Notch pathway mapped and linked to common pediatric brain tumour.


A new study by Johns Hopkins researchers links a well-known cell communication pathway called Notch to one of the most common brain tumours found in children.  Their study suggests the pathway’s involvement with a low-grade brain tumour called pilocytic astrocytoma, or PA.  The opensource study is published in the Journal of Neuropathology & Experimental Neurology.

The tumour, which makes up an estimated 15 percent of primary brain tumours in children and adolescents, is slow growing. Surgical removal is usually the only treatment necessary, according to the team, although cases occur in hard-to-reach spots in the brain where they may grow and cause seizures, vision loss, and physical coordination problems.  An estimated one in 100,000 children is diagnosed with PA each year in the United States, according to the Central Brain Tumor Registry of the United States.

The team made their discovery while comparing the expression of genes, as measured by the amount of RNA the genes made, in the Notch pathway between brain tissue from a mix of healthy children and those with PA.

They found that by this measure, one or more of the pathway’s genes were overexpressed in nearly all 22 samples of PA brain tissue, as compared with normal brain tissue. Depending on the gene under study, overexpression spanned from four to up to 21 of the 22 samples. Notch-related proteins, specifically HES1, were present in 58 of 61 additional samples, and 40 of those 61 samples showed moderate to strong protein expression.

The team explain that notch is a very basic signaling pathway used for cell-to-cell communication during development. It is known that cancer can abnormally activate such signaling pathways to promote cell growth and survival, and the new findings line up with that knowledge.  The team state that changes in the Notch pathway have been implicated in various cancers, from leukemia to breast cancers. In previous studies the team has shown the pathway to be critical for medulloblastoma and glioblastoma, two other far more lethal brain cancers affecting children and adult patients.

In the current study the researchers wanted to see if Notch also was inappropriately active in lower-grade tumours like PA, and that appears to be the case.

In further experiments with implications for improved treatment of PA, the scientists were able to block the Notch pathway’s abnormal activity in PA tumour cells with two methods, a technique that uses ‘short hairpin’ RNA, a form of genetic material, to specifically silence the genes’ expression, and a drug class called gamma secretase inhibitors that are being tested in several cancer clinical trials.

The new findings suggest that Notch might someday be a therapeutic target for PA treatment, especially for tumours that can’t be reached surgically. The team explain that this type of tumour often doesn’t respond as well to other therapies, such as radiation or chemotherapy, because it is very slow growing.

The team have studied other cell signaling pathways involved in PA, including the BRAF and mTOR pathways, and state that targeting these pathways with drugs is a new potential avenue of treatment for tumours that don’t respond to current treatments.

In particular, the researchers were intrigued by how the gamma secretase inhibitor prevented cell migration in the tumour cell lines.  There’s a subset of these low-grade tumours that can disseminate and migrate, and targeting this Notch pathway could be potentially useful in keeping these tumours from spreading to places like the surface of the brain or cerebrospinal fluid.

Source:  The Johns Hopkins University

 

Model of the Notch signaling pathway. (a) The Notch signaling pathway is activated when a Notch ligand and a Notch receptor from adjacent cells bind to one another. (b) Binding of a Notch ligand and receptor initiates sequential cleavage steps, including extracellular ADAM protease, followed by intracellular γ-secretase cleavage, of the Notch receptor. (c) An activated form of the receptor (NICD) is released and immediately translocates to the nucleus. (d) The NICD then binds to cofactors, including CSL, to initiate transcription of downstream targets, typically transcriptional repressors from the HES and HEY families. ADAM, a disintegrin and metalloprotease; CSL, CBF1/Suppressor of Hairless/LAG-1 family DNA-binding protein.  Notch Signaling Activation in Pediatric Low-Grade Astrocytoma.  Rodriguez et al 2015.

Model of the Notch signaling pathway. (a) The Notch signaling pathway is activated when a Notch ligand and a Notch receptor from adjacent cells bind to one another. (b) Binding of a Notch ligand and receptor initiates sequential cleavage steps, including extracellular ADAM protease, followed by intracellular γ-secretase cleavage, of the Notch receptor. (c) An activated form of the receptor (NICD) is released and immediately translocates to the nucleus. (d) The NICD then binds to cofactors, including CSL, to initiate transcription of downstream targets, typically transcriptional repressors from the HES and HEY families. ADAM, a disintegrin and metalloprotease; CSL, CBF1/Suppressor of Hairless/LAG-1 family DNA-binding protein. Notch Signaling Activation in Pediatric Low-Grade Astrocytoma. Rodriguez et al 2015.

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