodies against these proteins as a novel therapeutic approach to this pediatric cancer," says Rakesh K. Jain, PhD, director of the Steele Laboratory for Tumor Biology at MGH and corresponding author of the study.

A highly malignant tumor that originates in the cerebellum, medulloblastoma accounts for about 20 percent of all pediatric brain tumors and is ten times more common in children than in adults. While aggressive treatment with surgery, chemotherapy and radiation significantly improves patient survival, those treatments can have long-term developmental, behavioral, and neurological side effects, particularly in the youngest patients, making the need for less damaging therapies essential.

Impetus for the current investigation began with studies by Peter Carmeliet, MD, PhD, of the Vesalius Research Center in Belgium, a co-author of the current study. Carmeliet found that an antibody against placental growth factor (PlGF) could block angiogenesis in a number of adult tumors. Since PlGF, unlike other angiogenic proteins, is not required for normal postnatal development, Jain and his Steele Lab colleague Lei Xu, MD, PhD, proposed targeting PlGF as anti-angiogenic treatment for pediatric tumors. Matija Snuderl, MD, of the Steele Lab, a co-lead author of the current study, then found that PlGF was highly expressed in all types of medulloblastoma. Other members of Jain's team found that high expression of the P1GF receptor neuropilin 1 (Nrp1) was associated with poor survival in medulloblastoma patients.

To investigate mechanisms behind the potential role of PlGF in medulloblastoma, the MGH investigators collaborated with colleagues in the U.S., Belgium, Canada and Germany. They first confirmed that PlGF is expressed in patient samples of all subtypes of medulloblastoma and that expression of Nrp1 was more significant than that of PlGF's more common receptor, VEGFR1. Experiments in several mouse models revealed that the presence of PlGF is essential for the progression of medulloblastoma and that treatment with several antibodies against the growth factor reduced tumor growth and spread, increasing animal survival even without substantially inhibiting angiogenesis

The researchers were surprised to find that most PlGF was produced by surrounding supportive tissue called stroma and not by the tumor cells. Further investigation revealed that release of the developmental protein Shh (sonic hedgehog) by tumor cells induces expression in nearby stromal cells of PlGF, which then binds to the Nrp1 receptor on tumor cells, leading to further tumor growth. The authors note that therapies that block the interaction between PlGF and Nrp1 are less likely to lead to treatment resistance than are therapies directly targeting mutations that drive tumor growth.

"The importance of tumor-stromal interactions has been recognized for decades, especially the formation of new blood vessels to supply tumors," says Jain, the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School. "Our discovery of an entirely different way that tumor-stromal interactions drive cancer progression supports the exciting possibility that targeting that pathway in medulloblastoma could be more broadly effective with fewer side effects for patients. Antibodies against both PlGF and Nrp1 have been developed and tested in adult patients. There is hope that they could be safe in pediatric patients, but that needs to be established in clinical trials."
-end-
In addition to Snuderl, co-lead authors of the Cell article are Ana Batista, PhD, and Nathaniel D. Kirkpatrick, PhD, of the Steele Lab, and Carmen Ruiz de Almodovar, PhD, of the Vesalius Research Center. Collaborating institutions include Children's Hospital Boston, the Vesalius Research Center, University of Leuven, Belgium; Genentech, Inc.; the University of British Columbia; and University Hospital, Münster, Germany. Support for this study includes a grant from Hoffmann-La Roche and National Institutes of Health grant R01CA163815. Carmeliet has patent applications for intellectual property related to this study, and Jain is on the boards of trustees of H&Q Healthcare Investors and H&Q Life Science Investors.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Tumor Cells Articles from Brightsurf:

A more sensitive way to detect circulating tumor cells
Breast cancer is the most frequently diagnosed cancer in women, and metastasis from the breast to other areas of the body is the leading cause of death in these patients.

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

How to prevent the spread of tumor cells via the lymph vessels
Scientists from the German Cancer Research Center and the Mannheim Medical Faculty of the University of Heidelberg identified a new way to block the dangerous spread of tumor cells via lymphatic vessels.

The CNIO reprograms CRISPR system in mice to eliminate tumor cells without affecting healthy cells
CNIO researchers destroyed Ewing's sarcoma and chronic myeloid leukaemia tumor cells by using CRISPR to cut out the fusion genes that cause them.

Feeding off fusion or the immortalization of tumor cells
Despite all recent progress, cancer remains one of the deadliest human diseases.

How do tumor cells divide in the crowd?
Scientists led by Dr. Elisabeth Fischer-Friedrich, group leader at the Excellence Cluster Physics of Life (PoL) and the Biotechnology Center TU Dresden (BIOTEC) studied how cancer cells are able to divide in a crowded tumor tissue and connected it to the hallmark of cancer progression and metastasis, the epithelial-mesenchymal transition (EMT).

How tumor cells evade the immune defense
Scientists are increasingly trying to use the body's own immune system to fight cancer.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

New pathway to attack tumor cells identified
A study led by the Institut de Neurociències (INc-UAB) describes a new strategy to tackle cancer, based on inducing a potent stress in tumor causing cell destruction by autophagy.

Nutrient deficiency in tumor cells attracts cells that suppress the immune system
A study led by IDIBELL researchers and published this week in the American journal PNAS shows that, by depriving tumor cells of glucose, they release a large number of signaling molecules.

Read More: Tumor Cells News and Tumor Cells 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.