What makes brain tumours highly aggressive?

Divya Vishwanath

MRI image showing the presence of glioblastoma
MRI image showing the presence of glioblastoma   (Photo: Christaras A, via wikimedia commons)

In a joint study published in Neuro Oncology, researchers from IISc and NIMHANShave unraveled pathways and proteins involved in Glioblastoma (GBM) - the most common form of brain cancer and also the deadliest.

Brain tumors, although rare are devastating. Patients are known to have very short survival rates (median survival rate is 15 months) and the economic burden on the families is highest when compared with other cancers. Known for its aggressiveness, GBM mostly occurs in the cerebral hemispheres but can be found anywhere in the brain or spinal cord. It is not known to spread elsewhere in the body. Treatment options include surgical excision of the tumor followed by aggressive radiation and chemotherapy. Complete excision of the tumor is difficult and rates of recurrence of the disease are high.

The present study, spearheaded by Paturu Kondaiah of IISc, has shown how Insulin-like growth factor binding protein-2 (IGFBP-2) affects tumor progression in GBM. Working on a type of brain tumour considered almost incurable was challenging for the research team, especially since existing knowledge about IGFBP-2 is insufficient to develop an effective treatment modality.

IGFBP-2 is one of six proteins, which bind Insulin-like growth factors (IGFs) I and II. IGFs are secreted by the liver in response to growth hormone. The IGFsignaling axis controls cell proliferation and inhibition of apoptosis in normal as well as in cancer cells. The research team found that IGFBP-2 regulates the protein β-catenin and inhibits expression of the glycogen synthase kinase-3β (GSK-3β) gene, causing malignant cell proliferation and tumour progression.

Knocking down IGFBP-2 in certain cell lines causes a decrease in β-catenin levels. Similarly, in other cell lines, overexpressing IGFBP-2 showed an increase in intracellular β-catenin levels. However, this trend does not show up in β-catenin RNA levels. This tells us that IGFBP-2 stabilises intracellular levels of β-catenin and does not allow it to be degraded. GSK-3β, a multifunctional enzyme, is known to protect GBM cells from apoptosis by promoting cell survival and proliferation. It is active in IGFBP-2 knockdowns and inactive in cell lines over-expressing IGFBP-2. The authors found that GSK-3β inactivation could be one of the mechanisms by which IGFBP-2 stabilizes β-catenin levels.

More importantly, the researchers identified the component of IGFBP-2 that might be responsible for the aggressiveness GBM is known for. Shilpa Patil, lead author of the study says, “We wanted to dissect out the functions of N and C terminal domains of IGFBP-2. These N and C terminal fragments have been detected in the cerebrospinal fluid and serum of GBM patients. We wanted to know if any of the domains individually have a major pro-tumorigenic function and if so, could it be targeted for therapeutic relevance.” They found that the C-terminal domain, containing the vital RGD domain, alone could activate β-catenin signaling and progression of in vivo tumour growth. Compared to the full-length protein or the N-terminal domain, this component caused faster tumour growth in mice, thus establishing itself as a potential drug target.

“Our study not only gives the proof of principle but also a preliminary therapeutic approach towards GBM. We believe, it opens up avenues to develop important therapeutic strategies against GBM,” says Priyanka Gokulnath from IISc, a co-author of the paper.

Can the results of this study be extrapolated to other aggressive cancers? IGFBP-2 has been proposed as a therapeutic target even for cancers of breast, prostate, and ovary. Possibly, inhibiting IGFBP-2 could be one of the important strategies against these cancers too.

As a follow-up to this study, the research team aims to generate a more effective inhibitor of IGFBP-2 with superior binding affinity and specificity. This may well be the shot in the arm for most scientists worldwide working on treatment options for Glioblastoma.