The research: Understanding the pathways that lead to the abnormal growth of cells in cancerous brain tumour
Brain tumour, the abnormal growth of a tissue in the brain, is one of the most dreaded diseases, especially those that involve cancerous cells. The most common form of cancerous brain tumour in adults, known by its medical name glioblastoma, also happens to be the most aggressive. There is no cure to it, and the median survival period of a patient, after the disease has been diagnosed, is barely 15 months.
The current strategy to deal with the disease is surgery, followed by radiation therapy, and then, if the patient can afford it, chemotherapy. Very often, patients return for surgery due to recurrence. Some pharmaceutical companies have more recently come out with drugs that claim to work on the antibodies that inhibit the growth of cancerous cells. But these have not produced expected results, delivering only incremental improvements over already existing medicines.
Our groups at the Molecular Reproduction Development and Genetics and the Department of Microbiology and Cell Biology (led by Prof Somasundaram) at the Indian Institute of Science, with clinical collaborations with NIMHANS and Sri Satya Sai Hospital have been working on gene expression profiling in glioma tumors for the past decade.
It has been known for some time that patients with glioblastoma have higher levels of a protein called Insulin like Growth Factor Binding Protein 2 (IGFBP-2). This protein is generally present in the plasma outside the cell membranes. Our first effort was to understand whether, and how, the IGFBP-2 activates the cancerous activity, and if it does, whether the IGFBP-2 can be inhibited.
The behaviour of a cell, including its abnormal growth, is determined by the proteins that are synthesized by the genetic material inside it. Any change in cell behaviour requires changes in the proteins that are inside it. The hypothesis, therefore, was that the IGFBP-2 protein, otherwise present outside the cell, would have found a way to travel inside the cell, thereby increasing its levels inside, and inducing a change in cell behaviour.
However, proteins cannot travel in and out of a cell on their own. They need ‘receptors’ or ‘carrier’ molecules which act as a vehicle for them. Proteins ‘bind’ to these receptors which are very specific. If we spot these receptor molecules and their pathways, and are able to inhibit them, we would be able to block the actions of these proteins effectively.
During our study, we noticed that the high levels of IGFBP-2 proteins activated actions of only a particular kind of receptor, called integrin. That led us to believe that IGFBP-2 was actually using this integrin receptor for its actions.
We also noticed that higher IGFBP-2 was also linked to higher levels of beta catenin, another protein that, unlike IGFBP-2, is able to move in and out of the nucleus upon some stimulus. This beta catenin fuels faster synthesis of other proteins but is kept in check by other molecules, one of them being another protein called GSK3ß.
It was seen that higher IGFBP-2 inhibits actions of GSK3ß, in turn leading to an increase in beta catenin levels, which results in aggressive nature of glioblastoma cells.
Our study has now given a much better understanding of the pathway that leads to the abnormal growth of cells in the glioblastoma tumour. The next stage is to develop specific antibodies that would intervene at one of the stages in this chain and inhibit the actions of IGFBP-2. An effective antibody could also lead us to the development of a drug for brain tumor, though that is still a very distant goal.
Paturu Kondaiah, Shilpa Patil and Vani Santosh
IISc and NIMHANS, Bangalore