Nestin Linked to Net Proliferation in Astrocytic and Oligoastrocytic Brain Tumor Cells

Astrocytomas and oligoastrocytomas are two of the most common gliomas, accounting for roughly 50% of all tumors of the brain. Nestin, a type VI intermediate filament protein, has recently been identified as a strong, adverse prognostic indicator of total survival in patients with grades II-III astrocytomas and oligoastrocytomas. Interestingly, this preliminary study has shown that while the expression of nestin is associated with tumor growth and shorter survival, nestin does not correlate with the mitotic proliferation index of the brain cancer cells. This observation leaves open the possibility that some other underlying mechanism associated with nestin expression causes the spread of tumor cells.

It was hypothesized that the protein nestin may inhibit cell apoptosis, which is a process of naturally occurring programmed cell death. The samples used to test this hypothesis were from patients diagnosed with brain cancer at UT Southwestern Medical Center from 1997 to 2010. Using immunohistochemistry, these brain tissue samples were stained for the proteins of interest – nestin, caspase-3, and MIB-1. The caspase-3 antibody was used to mark apoptosis and the MIB-1 antibody was used to mark mitosis. The protein levels were quantified using computer-assisted image analysis on tissue microarrays, and the data was analyzed using Aperio Image Scope and GraphPad Prism.

The study produced two significant findings about the role of apoptosis in gliomas. First, it showed that while nestin does not directly inhibit apoptosis, it does correlate strongly with the ratio between apoptotic rate and mitotic rate, thereby leading to a higher rate of net proliferation in malignant cancer cells. Further analysis revealed that this association is evident in grade IV gliomas as well. Secondly, the study showed that the apoptotic to mitotic rate ratio is a significant prognostic indicator of survival in grades II-III astrocytomas and oligoastrocytomas. By survival analysis, it was determined that brain cancer patients with low apoptotic to mitotic ratios experienced shorter survival. While the first finding yields insight into an underlying reason for which nestin correlates with patient survival, the latter finding serves as a novel and effective approach to diagnosing and predicting survival in brain cancer patients.

Future work involves testing more markers for apoptosis and mitosis to paint a more complete picture of the association between nestin and net proliferation. This research was funded by the National Institutes of Health (NIH) and was conducted in the neuropathology laboratory of Dr. Kimmo J. Hatanpaa, M.D., Ph.D., at UT Southwestern Medical Center.