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Scientists decipher a key puzzle in brain tumor research

“Its palliation is a daily task, its cure a fervent hope” - William Castle

It’s aggressive, it’s resistant, and it’s invasive. It’s your own cell gone awry. It is cancer.

Glioblastoma - one of the most common forms of brain tumor does not have a foolproof cure till date.  A person with glioblastoma, who has undergone radiation therapy coupled with chemotherapy and all the other latest therapies, survives for an average of just over a year (12-17 months). Needless to say, glioblastoma cells still remain an enigma.

In a study published in a recent issue of Neuro-Oncology, scientists from the Indian Institute of Science and NIMHANS, Bangalore, have unraveled some crucial aspects of this puzzle. “The most important insight is the revelation that in glioblastoma cells, IGFBP2 acts as a tumor promoter through a well known tumor promoting pathway, beta-catenin”, says Prof. Paturu Kondaiah, the lead member of the study and a Professor at the Department of Molecular Reproduction Development and Genetics at IISc.

Fluids like blood plasma surround the trillion odd cells present in the human body. IGFBP2 – Insulin like growth factor binding protein 2 is one of the proteins that is present in these extracellular (outside-cell) fluids. Previous studies have shown that patients with more aggressive forms of glioblastoma had higher IGFBP2 levels in their serum. However, the question of how IGFBP2 makes the tumor aggressive remained unanswered until now.

A cell’s behavior can be attributed to the proteins it makes. Inside the cell, the nucleus is the abode of our DNA. Segments of the DNA called genes produce proteins that dictate the behavior of a cell. In order to elicit any change in a cell, higher IGFBP levels outside the cell must be relayed to the cell’s nucleus. On the surface of the cell, big protein molecules called “receptors” are present.  Proteins like IGFBP2 bind to these receptors and bring about a change in the receptor. This change is then transmitted to the proteins present inside the cell. A signaling cascade ensues - Protein X activates Protein Y that activates Protein Z and so on.

For the study, the researchers used glioblastoma cells that were constantly secreting high levels of IGFBP2 proteins to test if there is a specific receptor that IGFBP2 binds to. They found that higher IGFBP2 levels correlated well with high p-FAK protein levels. p- FAK is phosphorylated form of Focal Adhesion Kinase (FAK), a protein that is activated following ligand binding to integrin (a protein) receptors. Thus, they concluded that in glioblastoma cells, IGFBP2 binds to integrin receptors.    

Unlike IGFBP2 that is present outside the cell, beta catenin is another protein that keeps shuttling in and out of the nucleus of the cell. When present inside, it influences the protein production. A group of proteins inside the nucleus collectively degrade beta catenin, keeping it preferentially on the membrane of the cell. The researchers observed a strong correlation between extracellular IGFBP2 and nuclear beta catenin levels. In glioblastoma cells with high levels of IGFBP2 expression, nuclear beta catenin levels were also high. And, in cells that made very little or no IGFBP2, nuclear beta catenin levels were low, suggesting a link between the two.

In their study, the researchers found that higher IGFBP2 levels led to inactivation of another protein - GSK3b. Inactivation of GSK3bimpairs the degradation of beta catenin inside the cell. Beta catenin can now easily transport to the nucleus and induce production of new proteins that instruct the tumor cells to proliferate faster than normal, and start invading other tissues. Are there other proteins involved in this signal cascade? With the cell being an amazingly complex entity, there certainly are.  “We are working on further delineation of the pathway and other players involved in IGFBP2 mediated tumor promotion”, says Prof. Kondaiah.

This study represents a fervent hope in the midst of daily palliation. As Sydney Farber rightly puts it, “To understand cancer as a whole, you needed to start at the bottom of its complexity, in its basement.” This research definitely has important findings that may save millions in future.

About the authors:

Dr. Paturu Kondiah is a Professorat the Department of Molecular Reproduction Development and Genetics at IISc. Shilpa S. Patil and Mohsin Bashir, former lab members and Priyanka Gokulnath, a current lab member in Dr. Pataru’s lab was also involved in the study. Other authors included Shivayogi D. Shwetha, Jahnvi Jaiswal, Arun H. Shastry and Dr. Arivazhagan Arimappamagan from the National Institute of Mental Health and NeuroSciences (NIMHANS).

Contact: Prof Paturu Kondiah 91-80-22932688


About the paper:

Title: Insulin-like growth factor binding protein-2 regulates b-catenin signaling pathway in glioma cells and together contributes to poor patient prognosis.
Publication: NeuroOncology