Biochemical alteration responsible for brain tumor resistance identified
Glioblastoma is the most aggressive manifestation of brain tumours. Due to its high invasive capacity and uncontrolled, infiltrating growth, it is particularly difficult to manage. Currently, the treatment for this disease consists of a combination of surgery (when possible), radiation and chemotherapy. Although current therapy raises the overall survival of patients by around 15 months, it remains inefficient at eradicating tumour cells and, unfortunately, recurrences are another of this cancer's characteristics.
A team of researchers from the Institute of Neuroscience at the UAB, together with the Hospital Universitari de Bellvitge – ICO, have identified a common molecular alteration in glioblastoma. The researchers observed that the cells of this type of tumour harbour a common intrinsic defect that prevents them from degrading their genetic material during apoptosis, the most important form of programmed cell death induced by radiotherapy and chemotherapy.
This defect is related to an enzyme: the endonuclease DFF40/CAD (Death Fragmentation Factor, 40 kDa subunit / Caspase-Activated DNase). This enzyme, which is essential for degrading DNA during apoptosis, appears both downregulated and improperly located inside the tumour cells when compared with non-tumoural cells. The researchers observed that overexpression of the enzyme allows the glioblastoma cells to properly degrade their DNA content as expected in an apoptotic cell death.
DNA degradation during apoptosis is an essential step that facilitates the subsequent proper removal of cellular debris from malignant cells. In fact, the lack of degradation and removal of genetic material from malignant cells could have detrimental consequences for the organism, such as new tumour processes, often more aggressive than the original one.
Despite the efforts made in the last decade to understand the biology of these tumours, until now no common genetic or biochemical defect had been found in glioblastoma cells. The low levels of expression observed in the enzyme endonuclease DFF40/CAD and the deficiency in degrading and properly compacting its genetic material constitute a potential molecular marker in this tumour. In addition, the fact that this alteration was observed in all the cases studied points to its importance as a possible explanation for the aggressiveness of this cancer. The researchers hope these new results will improve our understanding of what goes on inside the tumour, and perhaps enable new, more effective therapies to be designed in the future for this lethal disease.
This finding is the result of close collaboration between clinical and basic research. Dr Victor J. Yuste, from the Department of Biochemistry and Molecular Biology of the UAB and the Institute of Neuroscience of the UAB, has led a multidisciplinary team of basic researchers, neurooncologists, pathologists and neurosurgeons from the Institute of Neuroscience itself, the Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), the Institute of Biomedical Research of Bellvitge-University of Barcelona and the Hospital Universitari de Bellvitge-Catalan Institute of Oncology. The research was published recently in Neuro-Oncology, the leading journal in this field.
Victor J. Yuste